Dataset Information

High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma.

ABSTRACT:

Background

Gastric cancer is one of the leading cancer types in incidence and mortality, especially in Asia. In order to improve survival, identification of a catalogue of molecular alterations underlying gastric cancer is a critical step for developing and designing genome-directed therapies.

Methodology/principal findings

The Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mutation status of a large panel of known cancer genes. The mutation detection platform, termed OncoMap v4, interrogates 474 "hotspot" mutations in 41 genes that are relevant for cancer. We performed OncoMap v4 in formalin-fixed paraffin-embedded (FFPE) tissue specimens from 237 gastric adenocarcinomas. Using OncoMap v4, we found that 34 (14.4%) of 237 gastric cancer patients harbored mutations. Among mutations we screened, PIK3CA mutations were the most frequent (5.1%) followed by p53 (4.6%), APC (2.5%), STK11 (2.1%), CTNNB1 (1.7%), and CDKN2A (0.8%). Six samples harbored concomitant somatic mutations. Mutations of CTNNB1 were significantly more frequent in EBV-associated gastric carcinoma (P = 0.046). Our study led to the detection of potentially druggable mutations in gastric cancer which may guide novel therapies in subsets of gastric cancer patients.

Conclusions/significance

Using high throughput mutation screening platform, we identified that PIK3CA mutations were the most frequently observed target for gastric adenocarcinoma.

SUBMITTER: Lee J

PROVIDER: S-EPMC3377730 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma.

Lee Jeeyun J van Hummelen Paul P Go Christina C Palescandolo Emanuele E Jang Jiryeon J Park Ha Young HY Kang So Young SY Park Joon Oh JO Kang Won Ki WK MacConaill Laura L Kim Kyoung-Mee KM

PloS one 20120618 6

<h4>Background</h4>Gastric cancer is one of the leading cancer types in incidence and mortality, especially in Asia. In order to improve survival, identification of a catalogue of molecular alterations underlying gastric cancer is a critical step for developing and designing genome-directed therapies.<h4>Methodology/principal findings</h4>The Center for Cancer Genome Discovery (CCGD) at the Dana-Farber Cancer Institute (DFCI) has adapted a high-throughput genotyping platform to determine the mut ...[more]

PMID: 22723903

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Project description:BackgroundThe dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients.MethodsWe analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes.ResultsIn total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005).ConclusionsDynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients.

Dataset Information

High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma.

Background

Methodology/principal findings

Conclusions/significance

Publications

High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma.

Similar Datasets

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