Germline<i>CDKN2A</i>/P16INK4A mutations contribute to genetic determinism of sarcoma

Jouenne, Fanélie; Beauchêne, Isaure Chauvot de; Bollaert, Emeline; Avril, Marie-Françoise; Caron, Olivier; Ingster, Olivier; Lecesne, A.; Benusiglio, Patrick R.; Terrier, Philippe; Caumette, Vincent; Pissaloux, Daniel; Fouchardière, Arnaud de la; Cabaret, Odile; N’Diaye, Birama; Velghe, Amélie; Bougeard, Gaëlle; Mann, Graham J.; Koscielny, Serge; Barrett, Jennifer H.; Harland, Mark; Newton-Bishop, Julia; Gruis, Nelleke A.; Doorn, Remco van; Gauthier‐Villars, Marion; Stoppa‐Lyonnet, Dominique; Coupier, Isabelle; Guimbaud, Rosine; Scoazec, Jean‐Yves; Eggermont, Alexander M.M.; Feunteun, Jean; Tchertanov, Luba; Demoulin, Jean‐Baptiste; Frébourg, Thierry; Paillerets, Brigitte Bressac-de

doi:10.1136/jmedgenet-2016-104402

Cited by 18 publications

(10 citation statements)

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“…Almost all of these were copy number changes (loss) at 14.1%, with smaller numbers of SNVs (2.3%), and gene rearrangements (0.5%). There is emerging data on germline CDKN2A mutations that predispose towards the development of sarcoma [18], however, we found that these cases were exceedingly rare (0.2%). When broken down into histologic type (Fig.…”

Section: Resultsmentioning

confidence: 68%

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

Bui

Przybył

Trabucco³

et al. 2019

Clin Sarcoma Res

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Background Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. Patients and methods We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma. Results Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas. Conclusion Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.

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Section: Resultsmentioning

confidence: 68%

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

Bui

Przybył

Trabucco³

et al. 2019

Clin Sarcoma Res

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“…The exon 2 variant in our cohort was identified in an index patient whose grandfather was diagnosed with hypopharyngeal carcinoma, which is in line with CDKN2A PVs predisposing to tobacco-related cancers such as orolaryngeal cancer, next to its predominant role in hereditary melanoma, pancreatic cancer, and further tumor entities [MIM:600160]. Of note and with particular relevance to LFS and LFL, germline CDKN2A PVs have recently been demonstrated to account for a subset (8 of 190) of hereditary sarcoma cases negative for germline TP53 PVs [ 17 ]. Conversely, however, sarcomas are rare in CDKN2A mutation carriers, and the affected family of our cohort also does not present with sarcoma cases.…”

Section: Discussionmentioning

confidence: 99%

“…Few studies have approached the quest for further susceptibility genes in individual TP53 -negative LFS/LFL cases, either by specifically testing single genes associated with the spectrum of tumors appearing in LFS or by performing whole-exome sequencing. Associations have been suggested for LFS-associated brain tumors with nonsense PVs in CASP9 (caspase-9) [ 71 ], for a POT1 (protection of telomeres 1) missense variant with cardiac and breast angiosarcomas [ 72 ], and, as mentioned above, for CDKN2A PVs with hereditary sarcoma cases [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…This means that up to 45% of patients meeting classical LFS criteria and up to 80% of patients meeting Chompret or LFL criteria are left unexplained in a genetic sense. Few other candidate genes in the TP53 pathway have been investigated in this context, one of them being CDKN2A, which was recently found to be mutated on a germline level in several LFL families in which the index case had a sarcoma [ 17 ]. Moreover, germline PVs in CHEK2 have continuously but controversially been implicated in LFL phenotypes.…”

Section: Introductionmentioning

confidence: 99%

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Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

et al. 2018

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BackgroundBreast cancer is the most prevalent tumor entity in Li-Fraumeni syndrome. Up to 80% of individuals with a Li-Fraumeni-like phenotype do not harbor detectable causative germline TP53 variants. Yet, no systematic panel analyses for a wide range of cancer predisposition genes have been conducted on cohorts of women with breast cancer fulfilling Li-Fraumeni(-like) clinical diagnostic criteria.MethodsTo specifically help explain the diagnostic gap of TP53 wild-type Li-Fraumeni(-like) breast cancer cases, we performed array-based CGH (comparative genomic hybridization) and panel-based sequencing of 94 cancer predisposition genes on 83 breast cancer patients suggestive of Li-Fraumeni syndrome who had previously had negative test results for causative BRCA1, BRCA2, and TP53 germline variants.ResultsWe identified 13 pathogenic or likely pathogenic germline variants in ten patients and in nine genes, including four copy number aberrations and nine single-nucleotide variants or small indels. Three patients presented as double-mutation carriers involving two different genes each. In five patients (5 of 83; 6% of cohort), we detected causative pathogenic variants in established hereditary breast cancer susceptibility genes (i.e., PALB2, CHEK2, ATM). Five further patients (5 of 83; 6% of cohort) were found to harbor pathogenic variants in genes lacking a firm association with breast cancer susceptibility to date (i.e., Fanconi pathway genes, RECQ family genes, CDKN2A/p14ARF, and RUNX1).ConclusionsOur study details the mutational spectrum in breast cancer patients suggestive of Li-Fraumeni syndrome and indicates the need for intensified research on monoallelic variants in Fanconi pathway and RECQ family genes. Notably, this study further reveals a large portion of still unexplained Li-Fraumeni(-like) cases, warranting comprehensive investigation of recently described candidate genes as well as noncoding regions of the TP53 gene in patients with Li-Fraumeni(-like) syndrome lacking TP53 variants in coding regions.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1011-1) contains supplementary material, which is available to authorized users.

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“…It is unclear what role this germline CDKN2B N41D variant could play in sarcomagenesis, as cancer risks associated with CDKN2A / B gene variants include melanoma, pancreatic cancer, and astrocytomas. 17 , 18 There is a recent short report from Jouenne et al 19 that found an increased risk of soft tissue sarcoma development with germline loss of CDKN2A , though no data exist confirming this risk with CDKN2B variants. Additionally, little is known about this actual variant in CDKN2B .…”

Section: Discussionmentioning

confidence: 99%

Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant

Tramontana

Marshall

Helvie

et al. 2020

JCO Precision Oncology

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GermlineCDKN2A/P16INK4A mutations contribute to genetic determinism of sarcoma

Abstract: Background Sarcomas are rare mesenchymal malignancies whose pathogenesis is poorly

Cited by 18 publications

References 30 publications

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis

Breast cancer patients suggestive of Li-Fraumeni syndrome: mutational spectrum, candidate genes, and unexplained heredity

Sustained Complete Response to Palbociclib in a Refractory Pediatric Sarcoma With BCOR-CCNB3 Fusion and Germline CDKN2B Variant

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