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Hutton, Michael. « ?Missing ? tau mutation identified ». Annals of Neurology 47, no 4 (avril 2000) : 417–18. http://dx.doi.org/10.1002/1531-8249(200004)47:4<417 ::aid-ana1>3.0.co;2-b.
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Pawlik, Timothy M., Darrell R. Borger, Yuhree Kim, David Cosgrove, Sorin Alexandrescu, Ryan Thomas Groeschl, Vikram Deshpande et al. « Genomic profiling of intrahepatic cholangiocarcinoma : Refining prognostic determinants and identifying therapeutic targets. » Journal of Clinical Oncology 32, no 3_suppl (20 janvier 2014) : 210. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.210.
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210 Background: The molecular alterations that drive tumorigenesis in intrahepatic cholangiocarcinoma (ICC) remain poorly defined. We sought to define the incidence and prognostic significance of mutations associated with ICC among patients undergoing surgical resection. Methods: 138 patients who underwent resection at 6 centers in the United States and Europe were included in the cohort. Mutational profiling was performed using nucleic acids that were extracted from resected ICC tumor specimens; mutations were identified using a multiplexed mutational profiling platform. The frequency of mutations was ascertained and the impact on outcome determined. Results: Most patients had a solitary tumor (82%) and median tumor size was 6.0cm. Most patients had R0 resection (89%); 19% patients had N1 disease, while 15% had microscopic vascular invasion. A minority received adjuvant therapy (30%). The majority (55%) of patients had no genetic mutation identified. Among the 62 (45%) patients with a genetic mutation, only a small number of gene mutations were identified with a frequency of >5%: IDH1 (17.4%), KRAS (8.7%), BRAF (5.8%), PIK3CA (5.1%). In contrast, other genetic mutations were identified in very low frequency: IDH2 (3.6%), NRAS (3.6%), TP53 (2.2%), MAP2K1 (1.5%), CTNNB1 (0.7%), and PTEN (0.7%). Approximately 7% of IDH1-mutant tumors were associated with a concurrent PIK3CA gene mutation, and to a much lower extent, a mutation in MAP2K1 (2%). No concurrent mutations in IDH1 and KRAS were noted. Compared with ICC tumors that had no identified mutation, IDH1-mutant tumors were more often bilateral (OR 3.46), while KRAS-mutant tumors were more likely to be associated with perineural invasion (OR 5.72)(both P<0.05). While clinicopathological features such as tumor number and nodal status were associated with survival, no specific mutation was associated with prognosis. Conclusions: Most patients with resected ICC had no somatic mutation identified on multiplexed mutational profiling. IDH1 and KRAS were the most common mutations noted. While certain mutations were associated with ICC clinicopathological features, mutational status did not seemingly impact long-term prognosis.
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Dutta, Ravi Kumar, Thomas Arnesen, Anette Heie, Martin Walz, Piero Alesina, Peter Söderkvist et Oliver Gimm. « A somatic mutation in CLCN2 identified in a sporadic aldosterone-producing adenoma ». European Journal of Endocrinology 181, no 5 (novembre 2019) : K37—K41. http://dx.doi.org/10.1530/eje-19-0377.
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Objective To screen for CLCN2 mutations in apparently sporadic cases of aldosterone-producing adenomas (APAs). Description Recently, CLCN2, encoding for the voltage-gated chloride channel protein 2 (ClC-2), was identified to be mutated in familial hyperaldosteronism II (FH II). So far, somatic mutations in CLCN2 have not been reported in sporadic cases of APAs. We screened 80 apparently sporadic APAs for mutations in CLCN2. One somatic mutation was identified at p.Gly24Asp in CLCN2. The male patient had a small adenoma in size but high aldosterone levels preoperatively. Postoperatively, the patient had normal aldosterone levels and was clinically cured. Conclusion In this study, we identified a CLCN2 mutation in a sporadic APA comprising about 1% of all APAs investigated. This mutation was complementary to mutations in other susceptibility genes for sporadic APAs and may thus be a driving mutation in APA formation.
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Lowstuter, Katrina, Carin R. Espenschied, Duveen Sturgeon, Charité Ricker, Rachid Karam, Holly LaDuca, Julie O. Culver et al. « Unexpected CDH1 Mutations Identified on Multigene Panels Pose Clinical Management Challenges ». JCO Precision Oncology, no 1 (novembre 2017) : 1–12. http://dx.doi.org/10.1200/po.16.00021.
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Purpose Mutations in the CDH1 gene confer up to an 80% lifetime risk of diffuse gastric cancer and up to a 60% lifetime risk of lobular breast cancer. Testing for CDH1 mutations is recommended for individuals who meet the International Gastric Cancer Linkage Consortium (IGCLC) guidelines. However, the interpretation of unexpected CDH1 mutations identified in patients who do not meet IGCLC criteria or do not have phenotypes suggestive of hereditary diffuse gastric cancer is clinically challenging. This study aims to describe phenotypes of CDH1 mutation carriers identified through multigene panel testing (MGPT) and to offer informed recommendations for medical management. Patients and Methods This cross-sectional prevalence study included all patients who underwent MGPT between March 2012 and September 2014 from a commercial laboratory (n = 26,936) and an academic medical center cancer genetics clinic (n = 318) to estimate CDH1 mutation prevalence and associated clinical phenotypes. CDH1 mutation carriers were classified as IGCLC positive (met criteria), IGCLC partial phenotype, and IGCLC negative. Results In the laboratory cohort, 16 (0.06%) of 26,936 patients were identified as having a pathogenic CDH1 mutation. In the clinic cohort, four (1.26%) of 318 had a pathogenic CDH1 mutation. Overall, 65% of mutation carriers did not meet the revised testing criteria published in 2015. All three CDH1 mutation carriers who had risk-reducing gastrectomy had pathologic evidence of diffuse gastric cancer despite not having met IGCLC criteria. Conclusion The majority of CDH1 mutations identified on MGPT are unexpected and found in individuals who do not fit the accepted diagnostic testing criteria. These test results alter the medical management of CDH1-positive patients and families and provide opportunities for early detection and risk reduction.
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Zhu, Xiaoqiong, Xingnong Ye, Chen DAN et Jian Huang. « Uncommon Hpgd Mutation Identified in Familial Erythrocytosis ». Blood 138, Supplement 1 (5 novembre 2021) : 4627. http://dx.doi.org/10.1182/blood-2021-145881.
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Abstract Familial erythrocytosis (congenital erythrocytosis, FE), is a rare congenital disorder defined by elevated hemoglobin and hematocrit, with different genetic background. Clinically, FE is difficult to distinguish from polycythemia vera（PV）. A 53-years-old male was diagnosed with polycythemia vera without discovery of the JAK2 mutation when he was 31-years-old. The patient's family history revealed his father， a 86-years-old male， also suffered polycythemia for more than 20 years. The pedigree of the Chinese family with erythrocytosis is shown in Figure 1a. The index patient was a 53-years-old male (patient Ⅱ-1, Fig.1), who was hospitalized in our department in 2019 with a 22-year history of elevated red cell mass (RCM). When he was 31-years-old, he initially diagnosed with polycythemia vera without discovery of the JAK2 mutation. Over the last two decades he had irregular phlebotomy almost every two years and seldom prescribed any cytoreductive treatment. At our department he accepted 2 venesections because of Hct level of 64%. Upon medical history taking he reported that his father had suffered by polycythemia with more than 20 years, and were undergoing occasional phlebotomies.The father of the index patient was a 86-years-old male (patient Ⅰ-1, Fig.1), who was diagnosed with polycythemia for more than 20 years and suffered from diabetes. Similar to his son, he did not use any cytoreductive agent, and he had been phlebotomized occasionally. He was chronically treated with low-dose of aspirin . In our department he was treated with erythrocyte separation because of Hct level of 58.9%. He did not report any thrombembolic event. For the last one year of follow-up, the patient continued taking aspirin and her Hct level fluctuated between 54% and 57% while rejected to receive erythrocyte separation again.The elder sister (subject Ⅱ-2 Fig.1) of the index patient did not have any clinical and laboratory signs of elevated RCM as of January 2019, she was a 57-years-old female, who suffered from hypertension and diabetes.The daughter (subject Ⅲ-1 Fig.1) and the nephew (subject Ⅲ-2 Fig.1) of the index patient also did not have any clinical and laboratory signs of elevated RCM as of January 2019. They were subjected to whole exome sequencing (WES), the results revealed four mutations in all three of them, among, a frameshift mutation in the 15-hydroxyprostaglandin dehydrogenase（HPGD） gene is contained in both father and son, which at position c.310_311 ,translating into c.310_311delCT nucleotide mutation and p.L104Afs*3 amino acid mutation. In order to verify the mutation, we adopt the method of Sanger sequencing, then confirmed the presence of the same HPGD frameshift mutation in the index patient and his father. However, The mutation was absent in the elder sister of the index patient, when she was examined by WES and Sanger sequence. The ARHGAP26 mutation is contained in all three of them, but is a type of somatic mutation. The two mutations of VHL and FANCD2 are inexistent in the index patient, but are contained in his father and his elder sister. In conclusion, here we reported the first extensive genetic and clinical study of a family with two members carrying the HPGD gene frameshift mutation. Although functional studies were not made to confirm the pathogenic role of this mutation, the type and location of the mutation suggest that it can be the cause of the erythrocytosis observed in two patients. This study demonstrated the utility of the WES/NGS as the tool for identification of mutations in congenital erythrocytosis as well as helps to discovery these rare erythrocytosis-associated genes. The role and pathogenesis in haematopathy of HPGD mutation has been seriously underestimated, which is deserved to be explored in depth. Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Bradbury, Jane. « Canine epilepsy gene mutation identified ». Lancet Neurology 4, no 3 (mars 2005) : 143. http://dx.doi.org/10.1016/s1474-4422(05)01004-5.
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BRADBURY, J. « Canine epilepsy gene mutation identified ». Lancet Neurology 4, no 3 (mars 2005) : 143. http://dx.doi.org/10.1016/s1474-4422(05)70010-7.
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Shi, Zhongxun, Bing Li, Tiejun Qin, Zefeng Xu, Lijuan Pan, Shiqiang Qu, Gang Huang et Zhijian Xiao. « Clonal Architecture Analysis of TET2 Identified Distinct Origins in Myelodysplastic Syndromes ». Blood 136, Supplement 1 (5 novembre 2020) : 18. http://dx.doi.org/10.1182/blood-2020-139329.
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Next-generation sequencing (NGS) has deepened our understanding of myelodysplastic syndromes (MDS). Genetic mutations of TET2 were common in MDS and were also detected in asymptomatic elder persons, which were defined as aged related clonal haematopoiesis (ARCH) and considered as a myelodysplastic syndrome precursor state. In this study, we analyzed the mutation profiles of TET2 in 770 newly-diagnosed MDS subjects. 73 mutations were found in 67 of 770(8.7%) subjects. 14.9% were frame shifts, 29.9% were nonsense, 44.8% were missense and 10.7% harbored 2 TET2 mutations. TET2MT subjects were older than TET2WT subjects (P=0.024) and the variant allele frequency (VAF) of TET2 was positively correlated with age (r=0.318, P=0.009). Clonal architecture was determined using a copy number-adjusted VAF difference between 2 mutation events in 49 TET2MT subjects with 2 or more mutations. 19 (38.3%) were TET2ancestral and 30(61.2%) were TET2subclonal. TET2ancestral subjects were significantly older than TET2WT subjects (P=0.013) while no difference was found between TET2subclonal subjects and TET2WT subjects (P=0.509). The frequency of cytosine-to-thymine (C→T) transition was significantly higher in TET2ancestralsubjects compared with TET2subclonal subjects (P=0.029), which was considered to be a somatic mutational signature of aging, indicating that MDS driven by TET2ancestral was likely derived from TET2MT ARCH. The most common upstream mutations in TET2subclonal subjects were U2AF1 (16.7%) and ASXL1 (13.3%), and the most common downstream mutations in TET2ancestral subjects were ASXL1 (21.1%) and RUNX1 (15.8%). TET2 mutations rarely existed alone in TET2ancestral subjects (14.3%) and were always accompanied by another mutations like U2AF1, SF3B1 and ASXL1, suggesting that the acquisition of another mutation led to the progress of ARCH to MDS in TET2ancestral subjects. TET2MT had no impact on survivals in overall cohort (P=0.218) while predicted poorer survivals in IPSS-R lower risk group (P=0.004). Additional ASXL1, U2AF1 and RUNX1 mutations in TET2MT subjects indicated poorer prognosis compared with TET2WT subjects (P=0.005; P=0.04; P<0.001) .There was no significant difference in OS of TET2MT subjects with different clonal architecture (P=0.76). Subjects with TET2 VAF≥30% had poorer survivals compared with TET2WT subjects (P=0.057). In conclusion, TET2MT MDS subjects with different clonal architectures may have different origins. TET2ancestral subjects may be derived from ARCH and progressed to MDS after secondary hits. The effects of TET2 mutation on the prognosis depended on the accompanying mutations and clonal burdens. Disclosures No relevant conflicts of interest to declare.
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Claes, Kathleen, Eva Machackova, Michel De Vos, Bruce Poppe, Anne De Paepe et Ludwine Messiaen. « Mutation Analysis of the BRCA1 and BRCA2 Genes in the Belgian Patient Population and Identification of a Belgian Founder Mutation BRCA1 IVS5+3A>G ». Disease Markers 15, no 1-3 (1999) : 69–73. http://dx.doi.org/10.1155/1999/241046.
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Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in “sporadic” patients with early onset disease. We completed the analysis in 49 families and in 19 “sporadic” female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.
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Percy, Melanie J., F. G. C. Jones, T. R. J. Lappin et M. F. McMullin. « Mutations in the VHL Gene Are the Major Identified Cause of Inherited Erythrocytosis. » Blood 106, no 11 (16 novembre 2005) : 569. http://dx.doi.org/10.1182/blood.v106.11.569.569.
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Abstract The molecular basis of inherited erythrocytosis in most patients remains to be defined. Although all such patients have an absolute increase in red cell mass, their erythropoietin (EPO) levels differ widely, so they constitute a heterogeneous group of disorders known collectively as idiopathic erythrocytosis (IE). A proportion of individuals with IE progress to polycythemia vera (PV), a clonal disorder arising from a multipotent progenitor. Recently a gain-of-function mutation in Janus kinase 2 (JAK2), V617F, has been described in myeloproliferative disorders (MPD) and a stream of publications has confirmed its presence in the majority of patients with PV. Screening IE patients for this mutation will provide a useful additional means for delineating inherited and clonal disorders of erythrocytosis. Over the last decade we have maintained a registry of British and Irish erythrocytosis patients, consisting of clinical information and DNA samples obtained following full ethical approval. Screening the EPO receptor (EPO-R) in 120 patients identified one patient with a G6002A mutation, which leads to truncation of the receptor by 70 amino acids, increased sensitivity to EPO, and erythrocytosis. Screening the same patients for mutations in the von Hippel Lindau (VHL) gene has revealed individuals from 8 families of Asian origin who are homozygous for the Chuvash (R200W) mutation causing erythrocytosis. In addition, one Caucasian individual of English descent is compound heterozygous for R200W and the recently described G144R VHL mutation. A further individual, D1 (Percy et al, 2003Blood102:1097), of the same ethnicity is heterozygous for the Chuvash mutation and has been found to express the wild type allele. Both his mother and son, who are heterozygous for the Chuvash mutation, do not have IE, suggesting that the patient harbors a second unidentified genetic defect. Several such individuals have already been described (reviewed by Randi et al, 2005 Haematologica 90:689). In order to estimate the proportion of IE patients likely to progress to PV, 65 individuals from the registry with EPO levels in the low to normal range were screened by amplification refractory mutation system (ARMS) PCR for the MPD-associated V617F JAK2 mutation. Two individuals were positive, one of whom subsequently proceeded rapidly to PV, while the other has remained stable without any disease progression. In addition 9 families with VHL mutations were also screened and all were found to be negative for the JAK2 mutation, suggesting that the occurrence of these mutations tends to be mutually exclusive. Also the V617F JAK2 mutation does not constitute the second genetic defect in patient D1 who is heterozygous for the Chuvash VHL mutation. Although VHL mutations are the most frequent cause of inherited erythrocytosis in our registry they are present in only ~10% of patients, while the gain-of-function of JAK2 mutation is rare, leaving ~90% of the IE cases unexplained. Further study of this group may reveal additional regulatory mechanisms involved in red cell homeostasis.
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Burgess, Darren J. « Mutation identified for an inherited cancer ». Nature Reviews Cancer 12, no 6 (24 mai 2012) : 377. http://dx.doi.org/10.1038/nrc3289.
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FALLIK, DAWN. « Rare Mutation Identified for Tourette Syndrome ». Neurology Today 10, no 12 (juin 2010) : 1. http://dx.doi.org/10.1097/01.nt.0000383479.76782.a7.
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Wei, Shuanzeng, Virginia A. LiVolsi, Marcia S. Brose, Kathleen T. Montone, Jennifer J. D. Morrissette et Zubair W. Baloch. « STK11 Mutation Identified in Thyroid Carcinoma ». Endocrine Pathology 27, no 1 (11 décembre 2015) : 65–69. http://dx.doi.org/10.1007/s12022-015-9411-6.
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GARCÍA-DORADO, A., C. LÓPEZ-FANJUL et A. CABALLERO. « Properties of spontaneous mutations affecting quantitative traits ». Genetical Research 74, no 3 (décembre 1999) : 341–50. http://dx.doi.org/10.1017/s0016672399004206.
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Recent mutation accumulation results from invertebrate species suggest that mild deleterious mutation is far less frequent than previously thought, implying smaller expressed mutational loads. Although the rate (λ) and effect (s) of very slight deleterious mutation remain unknown, most mutational fitness decline would come from moderately deleterious mutation (s ≈ 0·2, λ ≈ 0·03), and this situation would not qualitatively change in harsh environments. Estimates of the average coefficient of dominance (h¯) of non-severe deleterious mutations are controversial. The typical value of h¯ = 0·4 can be questioned, and a lower estimate (about 0·1) is suggested. Estimated mutational parameters are remarkably alike for morphological and fitness component traits (excluding lethals), indicating low mutation rates and moderate mutational effects, with a distribution generally showing strong negative asymmetry and little leptokurtosis. New mutations showed considerable genotype–environment interaction. However, the mutational variance of fitness-component traits due to non-severe detrimental mutations did not increase with environmental harshness. For morphological traits, a class of predominantly additive mutations with no detectable effect on fitness and relatively small effect on the trait was identified. This should be close to that responsible for standing variation in natural populations.
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Liu, Musang, Rong Zeng, Lili Zhang, Dongmei Li, Guixia Lv, Yongnian Shen, Hailin Zheng et al. « Multiplecyp51A-Based Mechanisms Identified in Azole-Resistant Isolates of Aspergillus fumigatus from China ». Antimicrobial Agents and Chemotherapy 59, no 7 (20 avril 2015) : 4321–25. http://dx.doi.org/10.1128/aac.00003-15.
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ABSTRACTSeventy-twoA. fumigatusclinical isolates from China were investigated for azole resistance based on mutations ofcyp51A. We identified four azole-resistant strains, among which we found three strains highly resistant to itraconazole, two of which exhibit the TR34/L98H/S297T/F495I mutation, while one carries only the TR34/L98H mutation. To our knowledge, the latter has not been found previously in China. The fourth multiazole-resistant isolate (with only moderate itraconazole resistance) carries a new G432A mutation.
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Sakuma, Naoko, Hideaki Moteki, Hela Azaiez, Kevin T. Booth, Masahiro Takahashi, Yasuhiro Arai, A. Eliot Shearer et al. « Novel PTPRQ Mutations Identified in Three Congenital Hearing Loss Patients With Various Types of Hearing Loss ». Annals of Otology, Rhinology & ; Laryngology 124, no 1_suppl (18 mars 2015) : 184S—192S. http://dx.doi.org/10.1177/0003489415575041.
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Objectives: We present 3 patients with congenital sensorineural hearing loss (SNHL) caused by novel PTPRQ mutations, including clinical manifestations and phenotypic features. Methods: Two hundred twenty (220) Japanese subjects with SNHL from unrelated and nonconsanguineous families were enrolled in the study. Targeted genomic enrichment with massively parallel DNA sequencing of all known nonsyndromic hearing loss genes was performed to identify the genetic cause of hearing loss. Results: Four novel causative PTPRQ mutations were identified in 3 cases. Case 1 had progressive profound SNHL with a homozygous nonsense mutation. Case 2 had nonprogressive profound SNHL with a compound heterozygous mutation (nonsense and missense mutation). Case 3 had nonprogressive moderate SNHL with a compound heterozygous mutation (missense and splice site mutation). Caloric test and vestibular evoked myogenic potential (VEMP) test showed vestibular dysfunction in Case 1. Conclusion: Hearing loss levels and progression among the present cases were varied, and there seem to be no obvious correlations between genotypes and the phenotypic features of their hearing loss. The PTPRQ mutations appeared to be responsible for vestibular dysfunction.
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Vargas, Elizabeth, Robert de Deugd, Victoria E. Villegas, Fabian Gil, Lina Mora, Luis Fernando Viaña, Ricardo Bruges et al. « Prevalence of BRCA1 and BRCA2 Germline Mutations in Patients of African Descent with Early-Onset and Familial Colombian Breast Cancer ». Oncologist 27, no 2 (1 février 2022) : e151-e157. http://dx.doi.org/10.1093/oncolo/oyab026.
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Abstract Background Pathogenic germline mutations in the BRCA1 and BRCA2 (BRCA1/2) genes contribute to hereditary breast/ovarian cancer (OC) in White/mestizo Colombian women. As there is virtually no genetic data on breast cancer (BC) in Colombians of African descent, we conducted a comprehensive BRCA1/2 mutational analysis of 60 Afro-Colombian families affected by breast/OC. Materials and Methods Mutation screening of the complete BRCA1/2 genes for small-scale mutations and large genomic alterations was performed in these families using next-generation sequencing and multiplex ligation-dependent probe amplification analysis. Results Four pathogenic germline mutations, including one novel mutation, were identified, comprising 3 in BRCA1 and one in BRCA2. The prevalence of BRCA1/2 mutations, including one BRCA1 founder mutation (c.5123C>A) previously identified in this sample set, was 3.9% (2/51) in female BC-affected families and 33.3% (3/9) in those affected by both breast and OC. Haplotype analysis of 2 BRCA2_c.2701delC carriers (one Afro-Colombian and one previously identified White/mestizo Colombian patient with BC) suggested that the mutation arose in a common ancestor. Conclusion Our data showed that 2/5 (40%) mutations (including the one previously identified in this sample set) are shared by White/mestizo Colombian and Afro-Colombian populations. This suggests that these 2 populations are closely related. Nevertheless, variations in the BRCA1/2 mutational spectrum among Afro-Colombian subgroups from different regions of the country were observed, suggesting that specific genetic risk assessment strategies need to be developed.
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Lee, Sook-Kyung, Kyung-Eun Lee, Su Jeong Song, Hong-Keun Hyun, Sang-Hoon Lee et Jung-Wook Kim. « ADSPPMutation Causing Dentinogenesis Imperfecta and Characterization of the Mutational Effect ». BioMed Research International 2013 (2013) : 1–7. http://dx.doi.org/10.1155/2013/948181.
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Mutations in theDSPPgene have been identified in nonsyndromic hereditary dentin defects, but the genotype-phenotype correlations are not fully understood. Recently, it has been demonstrated that the mutations ofDSPPaffecting the IPV leader sequence result in mutant DSPP retention in rough endoplasmic reticulum (ER). In this study, we identified a Korean family with dentinogenesis imperfecta type III. To identify the disease causing mutation in this family, we performed mutational analysis based on candidate gene sequencing. Exons and exon-intron boundaries ofDSPPgene were sequenced, and the effects of the identified mutation on the pre-mRNA splicing and protein secretion were investigated. Candidate gene sequencing revealed a mutation (c.50C > T, p.P17L) in exon 2 of theDSPPgene. The splicing assay showed that the mutation did not influence pre-mRNA splicing. However, the mutation interfered with protein secretion and resulted in the mutant protein remaining largely in the ER. These results suggest that the mutation affects ER-to-Golgi apparatus export and results in the reduction of secreted DSPP and ER overload. This may induce cell stress and damage processing and/or transport of dentin matrix proteins or other critical proteins.
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Liu, Ji-Shi, Liang-Liang Fan, Hao Zhang, Xiaoxian Liu, Hao Huang, Li-Jian Tao, Kun Xia et Rong Xiang. « Whole-Exome Sequencing Identifies Two Novel TTN Mutations in Chinese Families with Dilated Cardiomyopathy ». Cardiology 136, no 1 (20 août 2016) : 10–14. http://dx.doi.org/10.1159/000447422.
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Objectives: Dilated cardiomyopathy (DCM) is a leading cause of sudden cardiac death. So far, only 127 mutations of Titin(TTN) have been reported in patients with different phenotypes such as isolated cardiomyopathies, purely skeletal muscle phenotypes or complex overlapping disorders of muscles. Methods: We applied whole-exome sequencing (WES) to investigate cardiomyopathy patients and a cardiomyopathy-related gene-filtering strategy was used to analyze the disease-causing mutations. Sanger sequencing was applied to confirm the mutation cosegregation in the affected families. Results: A nonsense mutation (c.12325C>T/p.R4109X) and a missense mutation (c.17755G>C/p.G5919R) of TTN were identified in 2 Chinese DCM families, respectively. Both mutations were cosegregated in all affected members of both families. The nonsense mutation is predicted to result in a truncated TTN protein and the missense mutation leads to a substitution of glycine by arginine. Both variants may cause the structure changes of titin protein. Conclusions: We employed WES to detect the mutations of DCM patients and identified 2 novel mutations. Our study expands the spectrum of TTN mutations and offers accurate genetic testing information for DCM patients who are still clinically negative.
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Maxwell, Kara Noelle, Daniel De Sloover, Lyndsey Emery, Bradley Wubbenhorst, Kurt P. D'Andrea, Jessica Long, Rebecca Mueller et al. « The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers. » Journal of Clinical Oncology 31, no 15_suppl (20 mai 2013) : 1510. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.1510.
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1510 Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.
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Maier, Dalila, Adrian Florea, Mariana Cornelia Tilinca, Ancuța Zazgyva et Rodica Cosgarea. « NIPAL4 mutation c.527C˃A identified in Romanian patients with autosomal recessive congenital ichthyosis ». Revista Romana de Medicina de Laborator 24, no 4 (1 décembre 2016) : 387–98. http://dx.doi.org/10.1515/rrlm-2016-0034.
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Abstract Introduction: Autosomal recessive congenital ichthyosis is a non-syndromic ichthyosis, with a genetic background of mutations in 9 genes. This case series presents clinical and paraclinical particularities of 3 Romanian ARCI patients with NIPAL4 mutation c.527C>A. Material and methods: Three Caucasian patients were investigated, two sisters and an unrelated female patient, aged 47, 49, and 42 respectively. Skin anomalies were recorded and documented photographically; peripheral blood samples were harvested for DNA extraction and gene analysis. Skin biopsies were used for histological assessment, electron microscopy, and evaluation of in situ transglutaminase 1 activity. Results: All patients presented with generalized ichthyosis, palmoplantar keratoderma, normal hair shafts, and significant oral manifestations. Natural evolution was relatively stable in all cases, without phenotype changing. Medical treatment with retinoids in patients 1 and 2 resulted in normalisation of the skin condition. Histological samples showed hyperkeratosis, acanthosisand perivascular inflammatory infiltrates in the dermis. Positive findings of transglutaminase 1 in situ activity excluded TGM1 deficiency. Direct sequencing of amplicons revealed one homozygous mutation in exon 4, a c.527C>A missense mutation. Conclusions: This is the first report of the hotspot mutation NIPAL4 c.527C>A in Romanian autosomal recessive congenital ichthyosis patients. The phenotype was similar to that reported in the literature, while transglutaminase 1 activity in situ assay detected differences in enzyme distribution between patients bearing the same mutation but different phenotypes. Based on the current data, NIPAL4 mutations are more frequent than TGM1 mutations in Romanian patients with autosomal recessive congenital ichthyosis.
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Wang, Li, Jingjing Li, Ge Wu et Xiangdong Kong. « A novel compound heterozygous variant in SMARCAL1 leading to mild Schimke immune-osseous dysplasia identified using whole-exome sequencing ». Journal of International Medical Research 49, no 4 (avril 2021) : 030006052110106. http://dx.doi.org/10.1177/03000605211010644.
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Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive inherited disorder that is caused by the SMARCAL1 mutation. The phenotype can vary from mild to severe on the basis of the patient’s age at onset. Herein, we report the case of a 14-year-old Chinese boy who presented with short stature, focal segmental glomerulosclerosis (FSGS), and facial dysmorphism. Genetic analysis revealed two compound heterozygous missense mutations, including a well-known mutation (c.1933C>T, p.R645C) and a novel mutation (c.2479G>A, p.V827M) in the SMARCAL1 gene, which were inherited from his parents. In silico analyses showed that the c.2479G>A (p.V827M) variant affects a highly conserved residue within the ATPase catalytic domain. Finally, we established the diagnosis of mild SIOD and treated the patient with diuretics and angiotensin receptor blockers. This report expands the mutational spectrum of SMARCAL1 and reinforces the importance of a detailed clinical evaluation, molecular detection, and appropriate genetic counseling.
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Chen, Ying, Luo Guo, Chen-long Li, Jing Shan, Hai-song Xu, Jie-ying Li, Shan Sun et al. « Mutation screening of Chinese Treacher Collins syndrome patients identified novel TCOF1 mutations ». Molecular Genetics and Genomics 293, no 2 (11 décembre 2017) : 569–77. http://dx.doi.org/10.1007/s00438-017-1384-3.
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Xu, Darui, Stephen Lyon, Chun Hui Bu, Sara Hildebrand, Jin Huk Choi, Xue Zhong, Aijie Liu et al. « Thousands of induced germline mutations affecting immune cells identified by automated meiotic mapping coupled with machine learning ». Proceedings of the National Academy of Sciences 118, no 28 (6 juillet 2021) : e2106786118. http://dx.doi.org/10.1073/pnas.2106786118.
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Forward genetic studies use meiotic mapping to adduce evidence that a particular mutation, normally induced by a germline mutagen, is causative of a particular phenotype. Particularly in small pedigrees, cosegregation of multiple mutations, occasional unawareness of mutations, and paucity of homozygotes may lead to erroneous declarations of cause and effect. We sought to improve the identification of mutations causing immune phenotypes in mice by creating Candidate Explorer (CE), a machine-learning software program that integrates 67 features of genetic mapping data into a single numeric score, mathematically convertible to the probability of verification of any putative mutation–phenotype association. At this time, CE has evaluated putative mutation–phenotype associations arising from screening damaging mutations in ∼55% of mouse genes for effects on flow cytometry measurements of immune cells in the blood. CE has therefore identified more than half of genes within which mutations can be causative of flow cytometric phenovariation in Mus musculus. The majority of these genes were not previously known to support immune function or homeostasis. Mouse geneticists will find CE data informative in identifying causative mutations within quantitative trait loci, while clinical geneticists may use CE to help connect causative variants with rare heritable diseases of immunity, even in the absence of linkage information. CE displays integrated mutation, phenotype, and linkage data, and is freely available for query online.
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Weller, Claudia M., Nadine Pelzer, Boukje de Vries, Mercè Artigas López, Oriol De Fàbregues, Julio Pascual, María A. Ramos Arroyo et al. « Two novel SCN1A mutations identified in families with familial hemiplegic migraine ». Cephalalgia 34, no 13 (4 avril 2014) : 1062–69. http://dx.doi.org/10.1177/0333102414529195.
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Background Familial hemiplegic migraine (FHM) is a rare monogenic subtype of migraine with aura, characterized by motor auras. The majority of FHM families have mutations in the CACNA1A and ATP1A2 genes; less than 5% of FHM families are explained by mutations in the SCN1A gene. Here we screened two Spanish FHM families for mutations in the FHM genes. Methods We assessed the clinical features of both FHM families and performed direct sequencing of all coding exons (and adjacent sequences) of the CACNA1A, ATP1A2, PRRT2 and SCN1A genes. Results FHM patients in both families had pure hemiplegic migraine with highly variable severity and frequency of attacks. We identified a novel SCN1A missense mutation p.Ile1498Met in all three tested hemiplegic migraine patients of one family. In the other family, novel SCN1A missense mutation p.Phe1661Leu was identified in six out of eight tested hemiplegic migraine patients. Both mutations affect amino acid residues that either reside in an important functional domain (in the case of Ile1498) or are known to be important for kinetic properties of the NaV1.1 channel (in the case of Phe1661). Conclusions We identified two mutations in families with FHM. SCN1A mutations are an infrequent but important cause of FHM. Genetic testing is indicated in families when no mutations are found in other FHM genes.
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Aksenenko, Maria B., A. V. Komina et T. G. Ruksha. « Analysis of the frequency of NRAS and c-Kit gene mutations in patients with BRAF-negative melanoma ». Russian Journal of Skin and Venereal Diseases 19, no 6 (15 décembre 2016) : 324–27. http://dx.doi.org/10.18821/1560-9588-2016-19-6-324-327.
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Identification of molecular subtypes of melanoma allowed to use a personalized approach in the treatment of melanoma. One of the most common driver mutations in melanoma is a mutation of the oncogene BRAF, that is determined in 40-60% of all melanomas. However, BRAF-negative tumors require further investigation of mutational status, which can be applied not only to select the means of personalized therapy of tumor, but also for the prediction of disease course. This article presents an analysis of 37 patients with melanoma BRAF-negative for mutations in the genes NRAS and c-Kit. Mutations were identified in the 3 exon of the gene NRAS in 8.1% of cases. In skin melanomas «silent» mutations were identified in 64.7% that confirm the occurrence ofpronounced mutation under the influence of ultraviolet radiation on the skin of the patient. We identified clinical and morphological features ofpatients with NRAS mutation in the 3 exon. This group ofpatients is characterized by a greater thickness of the tumor Breslow. Female gender and older age were dominated clinical characteristics in this group as compared with patients without NRAS mutations (p < 0.05).
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Gong, Bo, Bo Wei, Lulin Huang, Jilong Hao, Xiulan Li, Yin Yang, Yu Zhou et al. « Exome Sequencing Identified a RecessiveRDH12Mutation in a Family with Severe Early-Onset Retinitis Pigmentosa ». Journal of Ophthalmology 2015 (2015) : 1–7. http://dx.doi.org/10.1155/2015/942740.
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Retinitis pigmentosa (RP) is the most important hereditary retinal disease caused by progressive degeneration of the photoreceptor cells. This study is to identify gene mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in a Chinese family using next-generation sequencing technology. A Chinese family with 7 members including two individuals affected with severe early-onset RP was studied. All patients underwent a complete ophthalmic examination. Exome sequencing was performed on a single RP patient (the proband of this family) and direct Sanger sequencing on other family members and normal controls was followed to confirm the causal mutations. A homozygous mutation c.437T<A (p.V146D) in theretinol dehydrogenase 12 (RDH12)gene, which encodes an NADPH-dependent retinal reductase, was identified as being related to the phenotype of this arRP family. This homozygous mutation was detected in the two affected patients, but not present in other family members and 600 normal controls. Another three normal members in the family were found to carry this heterozygous missense mutation. Our results emphasize the importance of c.437T<A (p.V146D) substitution inRDH12and provide further support for the causative role of this mutation in the pathogenesis and clinical diagnosis of RP.
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Birch, Nigel P., Peter J. Browett, Paul B. Coughlin, Anita J. Horvath, Neil S. Van de Water, Paul A. Ockelford, Paul L. Harper et Laura K. Young. « Two missense mutations identified in venous thrombosis patients impair the inhibitory function of the protein Z dependent protease inhibitor ». Thrombosis and Haemostasis 107, no 05 (2012) : 854–63. http://dx.doi.org/10.1160/th11-10-0708.
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SummaryProtein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05–3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.
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Wu, Yanmei, Xiaodong Pan, Juan Dou, Quan Zhang, Yuantong Li, Yuan Sheng et Xishui Liu. « A novel germline BRCA1 mutation identified in a family with hereditary breast and ovarian cancer syndrome ». Clinical Medicine Insights : Oncology 15 (janvier 2021) : 117955492110285. http://dx.doi.org/10.1177/11795549211028569.
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Pathogenic germline mutations occurring in the BRCA1 (MIM:113705) and BRCA2 (MIM: 600185), which always result in truncated protein or nonsense-mediated mRNA decay, have been identified to increase the risk of hereditary breast, ovarian, pancreatic, prostate, and melanoma cancers. Recent studies show that BRCA1/2 germline mutations also contribute to half of all hereditary breast and ovarian cancer (HBOC). In this case series, we reported a novel frameshift mutation of the BRCA1 gene. This novel frameshift mutation occurs in exon10 of BRCA1 and may result in a lack of the serine cluster domain and BRCA1 C-terminus domain, which mediates the function of BRCA1 in DNA repair and are responsible for activation function of BRCA1. The mutation was present in a Chinese hereditary male/female breast and ovarian cancer family characterized by a high incidence of breast cancer and/or ovarian cancer among the relatives and by a high incidence of triple negative breast cancer (TNBC). Our findings speculate that BRCA1 E1148Rfs*7 mutation may be related to the occurrence of HBOC and even TNBC. Interestingly, three cases of TNBC with this novel BRCA1 mutation in this case series showed a good disease-free survival, one of them has a disease-free survival up to 7 years. Therefore, further study is required to confirm that whether this mutation is associated with good prognosis of HBOC.
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Li, Juan, Mingyao Lai, Qingjun Hu, Ruyu Ai et Linbo Cai. « PATH-33. MOLECULAR TYPING AND MUTATION SPECTRUM OF CHINESE CHILDREN WITH MEDULLOBLASTOMA WERE IDENTIFIED BY NEXT-GENERATION SEQUENCING ». Neuro-Oncology 23, Supplement_6 (2 novembre 2021) : vi122. http://dx.doi.org/10.1093/neuonc/noab196.485.
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Abstract There are few reports on molecular typing and mutation spectrum of Chinese children with medulloblastoma. Here, we aimed to update the clinical manifestations and MB transcriptional mutation spectrum in Chinese Mb patients. Medical records of 59 Mb patients were reviewed. Genomic DNA was extracted from pathological tissues of children. Mutation analysis of whole coding regions, promoter regions and flanking splice sites in whole genome sequencing was performed. Nine cases (15%)with WNT subtype: CTNNB1 mutation was found in all specimens, and TP53 mutation was found in 33.3%. DDX3X mutation occurred in 33.3%. 33.3% had SMARCA4 mutations. Chr6 - associated large fragment deletion occurred in 88.9s. Comparison results between 19 cases (32%) with SHH data and previous studies: The proportion of SHH-TP53 mutants was11% ( 2/19).The proportion of SHH-TP53 wild-type was 89%.The prognosis of the mutated SHH-TP53 was worse than that of the wild-type SHH-TP53, and patient follow-up information could be integrated for comparison. Secondly, PTCH1 is more prevalent in patients with SHH (16%). The DDX3X mutation proportion was 11%. The mutation ratio of Gli2 amplification5%.The mutation ratio of MYCN amplification was 5%.Comparison results of 3 cases with G3 subtype data and previous studies: Variations mainly occur at the chromosomal level. Only one G3 patient had a genetic mutation (TP53 mutation). The proportion of Chr17q+ was 33.3%. CHR7 + proportion was 33.3%. The incidence rates of CHR10Q and CHR11Q were 66.7%.No MYC amplification was found. For 28 cases with G4 subtype: Chr17q +, Chr7 +, Chr18 +, and Chr8 - are the major chromosomal mutations. The incidence rate of CHR17Q + was 61%, and CHR7 + was 61%. CHR8- occurred in 11%. The above results are consistent with previous reports. The Chinese population and other population have similar molecular genotyping gene variation map on medulloblastoma.
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Yang, Qing-Hua, Jason Schmidt, Genvieve Soucy, Robert Odze, Liza Dejesa-Jamanila, Keely Arnold, Christine Kuslich et Richard Lash. « KRAS mutational status of endoscopic biopsies matches resection specimens ». Journal of Clinical Pathology 65, no 7 (29 mars 2012) : 604–7. http://dx.doi.org/10.1136/jclinpath-2012-200746.
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AimsThis study was performed to determine systematically whether KRAS mutational analysis in biopsy tissue is a reliable indicator of KRAS status in subsequent corresponding resection specimens.Methods30 colorectal cancer (CRC) patients with biopsy and corresponding subsequent surgical resection specimens were studied. KRAS mutational analysis was performed on each biopsy sample as well as two separate samples from each resection specimen by PCR and Sanger sequencing.ResultsOverall, KRAS mutations were identified in 12/30 (40%) of the tumours. There was 100% correlation between biopsy and resection specimens regarding the presence or absence of KRAS mutations. In fact, the same point mutation was identified in both biopsy and corresponding resection specimens in 12/12 (100%) cases. In addition, in two cases, there were two different point mutations detected within the same biopsy specimen.ConclusionThis study shows perfect correlation between KRAS mutation status in biopsy and resection specimens from an individual patient, and suggests that biopsy material is adequate for KRAS mutational analysis in CRC patients.
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Mori, Hiroyuki, Yoshinori Akiyama et Koreaki Ito. « A SecE Mutation That Modulates SecY-SecE Translocase Assembly, Identified as a Specific Suppressor of SecY Defects ». Journal of Bacteriology 185, no 3 (1 février 2003) : 948–56. http://dx.doi.org/10.1128/jb.185.3.948-956.2003.
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ABSTRACT The SecY39(Cs) (cold-sensitive) alteration of Arg357 results in a defect of translocation initiation. As a means to dissect the Sec translocation machinery, we isolated mutations that act as suppressors of the secY39 defect. A specific secE mutation, designated secE105, was thus isolated. This mutation proved to be identical with the prlG2 mutation and to suppress a number of cold-sensitive secY mutations. However, other prlG mutations did not effectively suppress the secY defects. Evidence indicates that the Ser105-to-Pro alteration in the C-terminal transmembrane segment of SecE weakens SecY-SecE association. In vitro analyses showed that the SecE(S105P) alteration preferentially stimulates the initial phase of translocation. It is suggested that the S105P alteration affects the SecYEG channel such that it is more prone to open and to accept the translocation initiation domain of a preprotein molecule.
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Elit, L., E. Jack, E. Kwan, G. Baigal et S. Narod. « A unique BRCA1 mutation identified in Mongolia ». International Journal of Gynecological Cancer 11, no 3 (8 mai 2001) : 241–43. http://dx.doi.org/10.1046/j.1525-1438.2001.01020.x.
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Charikova, E. V. « Novel Mutation Identified in the PAH Gene ». Human Heredity 46, no 1 (1996) : 36–40. http://dx.doi.org/10.1159/000154323.
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Margraf, Rebecca L., Emily M. Coonrod, Jacob D. Durtschi, Nancy H. Augustine, Karl V. Voelkerding, Harry R. Hill et Attila Kumánovics. « TACI mutation p.Lys154Ter identified in Good Syndrome ». Clinical Immunology 146, no 1 (janvier 2013) : 10–12. http://dx.doi.org/10.1016/j.clim.2012.10.006.
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Arnoux, Fanny, Frederic Fina, Nathalie Lambert, Nathalie Balandraud, Marielle Martin, L'Houcine Ouafik, Sami B. Kanaan, Jean Roudier et Isabelle Auger. « Newly Identified BRAF Mutation in Rheumatoid Arthritis ». Arthritis & ; Rheumatology 68, no 6 (26 mai 2016) : 1377–83. http://dx.doi.org/10.1002/art.39588.
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Guo, Bing-Bing, Jie-Yuan Jin, Zhuang-Zhuang Yuan, Lei Zeng et Rong Xiang. « A Novel COMP Mutated Allele Identified in a Chinese Family with Pseudoachondroplasia ». BioMed Research International 2021 (8 mars 2021) : 1–8. http://dx.doi.org/10.1155/2021/6678531.
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Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia with an estimated incidence of ~1/60000 that is characterized by disproportionate short stature, brachydactyly, joint laxity, and early-onset osteoarthritis. COMP encodes the cartilage oligomeric matrix protein, which is expressed predominantly in the extracellular matrix (ECM) surrounding the cells that make up cartilage, ligaments, and tendons. Mutations in COMP are known to give rise to PSACH. In this study, we identified a novel nucleotide mutation (NM_000095.2: c.1317C>G, p.D439E) in COMP responsible for PSACH in a Chinese family by employing whole-exome sequencing (WES) and built the structure model of the mutant protein to clarify its pathogenicity. The novel mutation cosegregated with the affected individuals. Our study expands the spectrum of COMP mutations and further provides additional genetic testing information for other PSACH patients.
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Hsu, Lung-An, Yu-Shien Ko, Yung-Hsin Yeh, Chi-Jen Chang, Yi-Hsin Chan, Chi-Tai Kuo, Hsin-Yi Tsai et Gwo-Jyh Chang. « A Novel DES L115F Mutation Identified by Whole Exome Sequencing is Associated with Inherited Cardiac Conduction Disease ». International Journal of Molecular Sciences 20, no 24 (10 décembre 2019) : 6227. http://dx.doi.org/10.3390/ijms20246227.
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Inherited cardiac conduction disease (CCD) is rare; it is caused by a large number of mutations in genes encoding cardiac ion channels and cytoskeletal proteins. Recently, whole-exome sequencing has been successfully used to identify causal mutations for rare monogenic Mendelian diseases. We used trio-based whole-exome sequencing to study a Chinese family with multiple family members affected by CCD, and identified a heterozygous missense mutation (c.343C>T, p.Leu115Phe) in the desmin (DES) gene as the most likely candidate causal mutation for the development of CCD in this family. The mutation is novel and is predicted to affect the conformation of the coiled-coil rod domain of DES according to structural model prediction. Its pathogenicity in desmin protein aggregation was further confirmed by expressing the mutation, both in a cellular model and a CRISPR/CAS9 knock-in mouse model. In conclusion, our results suggest that whole-exome sequencing is a feasible approach to identify candidate genes underlying inherited conduction diseases.
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Yang, Liu, Jiahong Jiang, Lianpeng Chang, Yaping Xu, Chao Ni et Dongsheng Huang. « KLF4 p.A472D mutation : An acquired resistant mutation to cetuximab in colorectal cancer. » Journal of Clinical Oncology 37, no 15_suppl (20 mai 2019) : e15077-e15077. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e15077.
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e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.
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Kim, Mijin, Chae Hwa Kwon, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yun Kyung Jeon, Sang Soo Kim et al. « Whole-Exome Sequencing in Papillary Microcarcinoma : Potential Early Biomarkers of Lateral Lymph Node Metastasis ». Endocrinology and Metabolism 36, no 5 (31 octobre 2021) : 1086–94. http://dx.doi.org/10.3803/enm.2021.1132.
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Background: Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC.Methods: Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues.Results: The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher’s exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs.Conclusion: This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.
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Torricelli, Federica, Filippo Lococo, Teresa Severina Di Stefano, Eugenia Lorenzini, Simonetta Piana, Riccardo Valli, Ottavio Rena, Giulia Veronesi, Andrea Billè et Alessia Ciarrocchi. « Deep Sequencing Analysis Identified a Specific Subset of Mutations Distinctive of Biphasic Malignant Pleural Mesothelioma ». Cancers 12, no 9 (29 août 2020) : 2454. http://dx.doi.org/10.3390/cancers12092454.
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Malignant Pleural Mesothelioma (MPM) is a heterogeneous disease. Morphologically, three different phenotypes are distinguishable: epithelioid (e-), sarcomatoid (s-) and biphasic (biph-) MPM, the latest, being a mixture of e- and s-MPM cells. Being an intermediate entity, management of biph-MPM, remains debatable and controversial, with different guidelines recommending distinct approaches. Identification of biph-MPM associated genetic alterations, through deep sequencing analysis, may provide useful tools to understand these lesions. A retrospective cohort of 69 surgically resected MPMs, 39 biph-MPMs (56.5%) and 30 e-MPMs (43.5%) was selected. A separate set of 16 biph-MPM was used as validation set. Deep sequencing analysis on an MPM-specific custom panel (MPM_geneset) comprising 1041 amplicons spanning 34 genes was performed. A total of 588 variants and 5309 mutational events were detected. In total, 91.3% of MPMs showed at least one mutation and 76.8% showed co-occurrence of more than one alteration. Mutations in MXRA5 (p = 0.05) and NOD2 (p = 0.018) were significantly associated with biph-MPM both in the training and validation cohort and correlated with the extent of the sarcomatoid component. Mutations in NOD2 and XRCC6 correlated with patients’ survival. We demonstrated that biph-MPM are associated with a specific mutation set, and that genetic analysis at diagnosis may improve patients’ risk stratification.
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Caetano, Lílian A., Alexander A. L. Jorge, Alexsandra C. Malaquias, Ericka B. Trarbach, Márcia S. Queiroz, Márcia Nery et Milena G. Teles. « Incidental mild hyperglycemia in children : two MODY 2 families identified in Brazilian subjects ». Arquivos Brasileiros de Endocrinologia & ; Metabologia 56, no 8 (novembre 2012) : 519–24. http://dx.doi.org/10.1590/s0004-27302012000800010.
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Maturity-onset diabetes of the young (MODY) is characterized by an autosomal dominant mode of inheritance, early onset of hyperglycemia, and defects of insulin secretion. MODY subtypes described present genetic, metabolic, and clinical differences. MODY 2 is characterized by mild asymptomatic fasting hyperglycemia, and rarely requires pharmacological treatment. Hence, precise diagnosis of MODY is important for determining management and prognosis. We report two heterozygous GCK mutations identified during the investigation of short stature. Case 1: a prepubertal 14-year-old boy was evaluated for constitutional delay of growth and puberty. During follow-up, he showed abnormal fasting glucose (113 mg/dL), increased level of HbA1c (6.6%), and negative β-cell antibodies. His father and two siblings also had slightly elevated blood glucose levels. The mother had normal glycemia. A GCK heterozygous missense mutation, p.Arg191Trp, was identified in the proband. Eighteen family members were screened for this mutation, and 11 had the mutation in heterozygous state. Case 2: a 4-year-old boy investigated for short stature revealed no other laboratorial alterations than elevated glycemia (118 mg/dL); β-cell antibodies were negative. His father, a paternal aunt, and the paternal grandmother also had slightly elevated glycemia, whereas his mother had normal glycemia. A GCK heterozygous missense mutation, p.Glu221Lys, was identified in the index patient and in four family members. All affected patients had mild elevated glycemia. Individuals with normal glycemia did not harbor mutations. GCK mutation screening should be considered in patients with chronic mild early-onset hyperglycemia, family history of impaired glycemia, and negative β-cell antibodies. Arq Bras Endocrinol Metab. 2012;56(8):519-24
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Khan, Sundas, Heather Wright, Melissa Cuke, Edmund Folefac, Claire F. Verschraegen et Marie Wood. « Potential germline findings identified during somatic tumor testing : Room for improvement. » Journal of Clinical Oncology 38, no 15_suppl (20 mai 2020) : 1543. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.1543.
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1543 Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in >6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( < 50) did not enrich for germline mutations (p > 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
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Ma, C. X., L. Lin, F. Gao, T. Giuntoli, Y. H. Chia, Z. Guo, R. McDowell, M. Naughton, M. Watson et M. Ellis. « PIK3CA mutation analysis in recurrent breast cancer ». Journal of Clinical Oncology 27, no 15_suppl (20 mai 2009) : 11041. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11041.
Texte intégralRésumé :
11041 Background: Mutations in PIK3CA (encoding p110α catalytic subunit of phosphatidylinositol-3-kinase) are among the most common genetic events identified in breast cancer but the role of these mutations in determining the clinical course of the disease is uncertain. Furthermore the frequency of PIK3CA mutation in metastatic breast cancer samples has not been adequately studied but is an important concern in the design of studies with novel agents designed to inhibit mutant PIK3CA. Methods: We have established a tumor banking protocol for patients (pts) with metastatic breast cancer. In this study, we performed a mutational analysis of exons 9 (HD) and 20 (KD) of the PIK3CA using tumor DNA obtained from pts with recurrent disease and correlated mutational status with clinicopathological features and prognosis. Results: Biopsies were obtained from sites of recurrence in 51 pts with stage 4 disease. The median F/U was 44 (range: 0.9–239) months and death has occurred in 66%. Mutations in PIK3CA were identified in 24.5% (11.3% in HD and 13.2% in KD). PIK3CA mutation was significantly correlated with lower tumor grade (47% in grade 1/2 vs 8% in grade 3, p=0.004), positive ER (35% in ER+ vs 5% in ER-, p=0.017), and PR (37% in PR+ vs 5% in PR-, p=0.011). Overall survival (OS) was 139.5 and 53.7 months for mutation- and non-mutation- carriers respectively (p=0.014). Conclusions: About one quarter of pts with recurrent/advanced breast cancer carry PIK3CA mutations in samples of recurrent disease, which correlated with positive ER/PR status and a more indolent clinical course. These patients are good candidates for experimental protocols that combine endocrine agents with PI3 kinase inhibitors but the slower kinetics of disease progression in PIK3CA mutation carriers may have to be taken into account for statistical designs and power size calculations. No significant financial relationships to disclose.
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Sun, Hong-Yan, Ru-Xu Sun, Ying Wang, Jia-Nan Wang, Bing Qin, Wei-Wei Zhang et Jiang-Dong Ji. « A novel Nance-Horan syndrome mutation identified by next-generation sequencing in a Chinese family ». International Journal of Ophthalmology 15, no 6 (18 juin 2022) : 1015–19. http://dx.doi.org/10.18240/ijo.2022.06.22.
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AIM: To identify the disease-causing mutation in a four-generation Chinese family diagnosed with Nance-Horan syndrome (NHS). METHODS: A Chinese family, including four affected patients and four healthy siblings, was recruited. All family members received ophthalmic examinations with medical histories provided. Targeted next-generation sequencing approach was conducted on the two affected males to screen for their disease-causing mutations. RESULTS: Two male family members diagnosed with NHS manifested bilateral congenital cataracts microcornea, strabismus and subtle facial and dental abnormalities, while female carriers presented posterior Y-sutural cataracts. A novel frameshift mutation (c.3916_3919del) in the NHS gene was identified. This deletion was predicted to alter the reading frame and generate a premature termination codon after a new reading frame. CONCLUSION: The study discovers a new frameshift mutation in a Chinese family with NHS. The findings broaden the spectrum of NHS mutations that can cause NHS in Chinese patients.
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Balamurugan, Kuppareddi, Martin L. Tracey, Uwe Heine, George C. Maha et George T. Duncan. « Mutation at the Human D1S80 Minisatellite Locus ». Scientific World Journal 2012 (2012) : 1–8. http://dx.doi.org/10.1100/2012/917235.
Texte intégralRésumé :
Little is known about the general biology of minisatellites. The purpose of this study is to examine repeat mutations from the D1S80 minisatellite locus by sequence analysis to elucidate the mutational process at this locus. This is a highly polymorphic minisatellite locus, located in the subtelomeric region of chromosome 1. We have analyzed 90,000 human germline transmission events and found seven (7) mutations at this locus. The D1S80 alleles of the parentage trio, the child, mother, and the alleged father were sequenced and the origin of the mutation was determined. Using American Association of Blood Banks (AABB) guidelines, we found a male mutation rate of1.04×10-4and a female mutation rate of5.18×10-5with an overall mutation rate of approximately7.77×10-5. Also, in this study, we found that the identified mutations are in close proximity to the center of the repeat array rather than at the ends of the repeat array. Several studies have examined the mutational mechanisms of the minisatellites according to infinite allele model (IAM) and the one-step stepwise mutation model (SMM). In this study, we found that this locus fits into the one-step mutation model (SMM) mechanism in six out of seven instances similar to STR loci.
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Buelow, Daelynn R., Stanley Pounds, Yong-Dong Wang, Lei Shi, Yongjin Li, David Finkelstein, Sheila A. Shurtleff et al. « Genomic Profiling Identifies Novel Mutations and Fusion Genes in Newly Diagnosed and Relapsed Pediatric FLT3-ITD-Positive AML ». Blood 128, no 22 (2 décembre 2016) : 2838. http://dx.doi.org/10.1182/blood.v128.22.2838.2838.
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Abstract Pediatric cancers are distinct from adult cancers in both their genomic alterations and therapeutic responses. Fms-like tyrosine kinase 3 (FLT3) mutations, especially internal tandem duplications (ITD), are among the most common mutations in acute myeloid leukemia (AML). FLT3-ITD mutations occur in approximately 15% of pediatric and 25-30% of adult AML, and are generally associated with poor prognosis. However, a number of studies have suggested that FLT3-ITD-positive(+) AML requires additional cooperative mutations. The objective of this study was to characterize the mutational landscape in a cohort of FLT3-ITD+ pediatric AML patients (median age,12.6 years; range, 2.8-19.2 years) enrolled to the AML02 and AML08 trials using samples obtained at diagnosis (n=34) and paired diagnosis/relapse samples (n=5). Children with promyelocytic leukemia were excluded. Samples were analyzed by RNASeq, a targeted 95 gene next generation sequencing (NGS) panel, and whole exome sequencing (WES). At diagnosis, 58.8% of the samples contained fusion genes; 41.2% were NUP98-NSD1, 11.8% were novel fusions (NSD1-CAPRIN1, NSD1-RALBP1, RUNX1-BCL11B, ZEB2-BCL11B), and 5.9% were previously reported fusions (CBFB-MYH11, DEK-NUP214). The NGS panel identified that WT1 and NPM1 were routinely mutated at a frequency of 32.4% and 20.6% respectively. While the NPM1 mutation was either a 4bp insertion at amino acid (a.a.) 287 or 288, WT1 mutations were heterogenenous with missense mutations, insertions and deletions all being reported. WT1 mutations and NUP98-NSD1 co-associated in 7 patients, 1 patient also harbored a TYK2 mutation; in the remaining 7 patients with NUP98-NSD1 fusions, a mutation in RAD21 or NRAS was observed in 2 patients. For samples with other fusions (n=6), we detected an average of 1 additional mutation per sample, which included mutations (variant allele frequency; VAF) in DNMT3A (0.44), IDH2 (0.49), KIT (0.37), NPM1 (0.51), PLCG2 (0.44), RAD21 (0.55), and SMC1A (0.47). No fusion genes were observed in 13 patients. In this latter subset, mutations in NPM1 (n=6) and WT1 (n=3) were observed. Other alterations that were identified in these samples included mutations in DNMT3A, IDH2, PLCG2, and PRKCB, which co-occurred with NPM1 mutations. Three patients did not harbor a fusion gene or a gene mutation by our analysis. When looking at cumulative incidence of relapse or resistant disease, our study results are concordant with previous reports where a NUP98-NSD1 fusion associated with worse prognosis (hazard ratio [HR] = 3.2, p = 0.02), but FLT3-ITD allelic ratio >0.4 was not prognostic (HR = 1.1, p=0.87). NPM1 mutations were not significantly associated with better prognosis (HR = 0.2, p = 0.11). We next sought to identify relapse specific alterations by analysis of paired diagnosis/relapse samples by RNASeq, NGS panel, and WES. Notably, the FLT3-ITD mutation was maintained at relapse in all samples. From the NGS panel, we observed the emergence of a MED12 mutation (P1751Q, VAF 0.37) and WT1 mutation (p.S152*, VAF 0.19) at relapse; a mutational switch in WT1 from diagnosis to relapse was also observed (5bp insertion at a.a. 157 to 2bp insertion at a.a. 158). By RNASeq analysis, we found a novel relapse specific fusion gene, LUZP6-OSBL1A. From exome sequencing, mutations in transcription factors were observed at relapse such as CREBBP, GLI3, and TBX20. Our analysis of relapse specific genes showed recurrent mutations in HUWE1, OGT, NACAD, and UNC13A. Intriguingly, both OGT and HUWE1 have been implicated in cancer metabolic reprogramming, and regulate MYC transcriptional programs. OGT is an O-Linked β-N-acetylglucosamine (O-GlcNAc) transferase involved post-translational modification of serine and threonine residues. HUWE1 is an E3 ubiquitin ligase that has been established as a tumor suppressor and previously reported to be mutated in AML. In conclusion, we demonstrate that additional genomic alterations are observed in the majority of pediatric FLT3-ITD+ AML samples evaluated, with a high proportion of samples containing fusion genes, WT1 and NPM1 mutations. We also identified novel fusion genes and mutations that have not been previously reported in pediatric FLT3-ITD+ AML, including relapse specific mutations. These results provide further biological insight into the genomic heterogeneity of pediatric FLT3-ITD+ AML, warranting further investigations in larger patient cohorts. Disclosures Inaba: Arog: Research Funding.
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Finkielstain, Gabriela P., Wuyan Chen, Sneha P. Mehta, Frank K. Fujimura, Reem M. Hanna, Carol Van Ryzin, Nazli B. McDonnell et Deborah P. Merke. « Comprehensive Genetic Analysis of 182 Unrelated Families with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency ». Journal of Clinical Endocrinology & ; Metabolism 96, no 1 (1 janvier 2011) : E161—E172. http://dx.doi.org/10.1210/jc.2010-0319.
Texte intégralRésumé :
Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.
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Hughes, Timothy, Giuseppe Saglio, Giovanni Martinelli, Dong-Wook Kim, S. Soverini, Martin Mueller, A. Haque et al. « Responses and Disease Progression in CML-CP Patients Treated with Nilotinib after Imatinib Failure Appear To Be Affected by the BCR-ABL Mutation Status and Types. » Blood 110, no 11 (16 novembre 2007) : 320. http://dx.doi.org/10.1182/blood.v110.11.320.320.
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Abstract Nilotinib is a rationally designed 2nd-generation bcr-abl inhibitor. It is ∼30-fold more potent than imatinib against wild-type bcr-abl and active against 32/33 imatinib-resistant bcr-abl mutants in preclinical models. In an open-label phase II study of nilotinib in imatinib-resistant or -intolerant CML-CP patients (pts), we assessed the occurrence of mutations and the efficacy stratified by BCR-ABL mutational status. Prior to therapy, 35 mutations affecting 28 amino acids in the BCR-ABL kinase domain were identified by direct sequencing in 39% (106/270) of the pts analyzed. The incidence of baseline mutation was higher in imatinib-resistant (100/183, 55%) versus imatinib-intolerant pts (6/86, 7%). After 12 months of therapy, complete hematologic response (CHR) was achieved in 85%, major cytogenetic response (MCR) in 60%, and complete cytogenetic response (CCR) in 45% of pts without baseline mutations versus 67, 49 and 29% of pts with mutations. Among patients with baseline mutations, responses were observed broadly in all genotypes identified, but rates of responses differed by the in vitro sensitivity of the mutant clone against nilotinib. Pts with sensitive mutations of ≤100 nM cellular IC50 had the best response rate and were comparable to pts without baseline mutations. Pts with less sensitive mutations (IC50 201–800nM:Y253H, E255K, E255V, F359C) had responses but the response rate were lower then those of the two other groups (IC50 101–200nM and 201–800nM). The nilotinib-resistant T315I mutation (IC50>800nM) was identified at baseline in 5 cases (one pt had a limited response followed by progression). The less sensitive mutations (IC50 201–800nM) and the T315I mutation occurred in 8% and 2% of all pts assessed for baseline mutations, respectively. With a median follow up of 12 months, progression occurred in 15% (25/164) versus 40% (42/106) of pts without and with baseline mutations. Nine of 18 with less sensitive baseline mutations and 3 of 5 with T315I progressed, but the baseline mutation most frequently associated with progression was F359V (7/9). In 67 cases of progression, mutational data at or within 3 months of progression were available in 28 cases. Among the 28 pts, 7 (25%) had no mutation; 9 (32%) had the same baseline mutation (including F359V in 3; Y253F/H in 3; E255K in 1; and T315I in 1). A further 12 (43%) pts showed new emerging mutations at progression, 4 with T315I, 4 E255K, 3 Y253H, and 1 F359C. The other 7 pts with emerging mutations had not progressed. In total 21 pts were found with emerging mutations, 19 (90%) had a different mutation at baseline. In summary, nilotinib responses were observed across a variety of BCR-ABL mutations. Preliminary data suggest that mutational status at baseline and/or the emergence of new mutations may influence disease progression. Less sensitive or resistant mutations represented 10% of the pt population and may be associated with less favorable responses. Longer follow up is required.
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Stadler, Zsofia K., Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger et al. « Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels ». Journal of Clinical Oncology 34, no 18 (20 juin 2016) : 2141–47. http://dx.doi.org/10.1200/jco.2015.65.1067.
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Purpose Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. Methods We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. Results Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). Conclusion A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.