Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas

Lee, Jonathan J.; Sholl, Lynette M.; Lindeman, Neal I.; Granter, Scott R.; Laga, Alvaro C.; Shivdasani, Priyanka; Chin, Gary; Luke, Jason J.; Ott, Patrick A.; Hodi, F. Stephen; Mihm, Martín C.; Lin, Jennifer Y.; Werchniak, Andrew E.; Haynes, Harley A.; Bailey, Nancy; Liu, Robert; Murphy, Gëorge F.; Lian, Christine G.

doi:10.1186/s13148-015-0091-3

Cited by 49 publications

(40 citation statements)

References 66 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.

132

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.

132

128

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“…Indeed, this initiative has enabled a large number of other more focused studies of common and uncommon tumor types and, in particular, has permitted prospective identification of relatively uncommon genomic variants to facilitate clinical trial enrollment and biomarker studies (46)(47)(48)(49)(50)(51)(52)(53)(54). Migrating to a clinical test, identifying when in the course of a patient's disease genomic profiling should be used, and triaging patients in real-time for clinical trial enrollment should contribute to determining clinical utility on a broader scale.…”

Section: Discussionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

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349

314

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BACKGROUND.Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprisewide, unselected cancer patient population has yet to be reported. METHODS.We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested.RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS.Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale.

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“…The BAF subunit ARID1A has the highest mutation rate among SWI/SNF components (Helming et al 2014a). Mutations in its paralog, ARID1B, are less frequent but have also been observed in melanoma, gastric cancer, colorectal cancer, HCC, neuroblastoma, and pancreatic cancer (Fujimoto et al 2012;Khursheed et al 2013;Sausen et al 2013;Lee et al 2015). In HCC, >20% of the tumors present alterations in SWI/SNF components, and mutations in ARID1B are second only to ARID1A in frequency (Fujimoto et al 2012).…”

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confidence: 99%

SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

et al. 2016

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Oncogene-induced senescence (OIS) is a potent tumor suppressor mechanism. To identify senescence regulators relevant to cancer, we screened an shRNA library targeting genes deleted in hepatocellular carcinoma (HCC). Here, we describe how knockdown of the SWI/SNF component ARID1B prevents OIS and cooperates with RAS to induce liver tumors. ARID1B controls p16INK4a and p21 CIP1a transcription but also regulates DNA damage, oxidative stress, and p53 induction, suggesting that SWI/SNF uses additional mechanisms to regulate senescence. To systematically identify SWI/SNF targets regulating senescence, we carried out a focused shRNA screen. We discovered several new senescence regulators, including ENTPD7, an enzyme that hydrolyses nucleotides. ENTPD7 affects oxidative stress, DNA damage, and senescence. Importantly, expression of ENTPD7 or inhibition of nucleotide synthesis in ARID1B-depleted cells results in re-establishment of senescence. Our results identify novel mechanisms by which epigenetic regulators can affect tumor progression and suggest that prosenescence therapies could be employed against SWI/ SNF-mutated cancers.

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Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas

Cited by 49 publications

References 66 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

Institutional implementation of clinical tumor profiling on an unselected cancer population

SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer

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