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Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry.
- Source :
-
JAMA oncology [JAMA Oncol] 2015 May; Vol. 1 (2), pp. 214-21. - Publication Year :
- 2015
-
Abstract
- Importance: Li-Fraumeni syndrome, usually characterized by germline TP53 mutations, is associated with markedly elevated lifetime risks of multiple cancers, and has been linked to an increased risk of early-onset colorectal cancer.<br />Objective: To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer.<br />Design, Setting, and Participants: This was a multicenter cross-sectional cohort study of individuals recruited to the Colon Cancer Family Registry (CCFR) from 1998 through 2007 (genetic testing data updated as of January 2015). Both population-based and clinic-based patients in the United States, Canada, Australia, and New Zealand were recruited to the CCFR. Demographic information, clinical history, and family history data were obtained at enrollment. Biospecimens were collected from consenting probands and families, including microsatellite instability and DNA mismatch repair immunohistochemistry results. A total of a 510 individuals diagnosed as having colorectal cancer at age 40 years or younger and lacking a known hereditary cancer syndrome were identified from the CCFR as being potentially eligible. Fifty-three participants were excluded owing to subsequent identification of germline mutations in DNA mismatch repair genes (nā=ā47) or biallelic MUTYH mutations (nā=ā6).<br />Interventions: Germline sequencing of the TP53 gene was performed. Identified TP53 alterations were assessed for pathogenicity using literature and international mutation database searches and in silico prediction models.<br />Main Outcomes and Measures: Frequency of nonsynonymous germline TP53 alterations.<br />Results: Among 457 eligible participants (314, population-based; 143, clinic-based; median age at diagnosis, 36 years [range, 15-40 years]), 6 (1.3%; 95% CI, 0.5%-2.8%) carried germline missense TP53 alterations, none of whom met clinical criteria for Li-Fraumeni syndrome. Four of the identified TP53 alterations have been previously described in the literature in probands with clinical features of Li-Fraumeni syndrome, and 2 were novel alterations.<br />Conclusions and Relevance: In a large cohort of patients with early-onset colorectal cancer, germline TP53 mutations were detected at a frequency comparable with the published prevalence of germline APC mutations in colorectal cancer. With the increasing use of multigene next-generation sequencing panels in hereditary cancer risk assessment, clinicians will be faced with the challenge of interpreting the biologic and clinical significance of germline TP53 mutations in families whose phenotypes are atypical for Li-Fraumeni syndrome.
- Subjects :
- Adenocarcinoma epidemiology
Adenocarcinoma pathology
Adult
Age of Onset
Australia epidemiology
Canada epidemiology
Colorectal Neoplasms epidemiology
Colorectal Neoplasms pathology
Computer Simulation
Cross-Sectional Studies
DNA Glycosylases genetics
DNA Mismatch Repair
DNA Mutational Analysis
Female
Gene Frequency
Genetic Predisposition to Disease
Heredity
Humans
Li-Fraumeni Syndrome epidemiology
Male
Models, Genetic
New Zealand epidemiology
Pedigree
Phenotype
Predictive Value of Tests
Risk Assessment
Risk Factors
United States epidemiology
Young Adult
Adenocarcinoma genetics
Biomarkers, Tumor genetics
Colorectal Neoplasms genetics
Germ-Line Mutation
Li-Fraumeni Syndrome genetics
Registries
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2374-2445
- Volume :
- 1
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- JAMA oncology
- Publication Type :
- Academic Journal
- Accession number :
- 26086041
- Full Text :
- https://doi.org/10.1001/jamaoncol.2015.0197