GermlineTP53Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry

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. OBJECTIVE To examine the frequency of germline TP53 alterations in patients with early-onset colorectal cancer. 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 (n = 47) or biallelic MUTYH mutations (n = 6). 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. MAIN OUTCOMES AND MEASURES 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 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.

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

“…It was reported that TP53 germline mutations were found in 4-5% in Li-Fraumni syndrome (LFS). However, presence of TP53 mutations with absence of personal and family history that met LFS criteria was also observed in previous studies [46,47]. Consequently, TP53 had the highest number of investigated mutations including missense, short deletions and splicing mutations as mentioned in results sections; I. a, II and III.…”

Defining New Colorectal Cancer Syndromes in a Population-based Cohort of the Disease

“…Known cancer syndromes often involve an increased risk for a whole spectrum of tumours, such as CRC, endometrial, gastric, renal pelvis and other tumours in LS and breast cancer, leukemia, sarcoma, as well as brain tumours in LiFraumeni syndrome (12,13). Also, for the BRCA1, BRCA2 and APC genes and, in fact, almost all known cancer genes, a typical spectrum of different cancers is associated with each gene involved in the syndrome (14-16).…”

Clinical Outcomes of TP53 Mutations in Cancers

“…Recently, testing recommendations have been broadened to include women with early-onset breast cancer in the absence of family history or BRCA1/ BRCA2 mutations (McCuaig et al 2012), as they would be suspected of carrying de novo TP53 germline mutations (Gonzalez et al 2009). In addition, germline TP53 mutations have now been uncovered in patients who did not fulfill the clinical criteria for LFS testing, but presented with rare pediatric cancers including hypodiploid acute lymphoblastic leukemia (Holmfeldt et al 2013), melanoma (Lu et al 2015), gastric adenocarcinoma (Chang et al 2013), early-onset colorectal cancer (Yurgelun et al 2015), early-onset osteosarcoma (Mirabello et al 2015), or multiple early-onset malignancies (Yamada et al 2009;Chak et al 2015). The wide application of NGS technologies will undoubtedly lead to more such findings and require continued reassessment of the role of TP53 germline variants in cancer predisposition and the need for intense surveillance of mutation carriers and their families (Villani et al 2011).…”