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Frequency of Germline TP53 Mutations in Patients With Early-Onset Colorectal Cancer Not Meeting Criteria for Li-Fraumeni Syndrome

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Key Points

  • Germline TP53 mutations were identified in 1.6% of patients with early-onset colorectal cancer.
  • None of the patients met clinical criteria for Li-Fraumeni syndrome.

In a study reported in JAMA Oncology, Yurgelun et al identified germline TP53 mutations in multiple patients with early-onset colorectal cancer from the Colon Cancer Family Registry who did not meet clinical criteria for Li-Fraumeni syndrome. Li-Fraumeni syndrome is associated with increased risk for multiple cancers, including early-onset colorectal cancer, and is usually characterized by germline TP53 mutations.

Germline TP53 Mutations

The study included 510 patients in the registry who were diagnosed with colorectal cancer at age ≤ 40 years and who did not have a known hereditary cancer syndrome. Of these, 53 were excluded on the basis of subsequent identification of germline mutations in DNA mismatch repair genes (n = 47) or biallelic MUTYH mutations (n = 6).

Sequencing among the 457 eligible patients (median age at diagnosis of 36 years, range = 15–40 years) revealed germline missense TP53 alterations not previously described as benign alterations in 6 (1.3%, 95% confidence interval = 0.5%–2.8%), with none of the patients meeting clinical criteria for Li-Fraumeni syndrome. Four of the TP53 alterations (c.445C>T, c.869G>A, c.847C>T, c.704A>G) were previously identified in probands with clinical features of Li-Fraumeni syndrome and 2 (c.1136G>A, c.850A>T) were alterations not previously described in the literature.

The investigators concluded: “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.”

Sapna Syngal, MD, MPH, of Dana-Farber Cancer Institute, is the corresponding author for the JAMA Oncology article.

The study was funded by the National Cancer Institute and American Gastroenterological Association. Matthew B. Yurgelun, MD, reported research funding from Myriad Genetic Laboratories. Dr. Syngal is a collaborator on projects supported by Myriad.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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