<i>SETD2</i>histone modifier loss in aggressive GI stromal tumours

Huang, Kie Kyon; McPherson, John R.; Tay, Su Ting; Das, Kakoli; Tan, Iain Beehuat; Ng, Cedric Chuan Young; Chia, Na‐Yu; Zhang, Shen Li; Myint, Swe Swe; Hu, Longyu; Rajasegaran, Vikneswari; Huang, Dachuan; Loh, Jia Liang; Gan, Anna; Sairi, A.; Sam, Xin Xiu; Dominguez, Lourdes Trinidad; Lee, Ming‐Hui; Soo, Khee Chee; Ooi, London Lucien Peng Jin; Ong, Hock Soo; Chung, Alexander; Chow, Pierce K. H.; Wong, Wai Keong; Selvarajan, Sathiyamoorthy; Ong, Choon Kiat; Lim, Kiat Hon; Nandi, Tannistha; Rozen, Steve; Teh, Bin Tean; Quek, Richard; Tan, Patrick

doi:10.1136/gutjnl-2015-309482

Cited by 51 publications

(41 citation statements)

References 61 publications

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“…Alterations of SETD2, PBRM1, and SMARCC1 have been linked to several human malignancies (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, disruptions of the SETD2 gene have been frequently observed in clear cell renal cell carcinomas (ccRCC), gliomas, chronic lymphocytic leukemia, breast fibroepithelial tumors, gastro-intestinal stromal tumors, and melanomas (30)(31)(32)(33)(34)(35)(36)(37). PBRM1 is one of the most frequently mutated genes in ccRCC (31), and its alterations were also found in cholangiocarcinomas and liver cancers (38).…”

Section: Discussionmentioning

confidence: 99%

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High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Yoshikawa

Emi

Hashimoto-Tamaoki

et al. 2016

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

135

128

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We used a custom-made comparative genomic hybridization array (aCGH; average probe interval 254 bp) to screen 33 malignant mesothelioma (MM) biopsies for somatic copy number loss throughout the 3p21 region (10.7 Mb) that harbors 251 genes, including BRCA1 (breast cancer 1)-associated protein 1 (BAP1), the most commonly mutated gene in MM. We identified frequent minute biallelic deletions (<3 kb) in 46 of 251 genes: four were cancer-associated genes: SETD2 (SET domain-containing protein 2) (7 of 33), BAP1 (8 of 33), PBRM1 (polybromo 1) (3 of 33), and SMARCC1 (switch/sucrose nonfermentable-SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily c, member 1) (2 of 33). These four genes were further investigated by targeted next-generation sequencing (tNGS), which revealed sequence-level mutations causing biallelic inactivation. Combined high-density aCGH and tNGS revealed biallelic gene inactivation in SETD2 (9 of 33, 27%), BAP1 (16 of 33, 48%), PBRM1 (5 of 33, 15%), and SMARCC1 (2 of 33, 6%). The incidence of genetic alterations detected is much higher than reported in the literature because minute deletions are not detected by NGS or commercial aCGH. Many of these minute deletions were not contiguous, but rather alternated with segments showing oscillating copy number changes along the 3p21 region. In summary, we found that in MM: (i) multiple minute simultaneous biallelic deletions are frequent in chromosome 3p21, where they occur as distinct events involving multiple genes; (ii) in addition to BAP1, mutations of SETD2, PBRM1, and SMARCC1 are frequent in MM; and (iii) our results suggest that high-density aCGH combined with tNGS provides a more precise estimate of the frequency and types of genes inactivated in human cancer than approaches based exclusively on NGS strategy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Yoshikawa

Emi

Hashimoto-Tamaoki

et al. 2016

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

135

128

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“…SETD2-mediated H3K36me3 influences the splice site selection through the recruitment of MORF-related gene 15 (MRG15) and polypyrimidine tract binding protein 1 (PTB) (14). Consistent with its prominent role in maintenance of genomic integrity, SETD2 is frequently mutated or deleted in a variety of human tumors, most pronounced in clear cell renal cell carcinoma (ccRCC), but also in breast, glioma, gastrointestinal stromal tumors (GISTs), and leukemia (15)(16)(17)(18)(19). Nevertheless, the genetic characterization of SETD2 to determine its role in tumorigenesis and the signaling pathways coordinated remains largely undetermined.…”

Section: Introductionmentioning

confidence: 94%

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

Yuan¹,

Ni²,

Fu³

et al. 2017

Journal of Clinical Investigation

138

119

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“…In human development, germline mutations in SETD2 cause an overgrowth condition with features similar to Sotos syndrome [91]. Underexpression and mutation of SETD2 are associated with poor prognosis in breast and renal cancer, GI stromal tumors and acute leukemia [92][93][94][95][96]. SETD2 mutations are more common in leukemias with MLL rearrangements (22%) than leukemias without such rearrangements (5%), and SETD2 loss cooperates with MLL fusions such as MLL-AF9 and MLL-NRIP to create a more aggressive leukemia with increased self-renewal of leukemia stem cells [97].…”

Section: Ash1l: Hox Gene Activator With Emerging Role In Cancermentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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SETD2histone modifier loss in aggressive GI stromal tumours

Abstract: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.

Cited by 51 publications

References 61 publications

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma

Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

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