Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Liang, Han; Cheung, Lydia W.T.; Li, Jie; Zhang, Ju; Yu, Shuangxing; Stemke-Hale, Katherine; Dogruluk, Turgut; Lu, Yiling; Liu, Xiuping; Gu, Chao; Guo, Wei; Scherer, Steven E.; Carter, Hannah; Westin, Shannon N.; Dyer, Mary D.; Zhang, Fan; Karchin, Rachel; Liu, Chang Gong; Lu, Karen H.; Broaddus, Russell R.; Scott, Kenneth L.; Hennessy, Bryan T.; Mills, Gordon B.

doi:10.1101/gr.137596.112

Cited by 221 publications

(199 citation statements)

References 63 publications

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“…In vitro work using endometrial cancer cell lines supports this by showing increased AKT phosphorylation in response to ARID1A knockdown, demonstrating ARID1A as a regulator of the PI3K-Akt pathway in a similar manner as PTEN. 1 On the basis of these findings, we speculate that co-occurrence of PIK3CA mutations Loss of ARID1A in endometrial cancer and ARID1A loss may be explained by a mechanism of oncogenic addiction, in which mutational pressure on the PIK3CA gene is relatively high in ARID1A-mutated tumors. Understanding this relationship may become particularly important when targeting strategies are designed in the future.…”

Section: Modern Pathology (2013) 26 1525-1535mentioning

confidence: 68%

“…12 A possible association between ARID1A loss and MSI, as has been reported for gastric cancer, has not been studied in endometrial cancer. Several studies 1,2,12 have shown an inverse relationship between TP53 and ARID1A mutations, suggesting that mutations in either of these two genes result in a similar downstream effect. Liang et al 1 showed in cell line models that ARID1A and TP53 may cooperate in one complex (ARID1A/ SMARCD3/TP53), explaining why ARID1A and TP53 mutations may be mutually exclusive.…”

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confidence: 99%

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Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

et al. 2013

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The switch/sucrose non-fermentable (SWI/SNF) subunit ARID1A (AT-rich interactive domain 1A gene) has been recently postulated as a novel tumor suppressor of gynecologic cancer and one of the driver genes in endometrial carcinogenesis. However, specific relationships with established molecular alterations in endometrioid endometrial cancer (EEC) are currently unknown. We analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry) and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), we included a 'Lynch syndrome set'. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in EECs in 31% (40/130) of the EEC cases. No loss of expression of the other subunits of the SWI/SNF complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P ¼ 0.0004). In contrast to Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14%) of the 'Lynch syndrome set' as compared with 24 cases (75%, Po0.0001) of the sporadic microsatellite-unstable tumors showed loss of ARID1A. These observations suggest that ARID1A is a causative gene, instead of a target gene, of microsatellite instability by having a role in epigenetic silencing of the MLH1 gene in endometrial cancer. Keywords: ARID1A; endometrial cancer; Lynch syndrome; microsatellite instability Recent genome-wide sequencing studies have demonstrated that the AT-rich interactive domain 1A (ARID1A) gene is frequently mutated in a wide variety of cancer types 1 including a subset of gynecological cancers. 2 In ovarian cancer, near half of the clear-cell subtype and 30% of the endometrioid subtype showed ARID1A mutations, 3 particularly those that are related to endometriosis. 4,5 In endometrial cancer, mutations in the ARID1A gene have been reported in approximately 30% of both low-and high-grade endometrioid endometrial cancers (EECs) but not in serous endometrial carcinomas. [6][7][8] ARID1A encodes a large nuclear protein involved in chromatin remodeling and interacts with several other proteins, including the core protein

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Section: Modern Pathology (2013) 26 1525-1535mentioning

confidence: 68%

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confidence: 99%

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

et al. 2013

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“…Mutations in TRPS1 lead to Tricho-rhino-phalangeal syndrome, an autosomal-dominant disorder characterized by craniofacial and skeletal malformations (45). Mutations in TRPS1 have been reported in several human cancers, including leukemia, prostate, colon, endometrial, and breast cancer (46)(47)(48)(49). Quantitative immunohistochemistry has also shown that TRPS1 is a prognostic marker in early-stage breast cancer and I-II ER+ patients receiving antihormone therapy (50).…”

Section: Sb-identified Ccgs Act As Tumor Suppressors In Human Breast mentioning

confidence: 99%

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

Rangel

Lee

Ban

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1. Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.Sleeping Beauty | breast cancer | TRPS1 | metastasis | tumor suppressors B reast cancer is the second leading cause of cancer-related deaths in the United States. The Cancer Genome Atlas (TCGA) network has classified breast cancer into four main subtypes: luminal A, luminal B, HER2+, and basal-like (1-5). Basal-like or triplenegative breast cancer (TNBC) constitutes 10-20% of all breast cancers and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 y and almost all die from their disease despite adjuvant chemotherapy (1, 3-5). Mutations, rearrangements, or deletions in highly penetrant genes such as BRCA1, BRCA2, TP53, CDH1, STK11, and PTEN are important drivers of TNBC (6-8). PTEN is a dual-specificity phosphatase that antagonizes the PI3K/AKT pathway through its lipid phosphatase activity and negatively regulates the MAPK pathway through its protein phosphatase activity (9, 10). Mutations in PTEN drive epithelial-mesenchymal transition (EMT) and promote metastasis in TNBC (11-13). Similarly, in mice, heterozygous deletion of Pten induces mammary tumors with basal-like characteristics (14)(15)(16)(17).Despite all of the cancer genome-sequencing efforts, there is still an incomplete understanding of the genes and genetic networks driving TNBC. New technologies that would provide a more complete understanding of the genetics of TNBC are still needed to deconvolute the complexity of this deadly cancer. Our laboratory and others have pioneered the use of transposon mutagenesis in mice as a tool for cancer gene discovery (18-26). Transposons induce cancer by randomly inserting into the mouse genome, mutating, and disrupting potential cancer genes. Transposon insertions in tumors thus serve as molecular tags for the high-throughput cloning and identification of cancer genes. In addition, because transposon insertions are PCR-amplified before they are sequenced, insertional mutations in cancer genes that are present in only a small fraction of tumor cells can be identified. Transposon mutagenesis can thus identify genes that are functioning at th...

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“…In other cancer types, both genome-wide and targeted loss-of-function studies were used to identify novel tumor suppressors in hepatocellular carcinoma (6) and epigenetic regulators in lymphomas (7). In addition, gain-offunction, cDNA-based approaches have uncovered novel driver roles for IKBKE (8) and PAK1 (9) in breast cancer, ERBB3 in endometrial cancer (10), and FGF19 in hepatocellular cancer (11). These studies demonstrate the utility of integrating evidence from both structural and functional assays to identify genes that represent tractable therapeutic targets.…”

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confidence: 99%

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

Dunn

Cheung

Agarwalla

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance High-grade serous ovarian cancers are characterized by widespread gain and loss of copy number involving large numbers of genes; however, the functional consequences of many of these changes remain unclear. To determine which of the many amplified genes exhibited tumor-promoting behavior, we developed a novel in vivo method to systematically screen potential oncogenes for tumor formation. We identified GAB2, a signaling adaptor protein, as a potent oncogene that is also significantly amplified in ovarian and breast cancer. GAB2 overexpression activates the phosphatidylinositol 3-kinase (PI3K) pathway and confers sensitivity to PI3K pathway inhibition. These results credential GAB2 as a potent oncogene in ovarian cancer and emphasize the importance of PI3K signaling in this cancer.

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Whole-exome sequencing combined with functional genomics reveals novel candidate driver cancer genes in endometrial cancer

Cited by 221 publications

References 63 publications

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

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