TP53 Mutations in Early-Onset CRC Not Linked With Li-Fraumeni Syndrome


Looking at a large group of early-onset colorectal cancer patients, only 1.3% had TP53 mutations, none of whom met criteria for Li-Fraumeni syndrome.

Should Li-Fraumeni syndrome be defined by the presence of pathogenic germline TP53 mutations? Image © Constantin-Ciprian/

Looking at a large group of patients with early-onset colorectal cancer, only 1.3% of patients had TP53 mutations, and none of those individuals met criteria for Li-Fraumeni syndrome, an inherited cancer syndrome.

“Given that none of the TP53 probands in our study met clinical criteria for Li-Fraumeni syndrome, our data raise the question as to whether Li-Fraumeni syndrome should be defined by the presence of pathogenic germline TP53 mutations,” wrote researchers Matthew B. Yurgelun, MD, of the department of medical oncology at Dana-Farber Cancer Institute, and colleagues in the discussion of their study published recently in JAMA Oncology.

“This reflects a growing quandary in the field of cancer genetics, which, in recent years, has shifted toward using genotypic data (eg, carriage of a germline MMR mutation in Lynch syndrome) to define and diagnose specific hereditary cancer syndromes rather than the historical practice of using phenotypic information,” they wrote.

The large study looked at both clinic-based and population-based individuals recruited to the Colon Cancer Family Registry in the United States, Canada, Australia, and New Zealand from 1998 to 2007. The researchers collected biospecimens from consenting probands and families, including 510 individuals diagnosed with colorectal cancer prior to age 40, but lacking a known hereditary cancer syndrome. Ultimately, 53 individuals were excluded due to the discovery of other pathogenic germline mutations.

Of the final population of 457 individuals, only 6 were found to have germline TP53 missense alterations (1.3%; 95% CI, 0.5%–2.8%). Two of these individuals were aged younger than 30 at the time of their diagnosis. The researchers identified no significant difference in clinical and pathologic characteristics of carriers of the TP53 mutation and noncarriers.

Interestingly, the researchers noted that none of the six patients identified as TP53 carriers had a personal or family history meeting criteria for Li-Fraumeni syndrome.

“If a substantial fraction of TP53 mutation carriers indeed fail to meet clinical criteria for Li-Fraumeni syndrome, this calls into doubt the assumption that all germline TP53 alterations confer the 73% to 100% lifetime risks of cancer associated with classic LFS10 and raises important issues regarding the impact of ascertainment on counseling of families found to carry germline alterations,” Yurgelun and colleagues wrote.

The researchers acknowledged that this study had several imitations including verification of completeness of family history data as it related to subsequent development of Li-Fraumeni syndrome, and the possibility that individuals in this cohort may include those with undiagnosed Lynch syndrome.

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