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

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.

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ANALYSIS OF GENE MUTATION IN EARLY SPORADIC DIFFUSE-TYPE GASTRIC CANCER BASED ON HELICOBACTER PYLORI INFECTION STATUS THROUGH WHOLE-EXOME SEQUENCING

10.1055/s-0040-1704859 ◽

2020 ◽

Author(s):

K Namikawa ◽

J Fujisaki ◽

S Mori

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Exome Sequencing ◽

Gene Mutation ◽

Whole Exome Sequencing ◽

Helicobacter Pylori Infection ◽

Infection Status ◽

Diffuse Type ◽

Whole Exome ◽

Diffuse Type Gastric Cancer

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Genomic and immune intratumor heterogeneity in gastric linitis plastica.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16518 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16518-e16518

Author(s):

Jin Huang ◽

Guofeng Zhao ◽

Qiu Peng ◽

Jian Ma ◽

Pansong Li ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Cell Carcinoma ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Phylogenetic Trees ◽

Linitis Plastica ◽

Intratumor Heterogeneity ◽

Small Indels ◽

Whole Exome

e16518 Background: Gastric linitis plastica (LP) is a rare and aggressive type of gastric cancer (GC) for which the genomic landscape and architecture have gone largely undescribed. Methods: 4 LP patients were enrolled. 10 region tumor samples of each LP patient and matched peripheral blood were collected. Matched blood cells of each patient were also collected for removing germline background Whole-exome sequencing(WES), TCR sequencing, TCGA gastric cancer and several WES articles data were used to investigate intra and inter patient genomic and immune heterogeneity. Results: All 4 LP patients were female and were in stage III. LP biopsies were sequenced with median 290.6x effective depth. A total of 11,504 somatic mutations including 6,339 non-silent mutations were identified. The median non-silent tumor mutation burden (TMB) of biopsy samples was 3.23 mutations/Mb (range from 1.36 to 4.88), which was comparable to gastric adenocarcinoma(p = 0.3). Phylogenetic trees of 4 LP patients demonstrated clear evidence of branched evolution, and the phylogenetic trees varied extensively across the four cases. The percentages of trunk mutations of 4 LP were 12.8%, 5.4%, 5.4% and 30.7%, respectively, while the proportions of trunk neoantigens were 6.2%, 2.2%, 12% and 12.4, respectivelyWhen comparing LP to other multiregion WES studies, e.g., lung adenocarcinoma, renal cell carcinoma, and esophageal squamous cell carcinoma, LP was one of the most heterogeneous tumor types. The top mutational signatures in this cohort associated with spontaneous deamination, DNA mismatch repair (MMR), and small indels at repeats etc. Furthermore, profound TCR ITH was observed in all 4 LP patients. None of the T cell clones were shared among all tumor regions and 94.23-94.41% T cells were restricted to individual tumor regions. To quantify the TCR ITH, we utilized the Morisita overlap index (MOI), which ranged from 0.34 to 0.56 across different regions within the same tumors suggesting marked inter-individual TCR repertoire heterogeneity and profound intratumor TCR heterogeneity. Conclusions: Based on whole-exome sequencing and TCR sequencing, we demonstrate that LP is highly heterogeneous for mutations, neoantigens and T cells, which contributes to its poor prognosis.

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Identification of novel genes by whole-exome sequencing can improve gastric cancer precision oncology

Future Oncology ◽

10.2217/fon-2016-0430 ◽

2017 ◽

Vol 13 (10) ◽

pp. 883-892 ◽

Cited By ~ 5

Author(s):

Georgios D Lianos ◽

Georgios K Glantzounis ◽

Christina D Bali ◽

Christos Katsios ◽

Dimitrios H Roukos

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Precision Oncology ◽

Novel Genes ◽

Whole Exome

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Clonality analysis of synchronous gastro-oesophageal junction carcinoma and distal gastric cancer by whole-exome sequencing

The Journal of Pathology ◽

10.1002/path.4932 ◽

2017 ◽

Vol 243 (2) ◽

pp. 165-175 ◽

Cited By ~ 5

Author(s):

Xiaofang Xing ◽

Shuqin Jia ◽

Jianmin Wu ◽

Qin Feng ◽

Bin Dong ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Clonality Analysis ◽

Distal Gastric Cancer

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Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study

The Lancet Gastroenterology & Hepatology ◽

10.1016/s2468-1253(18)30079-7 ◽

2018 ◽

Vol 3 (7) ◽

pp. 489-498 ◽

Cited By ~ 23

Author(s):

Eleanor Fewings ◽

Alexey Larionov ◽

James Redman ◽

Mae A Goldgraben ◽

James Scarth ◽

...

Keyword(s):

Gastric Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Hereditary Diffuse Gastric Cancer ◽

Diffuse Gastric Cancer ◽

Pathogenic Variants ◽

Whole Exome ◽

Predisposing Genes ◽

Cdh1 Mutation

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Whole exome sequencing and gene expression profiling of neuroendocrine carcinoma in the stomach.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.57 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 57-57

Author(s):

Rie Makuuchi ◽

Masanori Terashima ◽

Masanori Tokunaga ◽

Yutaka Tanizawa ◽

Etsuro Bando ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Gene Expression Profiling ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Neuroendocrine Tumors ◽

Neuroendocrine Carcinoma ◽

Expression Profiling ◽

Neuroendocrine Cells ◽

Whole Exome

57 Background: Neuroendocrine carcinoma (NEC) in the stomach is a rare disease with the incidence of about 0.6 % of all gastric cancer and is well known as a highly malignant tumor with poor survival. Despite the malignant phenotype of this disease, the global gene expression profiling of gastric NEC has not yet been elucidated. We have started a comprehensive molecular profiling project that analyzes genome and transcriptome of tumor obtained from cancer patients admitted to Shizuoka Cancer Center from January 2014, setting a goal to get 3,000 samples in 3 years. We had already evaluated more than 1,500 samples from various types of malignancies, including 111 samples from gastric cancer. Here, we performed deep sequencing of 409 cancer-related genes for gastric NEC patients, adding whole-exome sequencing and gene expression profiling, to identify a gene variant of gastric NEC. Methods: Surgically-resected fresh tumor samples and peripheral blood were analyzed by whole-exome sequencing (Ion Proton, Life Technologies) and gene expression profiling (DNA microarray, Agilent Technologies). A total of 111 patients with gastric cancer were evaluated until August 2015, including 6 gastric NEC (5.4 %). We compared single nucleotide variants (SNVs) and gene expression profiles between gastric NEC and gastric adenocarcinoma. Results: All the gastric NEC patients were male with median age of 69 years (59–79 years). According to classification of TNM 7th, there were two patients with stage IA, one with IIA, one with IIIB and two with IIIC. Three of them had adenocarcinoma components constituted > 30% of the respective tumors, fulfilling the criteria for mixed adenoneuroendocrine carcinoma (MANEC), as defined by the WHO classification. There was no specific SNV for NEC. However, gene expression profiling identified several specific genes expressing in NEC; most of the highly expressed genes were also known to be expressed in neuroendocrine cells. Furthermore, CPLX2 and SCG3, which had been reported to be expressed in various neuroendocrine tumors, were included. Conclusions: Gastric NEC could be characterized by specific gene expression including those expressed in neuroendocrine cells and neuroendocrine tumors.

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