High Frequency of Germline TP53 Mutations in a Prospective Adult-Onset Sarcoma Cohort

Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-on...

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Vydáno v:	PloS one Ročník 8; číslo 7; s. e69026
Hlavní autoři:	Mitchell, Gillian, Ballinger, Mandy L., Wong, Stephen, Hewitt, Chelsee, James, Paul, Young, Mary-Anne, Cipponi, Arcadi, Pang, Tiffany, Goode, David L., Dobrovic, Alex, Thomas, David M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 22.07.2013 Public Library of Science (PLoS)
Témata:	Adult Age of Onset Base Sequence Biology Blood Bone cancer Breast cancer Cancer Carriers Cohort Studies Copy number Deoxyribonucleic acid DNA DNA sequencing Ewings sarcoma Family medical history Female Gene mutation Genetic aspects Genetic counseling Genetic screening Genetics Germ-Line Mutation Humans Kaplan-Meier Estimate Male Medical diagnosis Medical genetics Medical research Medicine Middle Aged Multiplexing Mutation Oncology p53 Protein Pathology Pediatrics Pedigree Prospective Studies Sarcoma Sarcoma - epidemiology Sarcoma - genetics Sequences Tissues Tumor proteins Tumor Suppressor Protein p53 - genetics Australia Victoria Australia
ISSN:	1932-6203, 1932-6203
On-line přístup:	Získat plný text
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Shrnutí:	Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10(-3)), and earlier cancer onset (33 vs 48 years, P = 1.19×10(-3)). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceived and designed the experiments: DMT MLB GM. Performed the experiments: MLB SW CH TP AC. Analyzed the data: DMT GM AD DG MAY PJ. Contributed reagents/materials/analysis tools: MLB DMT. Wrote the paper: GM MLB DMT. Competing Interests: The authors have declared that no competing interests exist. These authors also contributed equally to this work.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0069026