계명대학교 의학도서관 Repository

Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers

Metadata Downloads
Author(s)
Soo Young ChoJun Won ParkYang LiuYoung Soo ParkJu Hee KimHanna YangHyejin UmWoo Ri KoByung Il LeeSun Young KwonSeung Wan RyuChae Hwa KwonDo Youn ParkJae-Hyuk LeeSang Il LeeKyu Sang SongHoon HurSang-Uk HanHeekyung ChangSu-Jin KimByung-Sik KimJeong-Hwan YookMoon-Won YooBeom-Su KimIn-Seob LeeMyeong-Cherl KookNina ThiessenAn HeChip StewartAndrew DunfordJaegil KimJuliann ShihGordon SaksenaAndrew D. CherniackSteven SchumacherAmaro-Taylor WeinerMara RosenbergGad GetzEun Gyeong YangMin-Hee RyuAdam J. BassHark Kyun Kim
Keimyung Author(s)
Kwon, Sun Young
Department
Dept. of Pathology (병리학)
Journal Title
Gastroenterology
Issued Date
2017
Volume
153
Issue
2
Keyword
AgeGenomicStomachYoung
Abstract
BACKGROUND & AIMS:

Early-onset gastric cancer, which develops in patients younger than most gastric cancers, is usually detected at advanced stages, has diffuse histologic features, and occurs more frequently in women. We investigated somatic genomic alterations associated with the unique characteristics of sporadic diffuse gastric cancers (DGCs) from younger patients.

METHODS:

We conducted whole exome and RNA sequence analyses of 80 resected DGC samples from patients 45 years old or younger in Korea. Patients with pathogenic germline mutations in CDH1, TP53, and ATM were excluded from the onset of this analysis, given our focus on somatic alterations. We used MutSig2CV to evaluate the significance of mutated genes. We recruited 29 additional early-onset Korean DGC samples and performed SNP6.0 array and targeted sequencing analyses of these 109 early-onset DGC samples (54.1% female, median age, 38 years). We compared the SNP6.0 array and targeted sequencing data of the 109 early-onset DGC samples with those from diffuse-type stomach tumor samples collected from 115 patients in Korea who were 46 years or older (late onset) at the time of diagnosis (controls; 29.6% female, median age, 67 years). We compared patient survival times among tumors from different subgroups and with different somatic mutations. We performed gene silencing of RHOA or CDH1 in DGC cells with small interfering RNAs for cell-based assays.

RESULTS:

We identified somatic mutations in the following genes in a significant number of early-onset DGCs: the cadherin 1 gene (CDH1), TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. None of 109 early-onset DGC cases had pathogenic germline CDH1 mutations. A higher proportion of early-onset DGCs had mutations in CDH1 (42.2%) or TGFBR1 (7.3%) compared with control DGCs (17.4% and 0.9%, respectively) (P < .001 and P = .014 for CDH1 and TGFBR1, respectively). In contrast, a smaller proportion of early-onset DGCs contained mutations in RHOA (9.2%) than control DGCs (19.1%) (P = .033). Late-onset DGCs in The Cancer Genome Atlas also contained less frequent mutations in CDH1 and TGFBR1 and more frequent RHOA mutations, compared with early-onset DGCs. Early-onset DGCs from women contained significantly more mutations in CDH1 or TGFBR1 than early-onset DGCs from men. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times in patients with early-onset DGCs (hazard ratio, 3.4; 95% confidence interval, 1.5-7.7). RHOA activity was reduced by an R5W substitution-the RHOA mutation most frequently detected in early-onset DGCs. Silencing of CDH1, but not RHOA, increased migratory activity of DGC cells.

CONCLUSIONS:

In an integrative genomic analysis, we found higher proportions of early-onset DGCs to contain somatic mutations in CDH1 or TGFBR1 compared with late-onset DGCs. However, a smaller proportion of early-onset DGCs contained somatic mutations in RHOA than late-onset DGCs. CDH1 alterations, but not RHOA mutations, were associated with shorter survival times of patients, which might account for the aggressive clinical course of early-onset gastric cancer. Female predominance in early-onset gastric cancer may be related to relatively high rates of somatic CDH1 and TGFBR1 mutations in this population.
Keimyung Author(s)(Kor)
권선영
Publisher
School of Medicine (의과대학)
Citation
Soo Young Cho et al. (2017). Sporadic Early-Onset Diffuse Gastric Cancers Have High Frequency of Somatic CDH1 Alterations, but Low Frequency of Somatic RHOA Mutations Compared With Late-Onset Cancers. Gastroenterology, 153(2), 536–549. doi: 10.1053/j.gastro.2017.05.012
Type
Article
ISSN
0016-5085
DOI
10.1053/j.gastro.2017.05.012
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/41482
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Pathology (병리학)
공개 및 라이선스
  • 공개 구분공개
파일 목록

Items in Repository are protected by copyright, with all rights reserved, unless otherwise indicated.