Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes

Cellular and Molecular Research, National Cancer Centre, Singapore.
Nature Genetics (Impact Factor: 29.35). 04/2012; 44(5):570-4. DOI: 10.1038/ng.2246
Source: PubMed


Gastric cancer is a major cause of global cancer mortality. We surveyed the spectrum of somatic alterations in gastric cancer by sequencing the exomes of 15 gastric adenocarcinomas and their matched normal DNAs. Frequently mutated genes in the adenocarcinomas included TP53 (11/15 tumors), PIK3CA (3/15) and ARID1A (3/15). Cell adhesion was the most enriched biological pathway among the frequently mutated genes. A prevalence screening confirmed mutations in FAT4, a cadherin family gene, in 5% of gastric cancers (6/110) and FAT4 genomic deletions in 4% (3/83) of gastric tumors. Frequent mutations in chromatin remodeling genes (ARID1A, MLL3 and MLL) also occurred in 47% of the gastric cancers. We detected ARID1A mutations in 8% of tumors (9/110), which were associated with concurrent PIK3CA mutations and microsatellite instability. In functional assays, we observed both FAT4 and ARID1A to exert tumor-suppressor activity. Somatic inactivation of FAT4 and ARID1A may thus be key tumorigenic events in a subset of gastric cancers.

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Available from: Ioana Cutcutache, Feb 23, 2015
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    • "In particular, ARID1A mutations have been found in up to 10% of tumours, often concurrent with microsatellite instability and PIK3CA-activating mutations. ARID1A may also be a novel tumour suppressor gene, presenting possible therapeutic opportunities [28]. Receptor tyrosine kinase (RTK)/RAS amplifications (e.g. "
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    ABSTRACT: Although the incidence of gastric cancer has fallen steadily in developed countries over the past 50 years, outcomes in Western countries remain poor, primarily due to the advanced stage of the disease at presentation. While earlier diagnosis would help to improve outcomes for patients with gastric cancer, better understanding of the biology of the disease is also needed, along with advances in therapy. Indeed, progress in the treatment of gastric cancer has been limited, mainly because of its genetic complexity and heterogeneity. As a result, there is an urgent need to apply precision medicine to the management of the disease in order to ensure that individuals receive the most appropriate treatment. This article suggests a number of strategies that may help to accelerate progress in treating patients with gastric cancer. Incorporation of some of these approaches could help to improve the quality of life and survival for patients diagnosed with the disease. Standardisation of care across Europe through expansion of the European Registration of Cancer Care (EURECCA) registry – a European cancer audit that aims to improve quality and decrease variation in care across the region – may also be expected to lead to improved outcomes for those suffering from this common malignancy.
    Cancer Treatment Reviews 07/2014; 40(6). DOI:10.1016/j.ctrv.2014.03.002 · 7.59 Impact Factor
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    • "Interestingly, ARID1A mutations frequently coexist with activating mutations of PIK3CA [12, 19] and/or loss of PTEN expression [20], which both lead to a downstream activation of the PI3K/AKT pathway. Furthermore, it has recently been shown in endometrial cancer that loss of ARID1A expression leads to an increased phosphorylation of AKT at Ser-473[21]. "
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    ABSTRACT: ARID1A mutations are observed in various tumors, including ovarian clear cell (OCCC) and endometrioid carcinomas, endometrial, and breast carcinomas. They commonly result in loss of ARID1A-protein expression and frequently co-occur with PI3K/AKT-pathway activating mechanisms. The aim of this study was to test the hypothesis as to whether PI3K/AKT-pathway activation is a critical mechanism in ARID1A-mutated tumors and if consequently ARID1A-deficient tumors show increased sensitivity to treatment with PI3K- and AKT-inhibitors. Upon ARID1A knockdown, MCF7 breast cancer cells and primary MRC5 cells exhibited a significantly increased sensitivity towards the AKT-inhibitors MK-2206 and perifosine, as well as the PI3K-inhibitor buparlisib. Knockdown of ARID1A in MCF7 led to an increase of pAKT-Ser473. AKT-inhibition with MK-2206 led to increased apoptosis and to a decrease of pS6K in ARID1A-depleted MCF7 cells but not in the controls. In five OCCC cell lines ARID1A-deficiency correlated with increased pAKT-Ser473 levels and with sensitivity towards treatment with the AKT-inhibitor MK-2206. In conclusion, ARID1A-deficient cancer cells demonstrate an increased sensitivity to treatment with small molecule inhibitors of the PI3K/AKT-pathway. These findings suggest a specific requirement of the PI3K/AKT pathway in ARID1A-deficient tumors and reveal a synthetic lethal interaction between loss of ARID1A expression and inhibition of the PI3K/AKT pathway.
    Oncotarget 06/2014; 5(14). DOI:10.5167/uzh-106117 · 6.36 Impact Factor
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    • "Hippo pathway inactivation has been observed in cancer [29] including CRC in which both FAT4 and FAT2, putative Hippo pathway receptors [30], are significantly mutated in 24% of the cases [15]. FAT4 has been recently established as a tumor suppressor [31], generally mutated in less than 10% of epithelial cancers (Additional file 3: Table S12). Our results therefore suggest that the inactivation of genes in the Hippo pathway may contribute to MNA development in ways similar to CRC. "
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    ABSTRACT: Background Mucinous neoplasms of the appendix (MNA) are rare tumors which may progress from benign to malignant disease with an aggressive biological behavior. MNA is often diagnosed after metastasis to the peritoneal surfaces resulting in mucinous carcinomatosis peritonei (MCP). Genetic alterations in MNA are poorly characterized due to its low incidence, the hypo-cellularity of MCPs, and a lack of relevant pre-clinical models. As such, application of targeted therapies to this disease is limited to those developed for colorectal cancer and not based on molecular rationale. Methods We sequenced the whole exomes of 10 MCPs of appendiceal origin to identify genome-wide somatic mutations and copy number aberrations and validated significant findings in 19 additional cases. Results Our study demonstrates that MNA has a different molecular makeup than colorectal cancer. Most tumors have co-existing oncogenic mutations in KRAS (26/29) and GNAS (20/29) and are characterized by downstream PKA activation. High-grade tumors are GNAS wild-type (5/6), suggesting they do not progress from low-grade tumors. MNAs do share some genetic alterations with colorectal cancer including gain of 1q (5/10), Wnt, and TGFβ pathway alterations. In contrast, mutations in TP53 (1/10) and APC (0/10), common in colorectal cancer, are rare in MNA. Concurrent activation of the KRAS and GNAS mediated signaling pathways appears to be shared with pancreatic intraductal papillary mucinous neoplasm. Conclusions MNA genome-wide mutational analysis reveals genetic alterations distinct from colorectal cancer, in support of its unique pathophysiology and suggests new targeted therapeutic opportunities.
    Genome Medicine 05/2014; 6(5):43. DOI:10.1186/gm559 · 5.34 Impact Factor
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