Whole exome sequencing to identify potentially causative gene variants in hereditary gastric cancer.

BackgroundThe genetic causes of the majority of male and female infertility caused by human non-obstructive azoospermia (NOA) and premature ovarian insufficiency (POI) with meiotic arrest are unknown.ObjectiveTo identify the genetic cause of NOA and POI in two affected members from a consanguineous Chinese family.MethodsWe performed whole-exome sequencing of DNA from both affected patients. The identified candidate causative gene was further verified by Sanger sequencing for pedigree analysis in this family. In silico analysis was performed to functionally characterise the mutation, and histological analysis was performed using the biopsied testicle sample from the male patient with NOA.ResultsWe identified a novel homozygous missense mutation (NM_007068.3: c.106G>A, p.Asp36Asn) in DMC1, which cosegregated with NOA and POI phenotypes in this family. The identified missense mutation resulted in the substitution of a conserved aspartic residue with asparaginate in the modified H3TH motif of DMC1. This substitution results in protein misfolding. Histological analysis demonstrated a lack of spermatozoa in the male patient’s seminiferous tubules. Immunohistochemistry using a testis biopsy sample from the male patient showed that spermatogenesis was blocked at the zygotene stage during meiotic prophase I.ConclusionsTo the best of our knowledge, this is the first report identifying DMC1 as the causative gene for human NOA and POI. Furthermore, our pedigree analysis shows an autosomal recessive mode of inheritance for NOA and POI caused by DMC1 in this family.

Download Full-text

Abstract 4694: Whole-exome sequencing of gastric cancer identifies germline PIK3R1 variant as a novel genetic biomarker for a PI3K beta-isoform selective inhibitor, GSK2636771

10.1158/1538-7445.am2015-4694 ◽

2015 ◽

Cited By ~ 2

Author(s):

Chan Kim ◽

Woo Sun Kwon ◽

Sun Young Rha ◽

Sun Kyung Kang ◽

Hyoki Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Selective Inhibitor ◽

Whole Exome ◽

Genetic Biomarker

Download Full-text

Whole-exome sequencing identifies prognostic mutational signatures in gastric cancer

Annals of Translational Medicine ◽

10.21037/atm-20-6620 ◽

2020 ◽

Vol 8 (22) ◽

pp. 1484-1484

Author(s):

Zhenxin Zhu ◽

Hongbing Fu ◽

Shengzhou Wang ◽

Xinxin Yu ◽

Qing You ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Mutational Signatures ◽

Whole Exome

Download Full-text

Genetic alterations and their clinical implications in gastric cancer peritoneal carcinomatosis revealed by whole-exome sequencing of malignant ascites

Oncotarget ◽

10.18632/oncotarget.6977 ◽

2016 ◽

Vol 7 (7) ◽

pp. 8055-8066 ◽

Cited By ~ 21

Author(s):

Byungho Lim ◽

Chan Kim ◽

Jeong-Hwan Kim ◽

Woo Sun Kwon ◽

Won Seok Lee ◽

...

Keyword(s):

Gastric Cancer ◽

Peritoneal Carcinomatosis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Malignant Ascites ◽

Genetic Alterations ◽

Clinical Implications ◽

Whole Exome

Download Full-text

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Journal of Child Neurology ◽

10.1177/0883073816664836 ◽

2016 ◽

Vol 31 (14) ◽

pp. 1534-1539 ◽

Cited By ~ 29

Author(s):

Maya Kuperberg ◽

Dorit Lev ◽

Lubov Blumkin ◽

Ayelet Zerem ◽

Mira Ginsberg ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Recessive ◽

Genetic Diagnosis ◽

Clinical Feature ◽

Causative Gene ◽

High Detection Rate ◽

Whole Exome ◽

Neurological Patients ◽

Low Costs

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

Download Full-text

Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4082 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4082-4082

Author(s):

David Paul Kelsen ◽

Kasmintan A. Schrader ◽

Raya Khanin ◽

Laura H. Tang ◽

Erin E. Salo-Mullen ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Germ Line ◽

Diffuse Gastric Cancer ◽

Second Hit ◽

Whole Exome ◽

Prophylactic Gastrectomy ◽

Variable Penetrance

4082 Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C>A(pro484his);c. 1792C>T (arg598ter);c. 1893dupA in exon 12;c. 1565+1G>A (IVS10+1G>A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible "second hit" is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.

Download Full-text