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

Soo Young Cho, Jun Won Park, Yang Liu, Young Su Park, Ju Hee Kim, Hanna Yang, Hyejin Um, Woo Ri Ko, Byung Il Lee, Sun Young Kwon, Seung Wan Ryu, Chae Hwa Kwon, Do Youn Park, Jae Hyuk Lee, Sang Il Lee, Kyu Sang Song, Hoon Hur, Sang Uk Han, Heekyung Chang, Su Jin KimByung Sik Kim, Jeong Hwan Yook, Moon Won Yoo, Beom Su Kim, In Seob Lee, Myeong Cherl Kook, Nina Thiessen, An He, Chip Stewart, Andrew Dunford, Jaegil Kim, Juliann Shih, Gordon Saksena, Andrew D. Cherniack, Steven Schumacher, Amaro Taylor Weiner, Mara Rosenberg, Gad Getz, Eun Gyeong Yang, Min Hee Ryu, Adam J. Bass, Hark Kyun Kim

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)536-549.e26
JournalGastroenterology
Volume153
Issue number2
DOIs
StatePublished - 1 Aug 2017

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Cadherins
Stomach Neoplasms
Mutation
Genes
Neoplasms
p53 Genes
Korea
Survival

Keywords

  • Age
  • Genomic
  • Stomach
  • Young

Cite this

Cho, Soo Young ; Park, Jun Won ; Liu, Yang ; Park, Young Su ; Kim, Ju Hee ; Yang, Hanna ; Um, Hyejin ; Ko, Woo Ri ; Lee, Byung Il ; Kwon, Sun Young ; Ryu, Seung Wan ; Kwon, Chae Hwa ; Park, Do Youn ; Lee, Jae Hyuk ; Lee, Sang Il ; Song, Kyu Sang ; Hur, Hoon ; Han, Sang Uk ; Chang, Heekyung ; Kim, Su Jin ; Kim, Byung Sik ; Yook, Jeong Hwan ; Yoo, Moon Won ; Kim, Beom Su ; Lee, In Seob ; Kook, Myeong Cherl ; Thiessen, Nina ; He, An ; Stewart, Chip ; Dunford, Andrew ; Kim, Jaegil ; Shih, Juliann ; Saksena, Gordon ; Cherniack, Andrew D. ; Schumacher, Steven ; Weiner, Amaro Taylor ; Rosenberg, Mara ; Getz, Gad ; Yang, Eun Gyeong ; Ryu, Min Hee ; Bass, Adam J. ; Kim, Hark Kyun. / 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. In: Gastroenterology. 2017 ; Vol. 153, No. 2. pp. 536-549.e26.
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title = "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",
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",
author = "Cho, {Soo Young} and Park, {Jun Won} and Yang Liu and Park, {Young Su} and Kim, {Ju Hee} and Hanna Yang and Hyejin Um and Ko, {Woo Ri} and Lee, {Byung Il} and Kwon, {Sun Young} and Ryu, {Seung Wan} and Kwon, {Chae Hwa} and Park, {Do Youn} and Lee, {Jae Hyuk} and Lee, {Sang Il} and Song, {Kyu Sang} and Hoon Hur and Han, {Sang Uk} and Heekyung Chang and Kim, {Su Jin} and Kim, {Byung Sik} and Yook, {Jeong Hwan} and Yoo, {Moon Won} and Kim, {Beom Su} and Lee, {In Seob} and Kook, {Myeong Cherl} and Nina Thiessen and An He and Chip Stewart and Andrew Dunford and Jaegil Kim and Juliann Shih and Gordon Saksena and Cherniack, {Andrew D.} and Steven Schumacher and Weiner, {Amaro Taylor} and Mara Rosenberg and Gad Getz and Yang, {Eun Gyeong} and Ryu, {Min Hee} and Bass, {Adam J.} and Kim, {Hark Kyun}",
year = "2017",
month = "8",
day = "1",
doi = "10.1053/j.gastro.2017.05.012",
language = "English",
volume = "153",
pages = "536--549.e26",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

Cho, SY, Park, JW, Liu, Y, Park, YS, Kim, JH, Yang, H, Um, H, Ko, WR, Lee, BI, Kwon, SY, Ryu, SW, Kwon, CH, Park, DY, Lee, JH, Lee, SI, Song, KS, Hur, H, Han, SU, Chang, H, Kim, SJ, Kim, BS, Yook, JH, Yoo, MW, Kim, BS, Lee, IS, Kook, MC, Thiessen, N, He, A, Stewart, C, Dunford, A, Kim, J, Shih, J, Saksena, G, Cherniack, AD, Schumacher, S, Weiner, AT, Rosenberg, M, Getz, G, Yang, EG, Ryu, MH, Bass, AJ & Kim, HK 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, vol. 153, no. 2, pp. 536-549.e26. https://doi.org/10.1053/j.gastro.2017.05.012

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. / Cho, Soo Young; Park, Jun Won; Liu, Yang; Park, Young Su; Kim, Ju Hee; Yang, Hanna; Um, Hyejin; Ko, Woo Ri; Lee, Byung Il; Kwon, Sun Young; Ryu, Seung Wan; Kwon, Chae Hwa; Park, Do Youn; Lee, Jae Hyuk; Lee, Sang Il; Song, Kyu Sang; Hur, Hoon; Han, Sang Uk; Chang, Heekyung; Kim, Su Jin; Kim, Byung Sik; Yook, Jeong Hwan; Yoo, Moon Won; Kim, Beom Su; Lee, In Seob; Kook, Myeong Cherl; Thiessen, Nina; He, An; Stewart, Chip; Dunford, Andrew; Kim, Jaegil; Shih, Juliann; Saksena, Gordon; Cherniack, Andrew D.; Schumacher, Steven; Weiner, Amaro Taylor; Rosenberg, Mara; Getz, Gad; Yang, Eun Gyeong; Ryu, Min Hee; Bass, Adam J.; Kim, Hark Kyun.

In: Gastroenterology, Vol. 153, No. 2, 01.08.2017, p. 536-549.e26.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Cho, Soo Young

AU - Park, Jun Won

AU - Liu, Yang

AU - Park, Young Su

AU - Kim, Ju Hee

AU - Yang, Hanna

AU - Um, Hyejin

AU - Ko, Woo Ri

AU - Lee, Byung Il

AU - Kwon, Sun Young

AU - Ryu, Seung Wan

AU - Kwon, Chae Hwa

AU - Park, Do Youn

AU - Lee, Jae Hyuk

AU - Lee, Sang Il

AU - Song, Kyu Sang

AU - Hur, Hoon

AU - Han, Sang Uk

AU - Chang, Heekyung

AU - Kim, Su Jin

AU - Kim, Byung Sik

AU - Yook, Jeong Hwan

AU - Yoo, Moon Won

AU - Kim, Beom Su

AU - Lee, In Seob

AU - Kook, Myeong Cherl

AU - Thiessen, Nina

AU - He, An

AU - Stewart, Chip

AU - Dunford, Andrew

AU - Kim, Jaegil

AU - Shih, Juliann

AU - Saksena, Gordon

AU - Cherniack, Andrew D.

AU - Schumacher, Steven

AU - Weiner, Amaro Taylor

AU - Rosenberg, Mara

AU - Getz, Gad

AU - Yang, Eun Gyeong

AU - Ryu, Min Hee

AU - Bass, Adam J.

AU - Kim, Hark Kyun

PY - 2017/8/1

Y1 - 2017/8/1

N2 - 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.

AB - 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.

KW - Age

KW - Genomic

KW - Stomach

KW - Young

UR - http://www.scopus.com/inward/record.url?scp=85025110206&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2017.05.012

DO - 10.1053/j.gastro.2017.05.012

M3 - Article

C2 - 28522256

AN - SCOPUS:85025110206

VL - 153

SP - 536-549.e26

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

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