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Gastroenterology. 2017 Aug;153(2):536-549.e26. doi: 10.1053/j.gastro.2017.05.012. Epub 2017 May 15.

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.

Author information

1
National Cancer Center, Goyang, Gyeonggi, Republic of Korea.
2
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
3
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
4
Department of Pathology, Keimyung University School of Medicine, Daegu, Republic of Korea.
5
Department of Surgery, Keimyung University School of Medicine, Daegu, Republic of Korea.
6
Department of Pathology and BioMedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Republic of Korea.
7
Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea.
8
Department of Surgery, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.
9
Department of Pathology, School of Medicine, Chungnam National University, Daejeon, Republic of Korea.
10
Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
11
Department of Pathology, Kosin University College of Medicine, Busan, Republic of Korea.
12
Department of Pathology, Dong-A University College of Medicine, Busan, Republic of Korea.
13
Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
14
British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
15
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
16
Korea Institute of Science and Technology, Seoul, Republic of Korea.
17
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
18
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address: adam_bass@dfci.harvard.edu.
19
National Cancer Center, Goyang, Gyeonggi, Republic of Korea; National Cancer Center Graduate School of Cancer Science and Policy, Goyang, Gyeonggi, Republic of Korea. Electronic address: hkim@ncc.re.kr.

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.

KEYWORDS:

Age; Genomic; Stomach; Young

PMID:
28522256
DOI:
10.1053/j.gastro.2017.05.012
[Indexed for MEDLINE]
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