title: Germline TP53 Mutations in Patients With Early-Onset   Colorectal Cancer in the Colon Cancer Family Registry.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer.
  
  
  METHODS
  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 (n = 47) or biallelic MUTYH mutations (n = 6).
  
  
  METHODS
  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.
  
  
  METHODS
  Frequency of nonsynonymous germline TP53 alterations.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Yurgelun
authors.forename: Serena
authors.initials: S
authors.lastname: Masciari
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Joshi
authors.forename: Rowena C
authors.initials: RC
authors.lastname: Mercado
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
mesh_terms: D000230:Adenocarcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000328:Adult; D017668:Age of Onset; D001315:Australia / Q000453:epidemiology; D014408:Biomarkers, Tumor / Q000235:genetics*; D002170:Canada / Q000453:epidemiology; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D003198:Computer Simulation; D003430:Cross-Sectional Studies; D045647:DNA Glycosylases / Q000235:genetics; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D040941:Heredity; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D009520:New Zealand / Q000453:epidemiology; D010375:Pedigree; D010641:Phenotype; D011237:Predictive Value of Tests; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014481:United States / Q000453:epidemiology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase