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Yanjun, Xu, Cao Wenming, Xu Qi, Guo Jianmin, Wang Xinbao, Cheng Xiangdong, and Ying Jieer. "Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients." Journal of Clinical Oncology 32, no. 3_suppl (January 20, 2014): 23. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.23.
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23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.
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Massari, Giulia, Francesca Magnoni, Giorgio Favia, Nickolas Peradze, Paolo Veronesi, Carlo La Vecchia, and Giovanni Corso. "Frequency of CDH1 Germline Mutations in Non-Gastric Cancers." Cancers 13, no. 10 (May 12, 2021): 2321. http://dx.doi.org/10.3390/cancers13102321.
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Hereditary Diffuse Gastric Cancer (HDGC) is a complex inherited syndrome caused by CDH1 germline mutations. DGC is the hallmark cancer of this genetic predisposition, but several other cancers are associated with these CDH1 mutations. In this review, we revised all studies reporting CDH1 mutations in non-GC patients. The selected studies included: (a) families aggregating with GC and other cancers, both, and (b) families presenting only non-gastric tumors association. Among non-gastric tumors, our results show that CDH1 mutations are most frequently identified in breast cancer. The frequency of missense mutations is higher in the non-GC group, as the age at diagnosis in this group. Moreover, the predominant CDH1 mutation affects the extracellular domain. Our data suggest that CDH1 genetic testing should be considered also in other cancers, especially breast tumors.
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Wang, Hai-Dan. "CDH1 germline mutation in hereditary gastric carcinoma." World Journal of Gastroenterology 10, no. 21 (2004): 3088. http://dx.doi.org/10.3748/wjg.v10.i21.3088.
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Graziano, Francesco, Anna Maria Ruzzo, Italo Bearzi, Enrica Testa, Vittorio Lai, and Mauro Magnani. "Screening E-Cadherin Germline Mutations in Italian Patients with Familial Diffuse Gastric Cancer: An Analysis in the District of Urbino, Region Marche, Central Italy." Tumori Journal 89, no. 3 (May 2003): 255–58. http://dx.doi.org/10.1177/030089160308900304.
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Aims & Background Hereditary diffuse gastric cancer is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the E-cadherin gene (CDH1). To date, 16 truncating germline CDH1 mutations have been described in hereditary diffuse gastric cancer families in different ethnic groups, but so far, no investigation has been addressed to Italian patients. In the District of Urbino, Region Marche, Central Italy, gastric cancer is the most common tumor in men and it is the second in women after breast cancer. In this area, we investigated CDH1 mutations in patients who fulfilled the hereditary diffuse gastric cancer criteria. Material and Methods Consecutive patients with diffuse gastric cancer were considered eligible for the study. After pedigree analysis, patients who met the International Gastric Cancer Linkage Consortium criteria were studied for CDH1 mutations. After blood samples collection and DNA extraction, standard polymerase chain reaction and sequencing techniques were used for CDH1 analysis. Results In a study population of 98 patients with diffuse gastric cancer, 11 patients (11%) showed familial clustering and 3 of them met the International Gastric Cancer Linkage Consortium criteria for hereditary diffuse gastric cancer. None of the 3 patients showed inactivating germline mutation in CDH1. Conclusions According to recent studies, the frequency of CDH1 inactivating germline mutations in patients who fulfil the hereditary diffuse gastric cancer criteria may be lower than that reported in early investigations. The results of the present study in a population of Italian patients seem to confirm these data. It is likely that unidentified mutations in CDH1 or other involved genes contribute to diffuse gastric cancer susceptibility.
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Figueiredo, Joana, Soraia Melo, Patrícia Carneiro, Ana Margarida Moreira, Maria Sofia Fernandes, Ana Sofia Ribeiro, Parry Guilford, Joana Paredes, and Raquel Seruca. "Clinical spectrum and pleiotropic nature of CDH1 germline mutations." Journal of Medical Genetics 56, no. 4 (January 19, 2019): 199–208. http://dx.doi.org/10.1136/jmedgenet-2018-105807.
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CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.
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Masciari, S., K. A. Schrader, J. Senz, N. Tung, J. Balmana, A. R. Razzak, P. Miron, D. G. Huntsman, and J. E. Garber. "Prevalence of CDH1 germline mutations in subjects with early onset or familial lobular breast cancer, a multicenter collaboration." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 11042. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11042.
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11042 Background: Invasive lobular breast carcinoma (LBC) is part of the hereditary diffuse gastric cancer (HDGC) syndrome, associated with germline mutations in the E-cadherin (CDH1) gene. CDH1 mutations can be identified in 80% of families ascertained by DGC. The risk of DGC in CDH1 mutation carriers is 67% in males, and 83% in females; the estimated risk of LBC in women is 39–50% to age 80. Management of HDGC includes prophylactic gastrectomy. In this study, we estimated the prevalence of germline CDH1mutations among women with LBC who were either diagnosed at young age or had family history of breast cancer (BC). Methods: Germline DNA was collected from 383 women with LBC or mixed, lobular/ductal, BC from breast cancer programs, familial cancer clinics, and population-based cohorts. Germline BRCA1or BRCA2mutations carriers were excluded. Eligible women had (1) LBC before age 45 or (2) LBC at any age with at least two 1st or 2nd degree relatives with BC of any type. Denaturing high pressure liquid chromatography was undertaken, followed by direct sequencing of exons displaying changes. Results: At the time of submission 310 of 383 samples have been fully sequenced. One previously characterized missense mutation and four novel non-synonymous variants (1.6%) were found. Three of these women had LBC before 45 years and no family history of BC; two had BC family history. No gastric cancers were reported in these families. Functional assays to assess the pathogenicity of the variants are in process. Conclusions: These results confirm that CDH1 is responsible for a small proportion of familial and early onset LBC. Given the difficulty of identifying CDH1 mutations from BC history alone and the importance of managing the gastric cancer risk in CDH1carriers, these findings should underscore the need to obtain an accurate abdominal cancer family history from women with LBC. No significant financial relationships to disclose.
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Pandalai, Prakash K., Greg Y. Lauwers, Daniel C. Chung, Devanshi Patel, and Sam S. Yoon. "Prophylactic total gastrectomy for individuals with germline CDH1 mutation." Surgery 149, no. 3 (March 2011): 347–55. http://dx.doi.org/10.1016/j.surg.2010.07.005.
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Corso, Giovanni, Giacomo Montagna, Joana Figueiredo, Carlo La Vecchia, Uberto Fumagalli Romario, Maria Sofia Fernandes, Susana Seixas, et al. "Hereditary Gastric and Breast Cancer Syndromes Related to CDH1 Germline Mutation: A Multidisciplinary Clinical Review." Cancers 12, no. 6 (June 17, 2020): 1598. http://dx.doi.org/10.3390/cancers12061598.
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E-cadherin (CDH1 gene) germline mutations are associated with the development of diffuse gastric cancer in the context of the so-called hereditary diffuse gastric syndrome, and with an inherited predisposition of lobular breast carcinoma. In 2019, the international gastric cancer linkage consortium revised the clinical criteria and established guidelines for the genetic screening of CDH1 germline syndromes. Nevertheless, the introduction of multigene panel testing in clinical practice has led to an increased identification of E-cadherin mutations in individuals without a positive family history of gastric or breast cancers. This observation motivated us to review and present a novel multidisciplinary clinical approach (nutritional, surgical, and image screening) for single subjects who present germline CDH1 mutations but do not fulfil the classic clinical criteria, namely those identified as—(1) incidental finding and (2) individuals with lobular breast cancer without family history of gastric cancer (GC).
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Corso, Giovanni, Federica Corso, Federica Bellerba, Patrícia Carneiro, Susana Seixas, Antonio Cioffi, Carlo La Vecchia, et al. "Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review." Cancers 13, no. 6 (March 12, 2021): 1269. http://dx.doi.org/10.3390/cancers13061269.
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Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that CDH1 mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of CDH1 alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.
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Pogodina, Jelena, Roberts Ribenieks, Dace Berzina, Genadijs Trofimovics, and Edvins Miklasevics. "CDH1 Mutation in Two Patients with Hereditary Gastric Cancer." Acta Chirurgica Latviensis 14, no. 1 (November 24, 2014): 35–37. http://dx.doi.org/10.2478/chilat-2014-0107.
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Summary CDH1 is currently the only gene in which mutations are known to cause hereditary diffuse gastric cancer (HDGC). Hereditary diffuse gastric cancer is defined as a syndrome of inherited predisposition to cancer with autosomal dominant inheritance pattern. Specific criteria are used to identify patients with suspected HDGC and who should be investigated for CDH1 germline mutations. Accurate screening is mandatory for unaffected carriers ofCDH1 mutations and selected high-risk individuals could be considered for prophylactic gastrectomy.
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Gianella, Carlos A., Beatriz Bendito, Carola Iglesias, Miguel P. Bengoechea, Celia Miñón, and Alberto Ruiz. "Risk‐reducing mastectomy in germline CDH1 mutation carriers: Pathologic findings." Breast Journal 26, no. 3 (March 2020): 583–84. http://dx.doi.org/10.1111/tbj.13604.
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Li, Lei, Ming Wu, Changbin Zhu, Di Shao, and Meng Liu. "Germline and somatic mutations in 25 hereditary breast and ovarian cancer related genes and platinum-based chemotherapy response among Chinese patients with epithelial ovarian cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18088-e18088. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18088.
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e18088 Background: Insight on the germline and somatic mutation in BRCA1/2 was predictable on the sensitivity on platinum-based therapy. The therapeutic impact of mutations in other hereditary breast and ovarian cancer related genes is uncertain. Methods: We sought to investigate the germline and somatic deleterious mutations through all exons in 25 hereditary breast and ovarian cancer related genes in paired blood and frozen tumor samples from 235 Chinese women diagnosed with epithelial ovarian carcinomas. Results: Forty-seven subjects (24.6%) had a germline deleterious mutation, and 126 subjects (66%) had a somatic deleterious mutation. Thirty-four (17.8%) had both a germline and somatic mutation. Of the 203 germline and somatic deleterious mutations, 114 (56.2%) occurred in TP53, 41 (20.2%) in BRCA1, 11 (5.4%) in BRCA2 and 37 (23.6%) in 13 other genes: ATM, BARD1, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, NF1, PALB2, PTEN, RAD51C and, STK11. In 235 patients, 215 (91.5%) and 20 (8.5%) cases were sensitive and resistant to the platinum-based chemotherapy. In the whole population, homologous recombination repair (HRR) mutations, non- homologous recombination repair(non-HRR) mutations, mismatch repair (MMR) mutations had no impact on the platinum-based chemotherapy response. No significant difference in platinum response were found in HRR, non-HRR and MRR mutation(P = 0.788). In 235 patients, ones with ATM (10), CHEK2(9), NF1(5), PALB2(8), PTEN (8) mutations were available for platinum response information; Among them, there were three patients with either ATM, CHEK2 or PALB2 mutation presented platinum resistance. Conclusions: Multi-gene panel testing of germline and somatic HBOC related gene mutations was feasible to characterize a comprehensive molecular profile of ovarian cancer and showed non-BRCA gene stratification potential value in predicting patient’s response for platinum-based chemotherapy.
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Suzuki, Akihiro, Hiroto Katoh, Daisuke Komura, Miwako Kakiuchi, Amane Tagashira, Shogo Yamamoto, Kenji Tatsuno, et al. "Defined lifestyle and germline factors predispose Asian populations to gastric cancer." Science Advances 6, no. 19 (May 2020): eaav9778. http://dx.doi.org/10.1126/sciadv.aav9778.
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Germline and environmental effects on the development of gastric cancers (GC) and their ethnic differences have been poorly understood. Here, we performed genomic-scale trans-ethnic analysis of 531 GCs (319 Asian and 212 non-Asians). There was one distinct GC subclass with clear alcohol-associated mutation signature and strong Asian specificity, almost all of which were attributable to alcohol intake behavior, smoking habit, and Asian-specific defective ALDH2 allele. Alcohol-related GCs have low mutation burden and characteristic immunological profiles. In addition, we found frequent (7.4%) germline CDH1 variants among Japanese GCs, most of which were attributed to a few recurrent single-nucleotide variants shared by Japanese and Koreans, suggesting the existence of common ancestral events among East Asians. Specifically, approximately one-fifth of diffuse-type GCs were attributable to the combination of alcohol intake and defective ALDH2 allele or to CDH1 variants. These results revealed uncharacterized impacts of germline variants and lifestyles in the high incidence areas.
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Lyubchenko, L. N., M. G. Filippova, O. A. Anurova, P. B. Nazliev, and I. S. Stilidi. "HEREDITARY DIFFUSE GASTRIC CANCER: GENETIC ASPECTS AND PROPHYLACTIC TOTAL GASTRECTOMY." Siberian journal of oncology 17, no. 4 (September 4, 2018): 48–52. http://dx.doi.org/10.21294/1814-4861-2018-17-4-48-52.
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For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer. The case report describes a rare case of hereditary diffuse gastric cancer (HDGC) associated with CDH1 gene mutation, which is reported in the Russian population for the first time. In 2013, a 28-year- old woman was referred to Clinical Oncogenetics Laboratory with a family history of gastric cancer. Molecular genetic analysis revealed CDH1 gene mutation. The lifetime risk of cancer in mutation positive members is more than 80. Histological examination of gastric biopsy specimens obtained during endoscopy revealed isolated signet ring cells in the lamina propria. Spleenpreserving D2-lymphodissection and total gastrectomy with Roux-en-Y reconstruction with a jejunal reservoir formation were performed at the Abdominal Oncology Surgery Department.
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Harlan, M., E. Sheehy, J. Randazzo, D. Schrag, M. M. Kemeny, D. P. Kelsen, and M. A. Shah. "Initial findings from the Memorial Sloan-Kettering Early Onset and Familial Gastric Cancer Registry (EOFGCR)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4619. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4619.
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4619 Background: Hereditary Diffuse Gastric Cancer(HDGC) is an autosomal dominant cancer susceptibility syndrome defined as having 2 or more diffuse GC(one of which diagnosed before the age of 50) or 3 or more diffuse GC in 1st or 2nd degree relatives. A germline mutation in E-Cadherin(CDH1) is found in 20–30% of HDGC families. HDGC is responsible for 30% of all hereditable GC. The genetic cause for the remaining 70% of hereditable GC is unknown. We created a registry for early onset and familial gastric cancer to capture epidemiologic and family history data matched with DNA and tissue to characterize various phenotypic and risk factor profiles and their associations with HDGC and other non-HDGC hereditable GC. Methods: Patients with a family history(patients with one first degree relative or 2 second degree relatives with GC) or who developed GC at an early age(age < 50) were eligible for registry participation. Participants complete a GC risk factor questionnaire, family history, provide blood and tissue for repository, and meet with a genetics counselor to consider germline CDH1 mutation testing. Results: 57 patients have enrolled since January 2006: 36 patients with early onset, 21 with familial GC. Eleven patients have a family history meeting HDGC criteria, two with known CDH1 mutations. Three of the 11 HDGC families are from Ecuador. GC risk factor questionnaires are available from 46 patients(81%), see table . Although no novel CDH1 mutations were found in 13 fully sequenced patients, 4 patients(31%) were found to have uncommon genotypes, including two with early onset of disease diagnosis (ages 22 and 34) with multiple variants in CDH1. Conclusions: HDGC patients tend to have more high risk features including smoking history, use of salt, and H. pylori infection. We have identified a cluster of patients with HDGC of Ecuadorian descent. Genetic variation in CDH1 suggests that novel haplotypes may be associated early onset GC risk.(Supported by the DeGregorio Family Foundation) [Table: see text] No significant financial relationships to disclose.
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Fang, Wen-Liang, Shih-Ching Chang, Yuan-Tzu Lan, Kuo-Hung Huang, Su-Shun Lo, Anna Fen-Yau Li, Chin-Wen Chi, Chew-Wun Wu, and Shih-Hwa Chiou. "Molecular and Survival Differences between Familial and Sporadic Gastric Cancers." BioMed Research International 2013 (2013): 1–10. http://dx.doi.org/10.1155/2013/396272.
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Mismatch repair (MMR) and germline E-cadherin (CDH1) mutations are two of the major pathways of carcinogenesis in familial gastric cancer (GC). A total of 260 sporadic and 66 familial GC patients were enrolled and molecular and survival differences were compared. Familial GC patients had earlier onset and were diagnosed at an earlier stage and had both a better 5-year overall survival rate and 3-year disease-free survival rate compared with sporadic GC patients. Only in diffuse type GC, the MSI-H phenotype and abnormal MMR protein expression were significantly higher in familial GC than in sporadic GC. In MSI-H GC, MLH1 promoter methylation was slightly higher in sporadic GC than familial GC (50% versus 23.1%), while the frequency of MMR gene mutation was slightly higher in familial GC than in sporadic GC (15.4% versus 3.1%). All of the patients with MMR gene mutation had diffuse type GC. Among familial GC patients with CDH1 mutation, most patients (72.3%) had diffuse type GC. In summary, for familial GC patients, we recommend screening of MSI status and CDH1 mutation especially for diffuse type GC. Because of the low incidence, mutation analysis of MMR gene might be considered in MSI-H familial GC with diffuse type only.
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Wang, H., and J. Ren. "E-cadherin germline gene (CDH1) mutation in hereditary gastric carcinoma families." Journal of Clinical Oncology 22, no. 14_suppl (July 15, 2004): 9634. http://dx.doi.org/10.1200/jco.2004.22.90140.9634.
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Wang, H., and J. Ren. "E-cadherin germline gene (CDH1) mutation in hereditary gastric carcinoma families." Journal of Clinical Oncology 22, no. 14_suppl (July 15, 2004): 9634. http://dx.doi.org/10.1200/jco.2004.22.14_suppl.9634.
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Weren, Robbert D. A., Rachel S. van der Post, Ingrid P. Vogelaar, J. Han van Krieken, Liesbeth Spruijt, Jan Lubinski, Anna Jakubowska, et al. "Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility." Journal of Medical Genetics 55, no. 10 (January 12, 2018): 669–74. http://dx.doi.org/10.1136/jmedgenet-2017-104962.
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BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population.ConclusionsBased on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.
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Kwong, Ava, Vivian Y. Shin, Cecilia Y. S. Ho, Aleena Khalid, Chun Hang Au, Karen K. L. Chan, Hextan Y. S. Ngan, Tsun-Leung Chan, and Edmond S. K. Ma. "Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients." Cancers 13, no. 16 (August 20, 2021): 4195. http://dx.doi.org/10.3390/cancers13164195.
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The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of the PALB2 mutation in Chinese breast and/or ovarian cancer patients. We performed sequencing with a 6-gene test panel (BRCA1, BRCA2, TP53, PTEN, PALB2, and CDH1) to identify the prevalence of the PALB2 germline mutation among 2631 patients with breast and/or ovarian cancer. In this cohort, 39 mutations were identified with 24 types of mutation variants, where the majority of the mutations were frame-shift mutations and resulted in early termination. We also identified seven novel PALB2 mutations. Most of the PALB2 mutation carriers had breast cancer (36, 92.3%) and were more likely to have family history of breast cancer (19, 48.7%). The majority of the breast tumors were invasive ductal carcinoma (NOS type) (34, 81.0%) and hormonal positive (ER: 32, 84.2%; PR: 23, 60.5%). Pathogenic mutations of PALB2 were found in 39 probands with a mutation frequency of 1.6% and 1% in breast cancer and ovarian cancer patients, respectively. PALB2 mutation carriers were more likely have hormonal positive tumors and were likely to have familial aggregation of breast cancer.
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Pogodina, Jelena, Genadijs Trofimovics, Edvins Miklasevics, and Roberts Ribenieks. "Hereditary Gastric Cancer: Review of Literature." Acta Chirurgica Latviensis 13, no. 1 (December 1, 2013): 71–74. http://dx.doi.org/10.2478/chilat-2013-0013.
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Summary Worldwide, gastric cancer is one of the most common forms of cancer, with a high morbidity and mortality. Both environmental and genetic factors have a role in the aetiology of gastric cancer. Familial clustering of gastric cancer is seen in 10-15% of cases, and approximately 3% of gastric cancer cases arise in the setting of hereditary diffuse gastric cancer ( HDGC). In families with HDGC, gastric cancer presents at relatively young age. Germline mutations in the CDH1 gene are the major cause of HDGC and are identified in approximately 25-40% of families which fulfill strict criteria. Prophylactic gastrectomy is the only option to prevent gastric cancer in individuals with a CDH1 mutation. However, in the majority of families with multiple cases of gastric cancer no germline genetic abnormality can be identified and therefore preventative measures are not available, except for general lifestyle advice. Future research should focus on identifying new genetic predisposing factors for all types of familial gastric cancer.
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Reis Figueiredo, Renata, Tatiana Strava Correa, Carlos Henrique dos Anjos, and Heinrich Bender Kohnert Seidler. "Metastatic Lobular Breast Cancer Mimicking Colitis." Reports — Medical Cases, Images, and Videos 3, no. 3 (June 29, 2020): 20. http://dx.doi.org/10.3390/reports3030020.
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Breast cancer is the most frequent cancer diagnosed in women in the world regardless of race or ethnicity. About 10% of invasive breast carcinomas are lobular subtype. The loss of the E-caderin expression that occurs in lobular carcinoma leads to a higher risk of metastases in membranes (meningeal, pleural, peritoneum) and gastrointestinal and/or endobronchial mucous, which may lead to several odd symptomatology. We report a 79 years old female patient with lobular breast cancer associated to CDH1 germline mutation. She was diagnosed with breast cancer in December 2016 after noticing a right-armpit nodule whose pathological examination demonstrated an immunohistochemistry profile compatible with lobular breast carcinoma metastasis and had estrogen receptors 98%, progesterone receptors < 1%, ki67 25%, negative her2 score. Family history of only one paternal uncle with stomach cancer. After two lines of hormone therapy, she had disease progression and started oral chemotherapy with capecitabine. In a few weeks, the patient had refractory diarrhea. At the beginning, it was defined like colitis chemotherapy related. However, the clinical features showed necessity of further investigation. Then, she was diagnosed with CDH1 germline mutation after massive progression at gastrointestinal mucous. This case made possible to inform the family about risk of germline mutation and necessity of genetic counseling.
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Qiu, Yuan, Liping Liu, Qiuhua Deng, Haihong Yang, Hanzhang Chen, Dakai Xiao, Weiwei Li, et al. "Characters of germline mutations in Chinese non-small cell lung cancer patients." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13542-e13542. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13542.
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e13542 Background: Environment factors are associated with lung cancer occurrence. Genetic susceptibility to lung cancer remains unclear. This study assessed germline mutations in Chinese non-small-cell lung cancer (NSCLC) patients. Methods: 506 FFPE samples were collected from 469 patients pathologically confirmed as lung adenocarcinoma. A 508-gene panel including 63 hereditary cancer genes was applied to detect mutations on MGI-seq 2000. Raw data was processed and analyzed. Variation pathogenicity was categorized following ACMG 2015 guideline. Results: 21 patients (4%) carried (likely) pathogenic (P or LP) mutations in 15 cancer predisposition genes. 11 germline variations included MUTYH (1/21), BLM (1/21), BRIP1(2/21), RAD50(1/21), PMS1(1/21), TP53(1/21), BRCA2(1/2), PALB2(1/21), NF1(1/21), CDH1(1/21) and MRE11A (1/21) genes. Nine likely pathogenic mutations were identified in MRE11A, RAD51C, RAD50, ATR, BRCA2, BLM, PMS1 and VHL genes. These mutations are involved in homologous recombination repair, mismatch repair, Fanconi anemia, and Li-Fraumeni syndrome. Germline mutations were commonly occurred in females (female vs Male: 13 vs 7) without statistical significance. No significant correlations of age of onset and TMB were observed between NSCLC patients with germline wild type and mutation. Other clinical characters like histology and clinical stage presented similar results. Somatic mutations with high frequency like EGFR, KRAS were distributed equally in patients with both germline mutation positive and negative. Conclusions: In this study, there is no significant correlation of germline susceptibility gene mutations with clinical and genetic characters of NSCLC patients. Further investigation on germline genetic aberrations of NSCLC is definitely needed to clarify germline impact on the etiology of NSCLC. [Table: see text]
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Lynch, H. T., C. Caldas, D. Wirtzfeld, C. Vaccaro, W. Rubinstein, S. Weissman, P. Kaurah, N. Boyd, R. Fitzgerald, and D. Huntsman. "Hereditary diffuse gastric cancer: Natural history, pathology, screening limitations, and prophylactic total gastrectomy in CDH1 mutation carriers." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4500. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4500.
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4500 Background: Hereditary diffuse gastric cancer (HDGC) is a potentially fatal disease that occurs due to mutations in the E- cadherin (CDH1) gene, as discovered in 1998. Its penetrance ranges between 70–80%. Its morbidity and mortality can be altered favorably through genetic counseling, germline mutation testing, and highly-targeted management that includes prophylactic total gastrectomy. Lobular breast cancer has been identified as an integral lesion in HDGC. Methods: This international collaborative group on HDGC is comprised of 56 mutation-positive families, which is the world’s largest resource of such families. Cancer diagnoses were verified with pathology slides/tissue block review when possible, or reports. Genetic counseling covering the pros and cons of mutation testing, screening and its limitations, and the option of prophylactic total gastrectomy was provided. Results: Findings on 56 HDGC mutation-positive families show carrier testing to have been performed on 267 individuals, of which 123 were CDH1 mutation positive. Prophylactic gastrectomies were performed on 14 families involving 50 individuals. Occult cancer was diagnosed in 31 (31/39=79.5%; results are pending on the remaining 11), based upon pathology and verbal reports. Five individuals underwent prophylactic gastrectomy prior to genetic counseling, 3 of whom later tested negative for mutations. In one of these remarkable HDGC families, 11 first cousins who tested positive for the CDH1 mutation underwent prophylactic total gastrectomy. On a post-surgery questionnaire, they each stated that the decision for the prophylactic procedure was the “right one” for them. In each case, a parent had died of HDGC sequelae, adding to the cousins’ acceptance of DNA testing and surgery. They considered their post-operative nutritional programs to have been acceptable. Conclusion: HDGC and its life-threatening sequelae were significantly ameliorated in CDH1 mutation carriers through total prophylactic gastrectomy in patients at enormous lifetime risk for HDGC. Decision for mutation testing and surgery may be more acceptable through intensive education in concert with a compassionate management team. No significant financial relationships to disclose.
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Efremidis, A. P., F. Fostira, C. Panopoulos, K. Papademitriou, N. Pistalmazian, N. Tsoukalas, and D. Yannoukakos. "CDH-1 germ line mutations in diffuse gastric and infiltrating ductal breast cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22218-e22218. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22218.
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e22218 Background: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is characterized by the predisposition to gastric cancer of the diffuse type and to breast cancer of the lobular type. The autosomal dominantly inherited germline mutations of the E- cadherin (CDH1) gene are the defects underlying the HDGC syndrome. The median age of onset for diffuse gastric cancer is 38 years. CDH1 mutations are highly penetrant, conferring a cumulative risk of diffuse gastric cancer of 75%. Methods: Genomic DNA was purified from peripheral blood leukocytes following standard chloroform extraction. The complete coding sequences of the CDH1-gene, including splice junctions, were amplified by Polymerase Chain Reaction (PCR) and electrophorized in an ABI Prism 310 Genetic Analyzer. Results: A pathogenic mutation located on exon 7 of the CDH1 gene was identified in a female patient diagnosed with bilateral breast cancer at the age of 36. She underwent bilateral mastectomy for an infiltrating ductal adenocarcinoma of the left breast and in situ lobular of the right breast. At the age of 45 the patient underwent gastrectomy for diffuse type gastric adenocarcinoma. She had a positive family history for breast and gastric cancer from both sides, but without meeting the absolute clinical criteria for hereditary diffuse gastric cancer syndrome. The nonsense mutation found was probably maternally inherited, since the maternal grandmother was diagnosed with breast cancer at the age of 38. Conclusions: The selection process of patients for genetic testing for the HDGC syndrome is not quite clear at the moment, as it is apparent that more types of breast cancer and not only lobular, can be associated with the syndrome. Criteria should be more flexible in respects to the histopathology of the cancer type. This is the first CDH1 mutation identified in a Greek patient. No significant financial relationships to disclose.
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van Dieren, Jolanda M., Liudmila L. Kodach, Peggy den Hartog, Lizet E. van der Kolk, Karolina Sikorska, Marie-Louise F. van Velthuysen, Johanna W. van Sandick, Willem J. Koemans, Petur Snaebjornsson, and Annemieke Cats. "Gastroscopic surveillance with targeted biopsies compared with random biopsies in CDH1 mutation carriers." Endoscopy 52, no. 10 (May 14, 2020): 839–46. http://dx.doi.org/10.1055/a-1157-8678.
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Abstract Background The International Gastric Cancer Linkage Consortium (IGCLC) consensus guideline advises prophylactic gastrectomy in early adulthood to prevent gastric cancer development in CDH1 germline mutation carriers; psychosocial reasons may postpone gastrectomy. We analyzed the yield of signet-ring cell carcinoma (SRCC) during surveillance gastroscopy in CDH1 mutation carriers. Methods A retrospective analysis on surveillance gastroscopies in CDH1 mutation carriers was performed. The yield of SRCC in both targeted and random biopsies was studied. Endoscopic (biopsy) results were compared with the histopathologic outcomes in gastrectomy specimens. Results 42 CDH1 mutation carriers (18 men; mean age 43, range 20–82 years) underwent 96 surveillance gastroscopies. SRCC lesions were identified on surveillance gastroscopy in 21 patients (50 %), by either targeted biopsies only (n = 11), random biopsies only (n = 3), or both random and targeted biopsies (n = 7). SRCC was detected in 41 /377 targeted biopsies (11 %), whereas random biopsies revealed SRCC in 14/1563 biopsies (0.9 %). At least one SRCC lesion was found in 26 of 30 gastrectomy specimens. In 18 of these 26 specimens (69 %), SRCC had been identified by endoscopic biopsies. Missed lesions were all small superficial SRCC foci, mainly in the body of the stomach. Conclusion In our cohort of CDH1 mutation carriers, SRCC lesions were identified by an extensive endoscopic surveillance protocol in 69 % of SRCC-positive patients who underwent a gastric resection. The low number of SRCC detected through random sampling demands a critical reappraisal of random biopsy sampling in the IGCLC guideline.
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Norero, Enrique, M. Alejandra Alarcon, Christopher Hakkaart, Tomas de Mayo, Cecilia Mellado, Marcelo Garrido, Gloria Aguayo, et al. "Identification of c.1531C>T Pathogenic Variant in the CDH1 Gene as a Novel Germline Mutation of Hereditary Diffuse Gastric Cancer." International Journal of Molecular Sciences 20, no. 20 (October 9, 2019): 4980. http://dx.doi.org/10.3390/ijms20204980.
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Germline pathogenic variants in the CDH1 gene are a well-established cause of hereditary diffuse gastric cancer (HDGC) syndrome. The aim of this study was to characterize CDH1 mutations associated with HDGC from Chile, a country with one of the highest incidence and mortality rates in the world for gastric cancer (GC). Here, we prospectively include probands with family history/early onset of diffuse-type of GC. The whole coding sequence of the CDH1 gene was sequenced from genomic DNA in all patients, and a multidisciplinary team managed each family member with a pathogenic sequence variant. Thirty-six cases were included (median age 44 years/male 50%). Twenty-seven (75%) patients had diffuse-type GC at ≤50 years of age and 19 (53%) had first or second-degree family members with a history of HDGC. Two cases (5.5%) carried a non-synonymous germline sequence variant in the CDH1 gene: (a) The c.88C>A missense variant was found in a family with three diffuse-type GC cases; and (b) c.1531C>T a nonsense pathogenic variant was identified in a 22-year-old proband with no previous family history of HDGC. Of note, six family members carry the same nonsense pathogenic variant. Prophylactic gastrectomy in the proband’s sister revealed stage I signet-ring cell carcinoma. The finding of 1531C>T pathogenic variant in the CDH1 in proband with no previous family history of HDGC warrants further study to uncover familial clustering of disease in CDH1 negative patients. This finding may be particularly relevant in high incidence countries, such as the case in this report.
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Almeda, Alison Figueroa, Susan M. Grimes, Giwon Shin, Hojoon Lee, Ignacio Alberto Wichmann, Stephanie Greer, and Hanlee P. Ji. "The Gastric Cancer Registry Genome Explorer: A tool for genomic discovery." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): 434. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.434.
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434 Background: The Gastric Cancer Registry (GCR) collects clinical questionnaire data and biospecimens from gastric cancer (GC) patients and individuals at high risk for GC (through family history of GC or a germline CDH1 mutation). Its purpose is to facilitate research into better detection and treatment strategies for GC. In 2020, the GCR Genome Explorer (GCR-GE), a publicly accessible and interactive database of clinical and genomic data, was launched to meet this goal. Methods: We generated genomic datasets from participants when GC status and archival gastric tumor tissue were available. We processed the tumor tissue (and paired normal tissue when possible) for whole genome, whole exome, and bulk RNA sequencing. The following genomic features were identified: copy number variations, gene mutations, gene expression, microbiome composition, estimation of tumor-infiltrating immune cells, and tumor neoantigens. We populated (1) all genomic alterations identified from GCR sequencing data, and (2) demographic and pathologic data regarding the tumor that were compiled from participant questionnaires and medical records into the GCR-GE. In addition, sequencing files from the Cancer Genome Atlas (TCGA) were similarly analyzed and uploaded as external datasets. Features of the GCR-GE include cross-study comparisons, study summaries, and queries down to the individual gene, neoantigen, and patient level. Results: In total, 243 GC patients donated tumor samples. The new GCR-GE release contains genomic datasets for 214 of these tumors, as well as datasets for 443 gastric tumors and 185 esophageal tumors from TCGA. Data generation was possible thanks to 756 subjects who enrolled in the GCR from 2011-2022. Most subjects were diagnosed with GC only (N=487), but interestingly, some met multiple criteria. For instance, 10 GC patients had a family history; 10 had a germline CDH1 mutation; and 21 patients had GC, a family history, and a germline CDH1 mutation. Efforts to upload additional datasets are ongoing. All data in the GCR-GE is downloadable. Conclusions: The GCR-GE is a comprehensive resource of genomic and clinical data. Given its accessibility, ease of use, and large cohort sizes, the GCR-GE presents a highly valuable tool for accelerating GC research.
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Shin, Hee-Chul, Wonshik Han, Han-Byoel Lee, Hyeong-Gon Moon, Eunshin Lee, and Dong Young Noh. "Frequency of germline patghogenic mutation in breast cancer patients at high risk hereditary cancer." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e13110-e13110. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e13110.
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e13110 Background: Next-generation sequencing technology allows the simultaneous sequencing of multiple target genes. We developed a gene panel containing 64 genes which were associated with various hereditary cancers. This study was performed to evaluate the frequency of pathogenic mutations associated with hereditary cancer among Korean patients at high risk hereditary breast cancer using multi-gene sequencing panel. Methods: A total of 252 breast cancer patients with high-risk hereditary cancer were included. Among them, 179 patients (71.0%) had multiple primary cancers including breast cancer, 27 patients (10.7%) were diagnosed with bilateral breast cancer at age 40 or younger. Thirty-five patients (13.9%) had breast cancer family history of more than 2 relatives. With the 64 gene panel, sequence variants were detected by next-generation sequencing technology. Results: Sixty seven patients (26.8%) were found to have 77 germline pathogenic mutations, 12 in BRCA1, 13 in BRCA2, 9 in CDH1, 3 in FH, 5 in MSH2, 2 in MSH6, 4 in NAT1, 6 in PTCH1, 3 in RAD51, 7 in RET, 4 in SPINK1, 3 in TP53 and one each in ALK, BRIP1, CHEK2, MLH2, MUTYH, and PTEN. In 20 patients (4.0%), 2 (n = 9) or 3 (n = 1) pathogenic mutations were detected. In 227 patients with BRCA1/2 negative, CDH1 (n = 7), RET (n = 7), PTCH1 (n = 5), and MSH2 (n = 5) were the most prevalent pathogenic mutations. Conclusions: The 64 gene panel detected germline pathogenic mutations in 26.8% of Korean breast cancer patients with feature of hereditary cancer. Mutations of BRCA1, BRCA2, CDH1, RET, and PTCH1 were the most prevalent variants.Mutation carriers were considered as high risk to develop malignancy and recommended to receive genetic counseling and intensive cancer screening.
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Zhu, Huili, Yvonne Sada, and Ramon Jin. "Molecular profiles of gastric adenocarcinoma among Hispanic patients at a safety-net healthcare system." Journal of Clinical Oncology 40, no. 16_suppl (June 1, 2022): e16067-e16067. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e16067.
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e16067 Background: Hispanic patients with gastric cancer are more likely to have advanced stage at diagnosis, signet ring histology, and worse survival outcomes than non-Hispanic patients. Although socioeconomic factors may contribute to these disparities, the molecular biology of gastric cancer in Hispanic patients has not been well characterized. Hispanic patients comprise < 0.05% of gastric adenocarcinoma cases in The Cancer Genome Atlas (TCGA). Methods: We conducted a retrospective study of patients with gastric adenocarcinoma diagnosed between January 2019 to January 2022 at a safety net hospital in Houston, Texas. The hospital serves a patient population of which 91% are racial/ethnic minorities and 57% are Hispanic. Next generation sequencing data was obtained via Tempus|xT tissue assay (DNA sequencing of 648 genes in tumor and matched normal samples at 500x depth) and/or Tempus|xF liquid biopsy assay (ctDNA sequencing of 105 genes in peripheral blood samples at 5,000x depth) for germline and/or somatic mutations. We compared mutation findings in Hispanic vs non-Hispanic patients. Results: Among 56 patients with gastric adenocarcinoma, 45 (80%) were Hispanic, 11 (20%) were non-Hispanic White, Black, or other, 30 (54%) were male, median age was 54±13, and 14 (25%) were younger than 50 years old. The majority were metastatic (65%), and 6 (11%) were signet ring cell subtype. The most common pathogenic somatic variants across the entire cohort included: TP53 (55%) , CDH1 (34%) , ARID1A (25%) , LRP1B (20%) , RHOA (16%) , SMAD4 (16%) , ERBB2 (14%) , KRAS (14%) , CDKN2A (12%), and PIK3CA (12%). Microsatellite instability was found in 1 (0.02%) patient. Somatic CDH1 mutations were present in 15 (33%) Hispanic patients, of whom 7 were younger than 50 years old, and 2 (18%) non-Hispanic patients. Germline CDH1 mutations was identified in 1 Hispanic patient. TP53 mutations occurred in 14 (31%) Hispanic patients and 6 (55%) non-Hispanic patients. Conclusions: CDH1 mutations, which are associated with familial gastric cancers and more aggressive disease, were present in 33% of Hispanic patients with gastric adenocarcinoma in our study. Nearly half of these identified patients were younger than 50 years old. The high frequency of CDH1 mutations may contribute to the unique pathogenesis of gastric cancers in Hispanic patients.
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Shah, M. A., Y. Pristyazhnyuk, M. Jhawer, S. Coombes, M. Harlan, J. Randazzo, R. J. Perera, K. M. Pascarelli, D. Coit, and D. P. Kelsen. "Hereditary diffuse gastric cancer (HDGC): Clinical characteristics of a prospective cohort of HDGC patients with and without CDH1 mutation and patients with sporadic GC." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4543. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4543.
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4543 Background: HDGC is an autosomal dominant cancer syndrome associated with early onset diffuse GC. Germline mutations in E-cadherin(CDH1) cause the disease but are identified in only 20–30% of pts meeting clinical criteria. We began a prospective multicenter GC registry to capture epidemiologic and family history data matched with DNA and tissue to characterize phenotypic and risk factor profiles and their associations with HDGC and other non-HDGC hereditable GC. Herein, we report the clinical characteristics of HDGC, the subset of HDGC pts with CDH1 mutation, pts with sporadic GC, and non-cancer controls. Methods: All patients with GC are eligible for registry participation. HDGC criteria: diffuse GC(< age 45), diffuse GC(< age 50) with 1 relative with GC, diffuse GC(any age) with 2 or more relatives with GC, or a personal or family history of diffuse GC with lobular breast cancer or signet ring colon cancer. Non-HDGC high risk pts: diagnosed < age 50 or with a family history of GC(at least one 1st degree or two 2nd degree relatives with GC), but do not meet HDGC criteria. Sporadic GC: diagnosed > age 50, without family history. Participants complete a family history and epidemiology/ risk factor questionnaire, and provide blood and tissue for repository. Results: 465 participants have enrolled since Jan 2006. Questionnaires are available from 331 participants(69%), see table . CDH1 mutations have been identified in 10 families(16%) and prophylactic gastrectomies in CDH1 mutation carriers have been performed in 8 pts, each without major complications. Pt demographics and epidemiology were not notably different amongst all groups. Conclusions: Except for age and histology, the demographic breakdown and epidemiology of HDGC pts with and without CDH1 mutation is similar to other non HDGC high genetic risk pts and similar to pts with sporadic GC. The GC registry will expand to international sites. (Supported by the DeGregorio Family Foundation) [Table: see text] No significant financial relationships to disclose.
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Wrubel, Erica, Saya Rene Dennis, Takahiro Tsukioki, Theresa Sciaraffa, Yuan Luo, and Seema A. Khan. "Abstract P2-09-15: Frequency of germline mutations in breast cancer susceptibility genes among women under age 50 presenting with parity associated breast cancer." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–09–15—P2–09–15. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-09-15.
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Abstract Background: Epidemiologic data have demonstrated an increased risk of breast cancer development following pregnancy which can last up to 10 years, particularly in women with older age at childbirth. The majority of women with parity associated breast cancer (PABC) undergo genetic testing based on their young age at onset, per current NCCN guidelines. Prior studies have evaluated the interaction of parity and germline BRCA1/2 mutation status, but these have not been extended to other pathogenic germline mutations in known breast cancer susceptibility genes (PALB2, TP53, PTEN, CDH1, CHEK2, ATM, and STK11). Our goal was to evaluate the prevalence of pathogenic germline mutations in a contemporary cohort of women less than 50 diagnosed with breast cancer in relation to their parity status and the time since their most recent pregnancy. Methods: The Northwestern Electronic Database Warehouse was queried for women diagnosed with a new breast cancer between 2010 - 2020 at the age of less than 50 and underwent genetic testing with results available. Patient demographic data, parity history, and genetic testing results were obtained from the structured electronic health records data as well as from semi-structured clinical notes using rule-based text mining methods. 929 women were identified with complete information on parity status, age at first birth, age at most recent birth, breastfeeding status, and germline mutation status. Statistical analyses included Pearson’s chi-square and logistic regression with adjustment for age at diagnosis. Results: 85 women (9.1%) had a germline genetic mutation, with the most prevalent mutations being BRCA1 (3.9%), BRCA2 (2.5%), CHEK2 (0.8%), PALB2 (0.6%) and ATM (0.5%). 90 women (9.7%) had a variant of uncertain significance (VUS) and were included in the no mutation group for analysis. There was no statistically significant difference between nulliparous and parous women in regard to likelihood of having a pathogenic germline genetic mutation (age-adjusted OR 0.85, CI 0.53 -1.29). Among parous women stratified by recency of pregnancy (<5 years, 5-10 years, and >10 years), there was an increased likelihood of having a germline genetic mutation with recency of pregnancy < 5 years (age adjusted OR 2.2, CI 1.07-3.75) compared to women with > 10 years since last pregnancy. Evaluation of each separate germline mutation demonstrated mixed results with CHEK2 mutations more likely with more recent pregnancy (age adjusted OR 3.58, CI 1.13 - 7.57), while PALB2 mutations were less likely with more recent pregnancy (age adjusted OR 0.72, CI 0.52-0.85). The remainder of the mutations were not statistically significantly different among nulliparous vs parous women or when stratified by recency of pregnancy. Conclusions: Nulliparous women with a new diagnosis of breast cancer under the age of 50 were equally as likely to have a germline genetic mutation compared to parous women. After adjusting for age, recency of pregnancy within 5 years of breast cancer diagnosis was associated with increased likelihood of having a germline genetic mutation. The influence of family history of cancer will be addressed in additional analyses. Our data suggest that these mutations may confer an increased risk of parity-associated breast cancer, but need confirmation in larger studies. Citation Format: Erica Wrubel, Saya Rene Dennis, Takahiro Tsukioki, Theresa Sciaraffa, Yuan Luo, Seema A Khan. Frequency of germline mutations in breast cancer susceptibility genes among women under age 50 presenting with parity associated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-15.
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Kelsen, David Paul, Kasmintan A. Schrader, Raya Khanin, Laura H. Tang, Erin E. Salo-Mullen, Kenneth Offit, Vijai Joseph, et al. "Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 4082. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.4082.
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4082 Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C>A(pro484his);c. 1792C>T (arg598ter);c. 1893dupA in exon 12;c. 1565+1G>A (IVS10+1G>A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible "second hit" is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.
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Vasas, Péter, and Patel Bijendra. "Genetic background and clinical features of the hereditary diffuse gastric cancer." Orvosi Hetilap 152, no. 28 (July 2011): 1105–9. http://dx.doi.org/10.1556/oh.2011.29160.
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With the development of the molecular biology more pathological condition have been identified (p53 mutation and breast cancer, Ret protooncogene point mutation and medullary thyroid cancer), which could lead to malignant disease. The recent advances in the molecular genetics lead to the recognition of the hereditary diffuse gastric cancer that inherited in a dominant autosomal manner with incomplete penetrance. About 25-30% of families fulfilling the criteria have germline mutation of the CDH1 gene coding the calcium-dependent E-cadherin protein. In confirmed cases, prophylactic gastrectomy suggested in the early adolescent age. Orv. Hetil., 2011, 152, 1105–1109.
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Pohl, Esther, Jan Hauke, Judit Horvath, Bernd Dworniczak, Andrea Gehrig, Dieter Niederacher, Norbert Arnold, et al. "NGS-based multi-gene panel analysis in BRCA1/2-negative breast and ovarian cancer families." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1526. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1526.
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1526 Background: 24% of familial breast cancer (BC) and/or ovarian cancer (OC) cases analyzed within the framework of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) are due to pathogenic mutations in the BRCA1 or BRCA2 genes. The population-specific mutation prevalence of non- BRCA1/2 genes associated with familial BC and/or OC is largely unknown and was determined in a large German cohort. Methods: Here, we present next-generation sequencing (NGS) data established from TruRisk (GC-HBOC-designed) or TruSight cancer gene panels. A cohort of 6,507 BRCA1/2-negative index cases fulfilling the inclusion criteria of the GC-HBOC for germline testing was analyzed. Illumina sequencing platforms were used and data analysis was carried out at each individual center using different analysis pipelines. Analysis of copy number variations (CNV) was not included in the present data evaluation. Results: By focusing on 8 confirmed BC/OC risk genes ( ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, TP53), the 6,507 cancer patients revealed 165 different deleterious variants in 378 unrelated mutation carriers (5.8%). We found a high prevalence of CHEK2 (n = 150, 2.3%), ATM (n = 89, 1.4% ), and PALB2 (n = 72, 1.1%) mutations while RAD51C (n = 21, 0.3%), TP53 (n = 16, 0.2%), NBN (n = 15, 0.2%), CDH1 (n = 10, 0.2%), and RAD51D (n = 5, 0.1%) were less frequently mutated. Conclusions: The high frequency of pathologic mutations in the genes ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53, together accounting for almost 6% of familial BC/OC risk, highlights the importance of these genes to be included in BC/OC routine diagnostics. The relevance of these mutations in a clinical setting for early detection of breast and ovarian cancer needs to be established.
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Hernandez, Jonathan, Michael A. Turner, Prerna Bali, Mojgan Hosseini, Michael Bouvet, Kaitlyn Kelly, and Marygorret Obonyo. "Genomically Silent Refractory Gastric Cancer in a Young Patient Exhibits Overexpression of CXCL5." Current Oncology 29, no. 7 (July 6, 2022): 4725–34. http://dx.doi.org/10.3390/curroncol29070375.
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Gastric cancer is the third leading cause of cancer-related deaths, with more than one million new cases and approximately 841,000 deaths annually worldwide. We report a case of a young patient (25 years old) with an aggressive form of gastric cancer. The patient had previously been treated for Helicobacter pylori (H. pylori), which is a main risk factor for developing gastric cancer. Genetic testing showed an E-cadherin (CDH1) germline mutation of unknown significance. After eight cycles of chemotherapy, a positron emission tomography (PET) scan showed disease progression with an enlarging hypermetabolic right adnexal mass suspicious for metastatic disease. Tumor pathology demonstrated invasive and poorly differentiated gastric carcinoma. The analysis of the tumor biopsy indicated the very high expression of a chemokine, C-X-C motif chemokine 5 (CXCL5). The combination of H. pylori infection with an existence of a rare CDH1 mutation could have contributed to this aggressive gastric cancer.
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Vietri, Maria Teresa, Giovanna D’Elia, Gemma Caliendo, Luisa Albanese, Giuseppe Signoriello, Claudio Napoli, and Anna Maria Molinari. "Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation." Genes 13, no. 2 (February 9, 2022): 321. http://dx.doi.org/10.3390/genes13020321.
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Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband’s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.
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Haverkamp, L., P. C. van der Sluis, M. G. E. M. Ausems, S. van der Horst, P. D. Siersema, J. P. Ruurda, G. J. A. Offerhaus, and R. van Hillegersberg. "Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation." Journal of Gastrointestinal Surgery 19, no. 12 (October 6, 2015): 2120–25. http://dx.doi.org/10.1007/s11605-015-2963-4.
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Salem, Mohamed E., Lisa Amacker-North, Mariah Gleason, Aly Athens, William Mills Worrilow, Lindsay McNeely, Katherine Broyhill, Alberto Puccini, Edward S. Kim, and Sara Elrefai. "Landscape of germline mutations in 1144 patients (Pts) with gastrointestinal (GI) cancers." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13660-e13660. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13660.
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e13660 Background: The efficacy of PARP inhibitors in germline BRCA-mutated pancreatic adenocarcinoma (PC) and immune checkpoint inhibitors in dMMR colorectal cancer (CRC) shows the importance of genetic testing. We aimed to characterize the frequency of pathogenic/likely pathogenic germline variants (PLPVs) in GI cancer pts. Methods: A retrospective review of pts referred to the Levine Cancer Institute Genetics Program was conducted. Genetic testing used a focused hereditary cancer 4-43 gene panel or pan-cancer 82-84 gene panel. Results: Out of 1144 GI cancer pts seen between 2010 and 2019, 869 underwent germline testing, and 199 (23%) pts had at least one PLPV in a hereditary cancer susceptibility gene, while 253 (29.3%) had a variant of uncertain significance. Of 630 CRC pts, 24% had a PLPV and 13% harbored a germline mutation in DNA MMR genes and were diagnosed with Lynch Syndrome, representing ~50% of all pts with a PLPV. Other germline PLPVs were found in APC, ATM, BRCA1, BRCA2, CHEK2, MUTYH, and PALB2. Of 163 PC pts, 16.6% had a PLPV in ATM, BRCA2, CDKN2A, and MEN1. Gastric cancer pts (17%) had germline PLPVs in APC, BRCA2, CDH1, MLH1, and MSH2; biliary cancer pts (17%) had germline PLPVs in PALB2, RAD50, and PTCH1; and GIST pts (60%) had PLPVs in SDHA or SDHB. Conclusions: Germline mutations were found in 23% of GI cancer pts, underlining the importance of multigene germline testing. Knowledge of inherited GI cancer risk helps determine the likelihood of benefit from possible specific targeted therapies. Genetic testing and counseling pose a challenge, but implications for pts with hereditary syndromes are highly significant. [Table: see text]
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Hall, Michael J., Olufunmilayo I. Olopade, Mary Beryl Daly, and Sonia Kupfer. "Germline ATM mutations in families with early-onset and familial gastroesophageal and colorectal cancers." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 11. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.11.
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11 Background: ATM is involved in repair of DNA damage due to radiation and environmental toxins via downstream interaction with CHEK2, BRCA1, and other proteins involved in double strand break repair. Mutations in ATM (Ataxia-Telangiectasia Mutated, 11q22) are among the most common hereditary cancer risk mutations in the general population (0.5-1.0% carrier rate), yet beyond risks of breast (BC) and pancreatic cancer (PC), the spectrum of clinically relevant cancer risks in ATM+ individuals remains uncertain. Thompson (JNCI 2005) previously reported possible risk of colorectal (CRC) (RR 2.54; 1.06-6.09) and gastric cancer (GC)(RR 3.39; 0.86-13.4) in ATM+ individuals, while more recently Hansford (JAMA Onc 2015) performed panel gene testing including CDH1 in patients meeting criteria for hereditary diffuse gastric cancer, and found possibly pathogenic ATM mutations in 3/144 (2%) CDH1-negative probands. In addition to GC, families contained multiple cases of BC, PC and CRC (5 cases, 2 < 50). To further describe the frequency of upper and lower GI cancer in ATM+ families, we reviewed pedigrees from 20 families seen for risk assessment in two high-risk clinics and found to have germline ATM mutations. Methods: Pedigrees from ATM+ families evaluated at Fox Chase Cancer Center and the University of Chicago are included in this analysis. Cancer type, age at diagnosis, number of genes clinically tested, and ATM mutation were collected. Cancers < 50 yrs are considered early-onset. Results: Among 20 total ATM+ families, 22 GI cancers were reported, with 5 families containing 16/22 (73%) of all GI cancers (see Table). Early-onset GI cancers were common in the 5 families (7/16, 44%), including 2/6 (33%) cases of GC, a 23 yr old man and his 45 yr old father both with GEJxn cancer (2/2, 100%), and 3/6 (50%) cases of CRC all from one large family. Conclusions: Our data lend evidence to support the need for early CRC and GC screening in ATM+ patients. [Table: see text]
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Bücker, Lara, and Ulrich Lehmann. "CDH1 (E-cadherin) Gene Methylation in Human Breast Cancer: Critical Appraisal of a Long and Twisted Story." Cancers 14, no. 18 (September 8, 2022): 4377. http://dx.doi.org/10.3390/cancers14184377.
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Epigenetic inactivation of a tumor suppressor gene by aberrant DNA methylation is a well-established defect in human tumor cells, complementing genetic inactivation by mutation (germline or somatic). In human breast cancer, aberrant gene methylation has diagnostic, prognostic, and predictive potential. A prominent example is the hypermethylation of the CDH1 gene, encoding the adhesion protein E-Cadherin (“epithelial cadherin”). In numerous publications, it is reported as frequently affected by gene methylation in human breast cancer. However, over more than two decades of research, contradictory results concerning CDH1 gene methylation in human breast cancer accumulated. Therefore, we review the available evidence for and against the role of DNA methylation of the CDH1 gene in human breast cancer and discuss in detail the methodological reasons for conflicting results, which are of general importance for the analysis of aberrant DNA methylation in human cancer specimens. Since the loss of E-cadherin protein expression is a hallmark of invasive lobular breast cancer (ILBC), special attention is paid to CDH1 gene methylation as a potential mechanism for loss of expression in this special subtype of human breast cancer. Proper understanding of the methodological basis is of utmost importance for the correct interpretation of results supposed to demonstrate the presence and clinical relevance of aberrant DNA methylation in cancer specimens.
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Shin, Saeam, Yoonjung Kim, Jin Kyung Lee, and Kyung-A. Lee. "Frequency and Clinical Characteristics of Unselected Korean Gastric Cancer Patients with a Germline CDH1 V832M Mutation." Journal of Cancer 11, no. 1 (2020): 208–12. http://dx.doi.org/10.7150/jca.36513.
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Gasperoni, Silvia, Laura Papi, Francesca Castiglione, Francesca Gensini, Roberta Sestini, Luca Messerini, Caterina Bartoli, et al. "Germline mutations in MSH2 and ATM gene in patients with GIST (gastrointestinal stromal tumor) and second epitelial tumors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e23520-e23520. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e23520.
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e23520 Background: In adult GISTs are frequently sporadic, while rarely GISTs are linked to Carney Triad and Carney-Stratakis Syndrome and NF1. GISTs with second primary tumors are reported in 4-33% of patients in literature and genetic counseling is suggested to explore an underlying germline mutations pathway. Methods: In our Academic Hospital Centre (EURACAN member) in Florence, Italy, we are following patients with GIST and multiple primary tumors with genetic counseling (72 GISTs with second tumors/185 patients with GIST) and germline analysis of the following genetic panel is performed as clinically indicated: BRCA1, BRCA2, MUTYH, MLH1, MSH2, MSH6, CDH1, ATM, TP53, PTEN, CHECK2, PALB2, BARD1, BRIP1, BLM, RAD51C, RAD51D, XRCC2, PMS2, MRE11A, RAD50, NBN, FAM175A, EPKAM, TSK1, MEN1 by sequencing analysis with Illumina MiSeq by kit multiplicom BRCA Hereditary cancer Mastr plus, and bioinformatic analysis by software SOPHIADDM (Sophia genetics) for point genetic alterations of BRCA1 NM_007294.3, BRCA2 NM_000059.3, MUTYH NM_000249, MSH2 NM_000251, MSH6 NM_000179, CDH1 NM_00444360, ATM NM_000051, TP53 NM_000546, PTEN NM_000314, CHEK2 NM_001005735, PALB2 NM_024675, BARD1 NM_000465, BRIP1 NM_032043, BLM NM_000057, RAD51C NM_002876, RAD51D NM_001142571, XRCC2 NM_005431, PMS2 NM_000535, MRE11A NM_005590, RAD50 NM_006732, NBN NM_002485, FAM175A NM_139076, EPCAM NM_002354, STK1 NM_000455, MEN1 NM_000244 and MLPA (Multiplex Ligation-dependent Probe Amplification) test analysis for patients with kit P087-BRCA1,P045-BRCA2(CHEK2, P248-MLH1-MSH2, P003-MLH1/MSH2, P072-MSH6-MUTYH (MRC-Holland). Results: In 3 patients germline mutations have been observed: 1 patient showed the c.1192dupG, p.(Ala398Glyfs*19) pathogenic mutation in exon 7 of MSH2 gene, confirmed by Sanger Sequencing, 1 patient showed c.565-?_1130+?del mutation consisting in heterozygous 3-4-5-6 exons deletion of MSH2 gene, confirmed by MLPA analysis, and in 1 patient the following ATM alteration has been identified in heterozygosis: ATM c.5319+2T > C, p.(?). In the 2 patients with Lynch syndrome with colon adenocarcinoma (MSI-H), synchronous GISTs (1 patient quadruple WT and 1 patient kit ex 11 mutated ) were diagnosed; in the patient with ATM mutation, the diagnosis of GIST (kit ex 11 mutated) occurred after prostate adenocarcinoma and before colon adenocarcinoma (MSI-H). Conclusions: Our analysis suggests that GIST diagnosis could be tumor-related to multiple hereditary tumor syndromes as Lynch Syndrome and Ataxia-Teleangectasia syndrome, the latter being linked in eterozygosis to tumor susceptibility to breast in female. This report represents a high value in terms of genetic counseling for relatives and in terms of therapeutic implications for the patients.
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Benesch, Matthew G. K., Stuart R. Bursey, Andrew C. O’Connell, Morag G. Ryan, Carrie L. Howard, Cecily C. Stockley, and Alexander Mathieson. "CDH1 Gene Mutation Hereditary Diffuse Gastric Cancer Outcomes: Analysis of a Large Cohort, Systematic Review of Endoscopic Surveillance, and Secondary Cancer Risk Postulation." Cancers 13, no. 11 (May 26, 2021): 2622. http://dx.doi.org/10.3390/cancers13112622.
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Hereditary diffuse gastric cancer (HDGC) is a rare signet-ring cell adenocarcinoma (SRCC) linked to CDH1 (E-cadherin) inactivating germline mutations, and increasingly other gene mutations. Female CDH1 mutation carriers have additional risk of lobular breast cancer. Risk management includes prophylactic total gastrectomy (PTG). The utility of endoscopic surveillance is unclear, as early disease lacks macroscopic lesions. The current systematic biopsy protocols have unknown efficacy, and other secondary cancer risks are postulated. We conducted a retrospective study of consecutive asymptomatic HDGC patients undergoing PTG, detailing endoscopic, pathologic, and outcome results. A systematic review compared endoscopic biopsy foci detection via random sampling versus Cambridge Protocol against PTG findings. A population-level secondary-cancer-risk postulation among sporadic gastric SRCC patients was completed using the Surveillance, Epidemiology, and End Results database. Of 97 patients, 67 underwent PTG, with 25% having foci detection on random endoscopic biopsy despite 75% having foci on final pathology. There was no improvement in the endoscopic detection rate by Cambridge Protocol. The postulated hazard ratio among sporadic gastric SRCC patients for a secondary colorectal SRCC was three-fold higher, relative to conventional adenocarcinoma patients. Overall, HDGC patients should not rely on endoscopic surveillance to delay PTG, and may have secondary SRCC risks. A definitive determination of actual risk requires collaborative patient outcome data banking.
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Adedokun, B., Y. Zheng, P. Ndom, A. Gakwaya, T. Makumbi, A. Sallam, O. Olopade, and D. Huo. "Prevalence and Spectrum of Breast Cancer Inherited Mutations in Uganda and Cameroon Women." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 43s. http://dx.doi.org/10.1200/jgo.18.60600.
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Background: Breast cancer among indigenous Africans is characterized by higher prevalence of triple-negative disease and poor prognosis. A previous study in Nigeria reported a strikingly high prevalence of deleterious germline mutations in BRCA1 and BRCA2 among Nigerian women with breast cancer. It is unknown if this is true in other sub-Saharan African countries. Aim: The objective of this study is to determine the frequency of germline mutations among an unselected sample of women in Africa. Methods: We conducted a case-control study of breast cancer in Uganda and Cameroon to investigate genetic and nongenetic risk factors for breast cancer. Breast cancer cases were enrolled in two tertiary hospitals in the two countries, unselected for age at diagnosis and family history. Controls who were free of breast cancer were enrolled in the same hospitals and matched to cases on age. A 24-gene sequencing panel was used to test germline mutations in cases and controls. Results: There were 176 cases and 177 controls with a mean age at diagnosis of 46.2 years for cases and mean age at interview of 46.7 years for controls. Among cases, 18.2% carried a pathogenic mutation in a breast cancer gene: 6.3% in BRCA1, 6.3% in BRCA2, 1.7% in ATM, 1.1% in PALB2, 0.6% in BARD1, 0.6% in CDH1, 0.6% in TP53, and 1.2% in any of 17 other genes. Among controls, 2.3% carried a pathogenic mutation in one of the 24 susceptibility genes. Cases were 9.6-fold more likely to carry a mutation compared with controls (odds ratio=9.61, 95% confidence interval: 3.28-38.1; P < 0.001). The mean age of breast cancer cases with pathogenic BRCA1 mutations was 38.3 years compared with 46.7 years among other cases without such mutations ( P = 0.03). There was a trend that cases with a positive family history had higher chance of carrying a mutation (33.3%) than cases without (17.1%), but few cases reported a positive family history. Conclusion: Our findings confirm the earlier report of a high proportion of deleterious mutations in BRCA1 and BRCA2 among breast cancer patients in sub-Saharan Africa. As most of these women present with advanced breast cancer, there is an urgent need to improve access to genomic testing and life saving cancer medicines including chemotherapy and clinical trials of novel agents like PARP inhibitors. Given the high burden of inherited breast cancer, genetic risk assessment should be integrated into cancer control plans in sub-Saharan Africa.
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Choi, Hyun-Jung, Chang-Seok Ki, Soon-Pal Suh, and Jong-Won Kim. "Presymptomatic Identification of CDH1 Germline Mutation in a Healthy Korean Individual with Family History of Gastric Cancer." Annals of Laboratory Medicine 34, no. 5 (September 1, 2014): 386–89. http://dx.doi.org/10.3343/alm.2014.34.5.386.
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Garziera, Marica, Valli De Re, Silvano Geremia, Raquel Seruca, Joana Figueiredo, Soraia Melo, Joana Simões-Correia, et al. "A novel CDH1 germline missense mutation in a sporadic gastric cancer patient in north-east of Italy." Clinical and Experimental Medicine 13, no. 2 (April 29, 2012): 149–57. http://dx.doi.org/10.1007/s10238-012-0184-7.
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Ku, Geoffrey Yuyat, Semanti Mukherjee, Chizoba Okoro, Medha Sharma, Vignesh Ravichandran, Kenneth Offit, Vijai Joseph, Yelena Yuriy Janjigian, Zsofia Kinga Stadler, and David Paul Kelsen. "Targeted next-generation sequencing (NGS) of germline DNA to identify genetic predisposition to gastric cancer (GC) in patients with CDH1-mutation negative early-onset (EO) or familial GC (FGC)." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 20. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.20.
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20 Background: While GC arises as part of several hereditary cancer syndromes, a genetic etiology is not identified for most FGC kindreds and EOGC patients. We hypothesize that NGS of germline DNA may reveal previously unsuspected genomic alterations that predispose to EOGC/FGC. Methods: We identified 42 Pts from a prospective GC registry with CDH1-mutation negative EOGC (≤50 years old) and/or with FGC. Germline DNA was analyzed by MSK-IMPACT, a 468-gene targeted NGS panel that includes > 70 genes associated with known cancer predisposition syndromes. GATK HaplotypeCaller (HTC) was used to call SNVs and Indels simultaneously from the sequence read data and joint calling of all samples was used to generate VCF files. We annotated the VCF with public annotators and public allele frequencies from large sequencing studies. Manual variant curation was performed and were classified by ACMG criteria (Genet Med 2015;17:405), with only likely pathogenic and pathogenic variants included. Results: 41 Pts (98%) had early onset and 11 Pts (26%) had FGC (9 had ≥1 1st or 2nd degree relatives with GC). Median age was 40 (range, 18 to 55) and 23 (55%) were men. Ethnicities were 21 (50%) White, 13 (31%) Black, 6 (14%) Asian and 2 (5%) unknown. 40 (95%) had poorly differentiated and/or diffuse histology. Pathogenic mutations were diagnosed in 4 Pts (10%). 1 Pt had a BRCA2 mutation; his father had prostate CA and a paternal aunt had breast CA but he did not meet current NCCN criteria for BRCA testing. Three additional pathogenic mutations were FGFR1, SOX17 and KMT2D; none has previously been described in GC susceptibility but are associated with GC carcinogenesis. All 3 Pts had EOGC. None had FGC but all 3 had ³1 1st-degree relative with CA ( FGFR1: breast, uterine, appendix; SOX17: breast; KMT2D: osteosarcoma). Further functional work of these variants and segregation analysis is on-going. Conclusions: MSK-IMPACT identified germline mutations in 10% of Pts; most are previously not known GC predisposition genes. NGS can be an important clinical tool for screening multiplex families and also a research tool for discovering genes that predispose to GC.
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Hall, Evan Thomas, Divya Ahuja Parikh, Tanya Gupta, Jennifer Lee Caswell, Meredith Mills, Kerry Kingham, Rachel Koff, James M. Ford, and Allison W. Kurian. "Pathogenic germline mutations in emerging cancer genes: What happens after panel testing?" Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 1528. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.1528.
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1528 Background: Next-generation sequencing technology enables more comprehensive germline genetic testing, including genes whose cancer risks are less well-characterized (particularly among patients with less striking family histories). Little is known about patient outcomes, particularly adherence to risk-reducing recommendations and family testing. Methods: We attempted a phone interview ≥3 times with each adult patient who had a germline pathogenic or likely pathogenic mutation found in an emerging cancer gene (defined as any gene other than BRCA1/2 or the Lynch Syndrome genes MLH1, MSH2/6, PMS2) at a single academic cancer genetics clinic from January 2013-July 2016. Results: Of 143 eligible patients, 53 (37%) were successfully contacted and all consented to participate. Median follow-up was 677 days (range 247–1401) and age was 52 years (21-82). Two-thirds (68%) had personal cancer history and 93% had a first-degree relative with cancer. Mutations in genes associated with named syndromes ( APC=5 , CDH1=3 , TP53=3, PTEN=2) were found in 23% (many of whom lacked family history typical of these syndromes) whereas 77% had mutations in less well-characterized genes ( MYH=10, CHEK2=10, ATM=6, PALB2=6 , NBN=3, RAD51C=2, RAD51D=2, SDHB=1, CDKN2A=1, MRE11A=1, RAD50=1, FLCN=1). Conclusions: Two years after panel testing, patients with germline mutations in less well-characterized genes reported high rates of adherence to recommendations, family communication and testing. Limitations include a relatively low response rate and a single academic center; this may bias toward a “best-case” scenario. Larger, population-based studies will be crucial to understand the real-world outcomes of germline multiple-gene panel testing and its contribution to precision oncology. [Table: see text]
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Stout, Leigh Anne Anne, Nawal Kassem, Cynthia Hunter, Santosh Philips, Milan Radovich, and Bryan P. Schneider. "Identification of germline cancer predisposition variants during clinical ctDNA testing." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15555-e15555. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15555.
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e15555 Background: Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. Identification of inherited germline cancer predisposition mutations that have significant implications for at-risk relatives may be missed during routine ctDNA testing. Allele frequency has the potential to enhance the likelihood that a mutation is germline; and is often reported in many NGS tests from ctDNA. Here, we report on the fidelity of allele frequency in ctDNA as a predictor for pathogenic germline variant carriage. Methods: ctDNA sequencing of patients with metastatic cancer from the Indiana University Health Precision Genomics Program was performed using the FoundationOne Liquid assay. All variants detected by the ctDNA assay report were considered. All patients also had germline testing information and pathogenicity of germline variants were determined using ClinVar. Germline variants with conflicting interpretations were manually reviewed to determine pathogenicity. Comparisons between ctDNA results with known germline status were performed. Results: Of 91 previously identified germline cancer predisposition variants, 36 (40%) were also identified by ctDNA analysis. All germline variants that were tested for in the ctDNA assay (n = 36, 100%) were identified. When detected, the allele frequencies of detected germline variants in the ctDNA ranged from 39-87.6% with an average of 52.1%. Conversely, 111 of 160 (69%) variants identified by ctDNA analysis with allele frequency between 40-60% in a cancer predisposition gene were found to be germline in origin (regardless of pathogenicity). Variants in the BRCA2, BRCA1, and CDH1 genes were most likely to be germline in origin (26/27 [96%], 20/22 [91%], 13/15 [87%], respectively). Variants in the TP53 and APC genes were least likely to be germline in origin (9/36 [25%] and 1/6 [17%], respectively). There was an 85% (95/111) concordance in actionability between the somatic testing lab and ClinVar germline classifications. Of the 16 discordant variants, 100% were determined to be actionable by the somatic testing lab but not actionable in ClinVar. Conclusions: ctDNA allele frequency can alter the likelihood that a variant is germline. Importantly, however, this testing is far from comprehensive and should not be used as a replacement for germline testing. Variants with allele frequency between 40-60% in cancer predisposition genes should induce a high level of suspicion for germline status.