Dataset Information

Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

ABSTRACT: Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

SUBMITTER: Behjati S

PROVIDER: S-EPMC4032873 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

Behjati Sam S Tarpey Patrick S PS Sheldon Helen H Martincorena Inigo I Van Loo Peter P Gundem Gunes G Wedge David C DC Ramakrishna Manasa M Cooke Susanna L SL Pillay Nischalan N Vollan Hans Kristian M HKM Papaemmanuil Elli E Koss Hans H Bunney Tom D TD Hardy Claire C Joseph Olivia R OR Martin Sancha S Mudie Laura L Butler Adam A Teague Jon W JW Patil Meena M Steers Graham G Cao Yu Y Gumbs Curtis C Ingram Davis D Lazar Alexander J AJ Little Latasha L Mahadeshwar Harshad H Protopopov Alexei A Al Sannaa Ghadah A GA Seth Sahil S Song Xingzhi X Tang Jiabin J Zhang Jianhua J Ravi Vinod V Torres Keila E KE Khatri Bhavisha B Halai Dina D Roxanis Ioannis I Baumhoer Daniel D Tirabosco Roberto R Amary M Fernanda MF Boshoff Chris C McDermott Ultan U Katan Matilda M Stratton Michael R MR Futreal P Andrew PA Flanagan Adrienne M AM Harris Adrian A Campbell Peter J PJ

Nature genetics 20140316 4

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which ...[more]

PMID: 24633157

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Project description:Angiosarcoma (AS) is a rare sarcoma subtype showing considerable clinicopathologic and genetic heterogeneity. Most radiation-induced AS show MYC gene amplifications, with a subset of cases harboring KDR, PTPRB, and PLCG1 mutations. Despite recent advances, the genetic abnormalities of most primary AS remain undefined. Whole-transcriptome sequencing was initiated in 2 index cases of primary soft tissue AS with epithelioid morphology occurring in young adults for novel gene discovery. The candidate abnormalities were validated and then screened by targeted sequencing and fluorescence in situ hybridization in a large cohort of 120 well-characterized AS cases. Findings were subsequently correlated with the status of KDR, PLCG1, MYC, and FLT4 gene abnormalities. The clinicopathologic relevance and prognostic significance of these genetic changes were analyzed by statistical methods. Concurrent CIC mutations and CIC rearrangements were identified in both index cases, with a CIC-LEUTX fusion detected in 1 case. Upon screening, an additional visceral AS in a young adult had a complex CIC rearrangement, whereas 6 others harbored only CIC mutations. All 3 CIC-rearranged AS cases lacked vasoformation and had a solid growth of round, epithelioid to rhabdoid cells, showing immunoreactivity for CD31 and Ets-related gene and sharing a transcriptional signature with other round cell sarcomas, including CIC-rearranged tumors. Overall, CIC abnormalities occurred in 9% (9/98) of cases, affecting younger patients with primary AS, with an inferior disease-free survival. In contrast, PLCG1 and KDR mutations occurred in both primary and secondary AS cases, accounting for 9.5% and 7%, respectively, with a predilection for breast and bone/viscera location, regardless of MYC status. MYC amplification was present in most secondary AS related to breast cancer (91%) compared with other causes (25%) or primary AS (7%). FLT4-amplified AS lacked PLCG1/KDR mutations, occurring predominantly in MYC-amplified population, and showed poor prognosis.

Dataset Information

Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

Publications

Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

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