mutation spectrum
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2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Huaru Zhang ◽  
Xiaojun Lu ◽  
Gang Huang ◽  
Meimian Hua ◽  
Wenhui Zhang ◽  
...  

Abstract Background Renal collecting duct carcinoma (CDC) is a rare and lethal subtype of renal cell carcinoma (RCC). The genomic profile of the Chinese population with CDC remains unclear. In addition, clinical treatments are contradictory. In this study, we aimed to identify the genomic mutation spectrum of CDC in the Chinese population. Methods Whole-exome sequencing was performed using the Illumina Novaseq™ 6000 platform. MuTect2 detects single-nucleotide variants (SNVs) and small scale insertions/deletions (INDELs). The identified mutations were annotated with ANNOVAR and validated by Sanger sequencing. Control-FREEC was used to detect copy number variation (CNV), and GISTIC was applied to detect frequently mutated altered regions. These data were compared with associated The Cancer Genome Atlas cohorts. Results Ten normal-matched CDC patients were included. The mean tumour mutation burden was 1.37 Mut/Mb. Six new recurrent somatic mutated genes were identified, including RBM14, MTUS1, GAK, DST, RNF213 and XIRP2 (20% and 2 of 10, respectively), and validated by Sanger sequencing. In terms of common mutated genes, SETD2 was altered in both CDC and other RCC subtypes but not in bladder urothelial carcinoma (BLCA); CDKN2A was a driver gene in both CDC (SNV: 10%, 1 of 10) and BLCA but not in other RCC subtypes. Next, 29 amplifications and 6 deletions of recurrent focal somatic CNVs were identified by GISTIC2.0, which displayed differences from kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and BLCA cohorts. Of note, CDKN2A (CNV alteration: 30%, 3 of 10) and CDKN2A-AS1 were the only overlapping genes of these four cohorts. Importantly, the CDKN2A mutation in our cohort differed from previous studies in urinary carcinomas. Moreover, CDKN2A-altered cases had significantly worse overall survival than wild-type cases in both KIRC and KIRP cohorts. In addition, the most frequently altered genomic pathway of our CDC cohort was the CDKN2A-mediated p53/RB1 pathway. Conclusions Our study offers the first genomic spectrum of the Chinese population with CDC, which differs from that of the Western population. The altered CDKN2A-mediated p53/RB1 pathway might provide new insight into potential therapeutic targets for CDC patients.


2022 ◽  
Vol 50 (1) ◽  
pp. 030006052110707
Author(s):  
Sanjeev Kharel ◽  
Suraj Shrestha ◽  
Siddhartha Yadav ◽  
Prafulla Shakya ◽  
Sujita Baidya ◽  
...  

Objective Breast cancer (BC) is the most common form of cancer among Asian females. Mutations in the BRCA1/ BRCA2 genes are often observed in BC cases and largely increase the lifetime risk of having BC. Because of the paucity of high-quality data on the molecular spectrum of BRCA mutations in South Asian populations, we aimed to explore these mutations among South Asian countries. Methods A systematic literature search was performed for the BRCA1 and BRCA2 gene mutation spectrum using electronic databases such as PubMed, EMBASE, and Google Scholar. Twenty studies were selected based on specific inclusion and exclusion criteria. Results The 185delAG (c.68_69del) mutation in exon 2 of BRCA1 was the most common recurrent mutation and founder mutation found. Various intronic variants, variants of unknown significance, large genomic rearrangements, and polymorphisms were also described in some studies. Conclusions The South Asian population has a wide variety of genetic mutations of BRCA1 and BRCA2 that differ according to countries and ethnicities. A stronger knowledge of various population-specific mutations in these cancer susceptibility genes can help provide efficient strategies for genetic testing.


2022 ◽  
Vol 100 (S267) ◽  
Author(s):  
Mohammed Derar ◽  
Emma C. Lord ◽  
James A. Poulter ◽  
Andrew R. Webster ◽  
Sandra M. Bell ◽  
...  

CYTOLOGIA ◽  
2021 ◽  
Vol 86 (4) ◽  
pp. 303-309
Author(s):  
Ryouhei Morita ◽  
Hiroyuki Ichida ◽  
Yoriko Hayashi ◽  
Kotaro Ishii ◽  
Yuki Shirakawa ◽  
...  

2021 ◽  
Vol 62 (15) ◽  
pp. 4
Author(s):  
Tianchang Tao ◽  
Ningda Xu ◽  
Jiarui Li ◽  
Hongyan Li ◽  
Jinfeng Qu ◽  
...  

Neurogenetics ◽  
2021 ◽  
Author(s):  
Ji-You Min ◽  
Seo-Jin Park ◽  
Eun-Joo Kang ◽  
Seung-Yong Hwang ◽  
Sung-Hee Han

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1996-1996
Author(s):  
Erina Nakahara ◽  
Keiko Yamamoto ◽  
Takako Aoki ◽  
Hiromi Ogura ◽  
Taiju Utsugisawa ◽  
...  

Abstract Background: Hereditary stomatocytosis (HSt) is a group of congenital hemolytic anemia caused by abnormally increased cation permeability of erythrocyte membranes. The most common subtype is dehydrated HSt (DHSt), and heterozygous mutations of the mechanosensitive calcium channel gene PIEZO1 have been associated with it most frequently. DHSt is suspected by screening tests such as erythrocyte morphology, cation concentration measurements inside and outside the erythrocyte membrane, or osmotic gradient ektacytometry; target-captured sequencing (TCS) is used for definitive diagnosis. We have shown that an increase in the residual red cells (%RRC) in a quantitative osmotic fragility test using a flow cytometer (FCM-OF) is useful as a screening test for DHSt. Purpose: We report the clinical findings and mutation spectrum of Japanese patients with DHSt confirmed by genetic testing. Methods: From April 2015 to June 2021, 27 patients who had a clinical diagnosis of DHSt and provided written consent were genetically tested. The clinical indications were hemolytic anemia with stomatocytes, accompanied by hemochromatosis, a family history, perinatal edema, and severe jaundice. Laboratory tests showed increased MCV, and subjects with an increased %RRC in FCM-OF were analyzed. TCS was performed using a hemolytic anemia-related gene panel. Results: Of the 27 patients, 14 had PIEZO1 variants, 3 had KCNN4 variants, and 2 had ABCB6 variants, for a total of 19 cases diagnosed as HSt. There was 1 SPTB mutation, 1 GCLC mutation, and 6 cases without mutations in genes known to be related to hemolytic anemia. There were 12 previously reported mutations (KCNN4: R352H, PIEZO1: V598M, T2014I, R2488Q, E2496ELE) and 5 novel mutations (KCNN4: P204R, A279T, PIEZO1: 427_428ins9AA, A1457V, K2323T).Notably, 5 E2496ELE mutations were found in unrelated individuals. There were no differences in age at diagnosis and severity of anemia between the E2496ELE mutation and other PIEZO1 mutations, but jaundice was more severe in patients with the E2496ELE mutation (p=0.007).The median age at diagnosis of the DHSt patients was 28 years (range: 2 months to 89 years); there were 6 men and 11 women. Three patients underwent splenectomy, and 2 patients with PIEZO1 mutations had postoperative thrombosis; 1 KCNN4 mutation had no complications, but no improvement in hemolytic anemia. Six patients had gallstones, 3 had fetal ascites, and 11 received red blood cell transfusions. Laboratory test results showed median Hb 10.4 g/dL (6.9-15.6), median MCV 99.7 fL (85-127.4), median MCHC 35.6% (33-39), and median T-Bil 3.4 mg/dL (0.5-37.9). The median ferritin level was 569.3 ng/mL (87.1-3895); of the 14 patients whose ferritin was measured at the time of diagnosis, 6 had already exceeded 1,000 ng/mL. The FCM-OF showed high values in all 16 cases tested. Discussion: Genetic testing was performed on cases in which DHSt was suspected based on clinical findings, smears, and FCM-OF; the diagnosis of DHSt was confirmed at a high percentage. As previously reported, the severity of hemolytic anemia was wide-ranging, and many cases of hemochromatosis were observed. The PIEZO1 mutation is the most common in the Japanese population, and the number of E2496ELE mutations is particularly conspicuous. Patients carrying E2496ELE mutations are reported to have a younger age at diagnosis and more severe hematological findings than other mutations; however, our results showed no significant differences in age at diagnosis or degree of anemia. Since the correlation between PIEZO1 gene mutation and phenotype has not yet been clarified, further research is considered necessary. Disclosures No relevant conflicts of interest to declare.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi122-vi122
Author(s):  
Juan Li ◽  
Mingyao Lai ◽  
Qingjun Hu ◽  
Ruyu Ai ◽  
Linbo Cai

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.


2021 ◽  
Vol 8 ◽  
Author(s):  
Xun Wang ◽  
Dongni Wang ◽  
Qiwei Wang ◽  
Weiming Huang ◽  
Meimei Dongye ◽  
...  

Purpose: To broaden the mutation and phenotype spectrum of the GJA8 and CHMP4B genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs).Methods: Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins.Results: Four heterozygous candidate variants in three different genes (CRYBB2, GJA8, and CHMP4B) were identified in affected individuals from the six families, including two novel missense variants (GJA8: c.64G > C/p. G22R, and CHMP4B: c.587C > G/p. S196C), one missense mutation (CRYBB2: c.562C > T/p. R188C), and one small deletion (GJA8: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the GJA8: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts.Conclusion: This study further expands the mutation spectrum and genotype-phenotype correlation of CRYBB2, GJA8, and CHMP4B underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.


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