Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

Morris, Luc G.T.; Kaufman, Andrew; Gong, Yongxing; Ramaswami, Deepa; Walsh, Logan A.; Turcan, Şevin; Eng, Stephanie; Kannan, Kasthuri; Zou, Yilong; Peng, Luke; Banuchi, Victoria E.; Paty, Phillip; Zeng, Zhaoshi; Vakiani, Efsevia; Solit, David B.; Singh, Bhuvanesh; Ganly, Ian; Liau, Linda M.; Cloughesy, Timothy; Mischel, Paul S.; Mellinghoff, Ingo K.; Chan, Timothy A.

doi:10.1038/ng.2538

Cited by 311 publications

(339 citation statements)

References 89 publications

(81 reference statements)

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“…FAT proteins play multiple roles in cell adhesion, motility, polarity, signaling, and proliferation, and mutations are implicated in a variety of cancers (50)(51)(52). Loss of FAT1 has been shown to promote WNT signaling, a critical mediator of EMT (53). Further exploration of these genes in sarcomatoid elements will be required to assess the significance of the role of FAT genes.…”

Section: Discussionmentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Zhao

Said

et al. 2016

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

104

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The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10 −4 ), increased frequency of nonsynonymous SSNVs in PanCancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10 −17 ); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers ATrich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.

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Section: Discussionmentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Zhao

Said

et al. 2016

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

104

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“…FAT1 is a protocadherin that can interact with b-catenin and sequester it to the cell membrane. Inactivation of FAT1 leads to aberrant Wnt/ b-catenin signaling in multiple types of cancer (61). In addition to head and neck squamous cell carcinomas, FAT1 mutations are frequently observed in central nervous system, colorectal, and ovarian cancers.…”

Section: Mutations That May Sensitize Cancer Cells To Secreted Wnt LImentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

102

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Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of b-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/b-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.

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“…In addition, loss of FAT1, by either somatic mutation or deletions, promotes tumorigenesis through activation of Wnt signaling [79] . Dysregulation of proteins involved in chromatin regulation can affect the genome-wide control of gene expression and play key roles in DNA repair and genome maintenance.…”

Section: Other Signaling Pathwaysmentioning

confidence: 99%

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

Sasaki¹,

Tamura²,

Koyama³

et al. 2016

WJG

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Two major types of cancer occur in the esophagus: squamous cell carcinoma, which is associated with chronic smoking and alcohol consumption, and adenocarcinoma, which typically arises in gastric reflux-associated Barrett's esophagus. Although there is increasing incidence of esophageal adenocarcinoma in Western counties, esophageal squamous cell carcinoma (ESCC) accounts for most esophageal malignancies in East Asia, including China and Japan. Technological advances allowing for massively parallel, high-throughput next-generation sequencing (NGS) of DNA have enabled comprehensive characterization of somatic mutations in large numbers of tumor samples. Recently, several studies were published in which whole exome or whole genome sequencing was performed in ESCC tumors and compared with matched normal DNA. Mutations were validated in several genes, including in TP53 , CDKN2A , FAT1 , NOTCH1 , PIK3CA , KMT2D and NFE2L2 , which had been previously implicated in ESCC. Several new recurrent alterations have also been identified in ESCC. Combining the clinicopathological characteristics of patients with information obtained from NGS studies may lead to the development of effective diagnostic and therapeutic approaches for ESCC. As this research becomes more prominent, it is important that gastroenterologist become familiar with the various NGS technologies and the results generated using these methods. In the present study, we describe recent research approaches using NGS in ESCC.

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Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

Cited by 311 publications

References 89 publications

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Genomic characterization of esophageal squamous cell carcinoma: Insights from next-generation sequencing

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