TP53 Mutations in Early-Onset CRC May Not Indicate Hereditary Cancer Syndrome

Germline TP53 mutations in early-onset colorectal cancer patients may not be synonymous with Li-Fraumeni syndrome

medwireNews: Germline TP53 mutations were found in a small number of patients with early-onset colorectal cancer (CRC) but no other personal or familial indicators of Li-Fraumeni syndrome (LFS), study findings show.

This result should be considered alongside earlier results indicating that around 5% of early-onset breast cancer patients carry germline TP53 mutations but do not meet LFS criteria, the researchers say.

“[O]ur data raise the question as to whether LFS should be defined by the presence of pathogenic germline TP53 mutations”, say Sapna Syngal, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers.

They suggest in JAMA Oncology that counselling and management of patients with germline mutations associated with hereditary cancer, such as TP53, APC or MUTYH, should take into account both genotype and phenotype.

“For patients found to carry TP53 mutations in the setting of early-onset CRC but no other clinical features of LFS, our data suggest that clinicians may be able to reassure such probands that the lifetime risk of classic LFS cancers may not be as high as the 73% to 100% risk typically quoted”, the authors write.

Of 457 patients registered in the Colon Cancer Family Registry between 1998 and 2007 who were tested for TP53 gene mutations, 1.3% had germline missense TP53 alterations. Two genetic alterations were new discoveries but four had previously been linked to patients with LFS.

However, a review of both personal and family history failed to uncover the marked lifetime risk of multiple malignancies associated with LFS in any of the six patients with germline TP53 alterations, Sapna Syngal et al report.

Nevertheless, the authors note that while the rate of germline TP53 mutations is low in early-onset CRC patients, it is similar to the proportion of patients with inherited CRC with a germline APC mutation associated with familial adenomatous polyposis.

“These findings highlight the inevitable challenges raised by comprehensive approaches to hereditary cancer risk assessment, namely, the interpretation of missense alterations and [variant of uncertain significance] in cancer susceptibility genes, as well as the difficulties in estimating future cancer risks in families with atypical phenotypes”, the researchers conclude.

“With modern techniques for comprehensively genotyping cancer patients, interpreting such germline results will undoubtedly be a prominent challenge in the counseling and management of at-risk individuals.”


Yurgelun MB, Masciari S, Joshi VA, et al. Germline TP53 mutations in patients with early-onset colorectal cancer in the Colon Cancer Family Registry. JAMA Oncol 2015; Advance online publication 12 March. doi:10.1001/jamaoncol.2015.0197

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