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Germline TP53 mutations detected in patients with early-onset colorectal cancer
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Patients with early-onset colorectal cancer who lacked clinical features of Li-Fraumeni syndrome had germline TP53 mutations, according to findings from a recent study.
Preliminary research has shown that Li-Fraumeni syndrome increases the risk for early-onset CRC, although it “is more classically associated with a large list of other cancers, like early-onset breast cancer, leukemia and lymphomas,” Matthew B. Yurgelun, MD, from the department of oncology at Dana-Farber Cancer Institute, told Healio Gastroenterology. “As a result, there is more testing happening for mutations in the TP53 gene in patients with CRC to evaluate if they have Li-Fraumeni as part of the hereditary cancer workup. So, the rationale for this study was to see in how many patients in a large cohort with young-onset CRC could we identify germline mutation in TP53.”
Yurgelun and colleagues performed a multicenter cross-sectional cohort study involving 457 patients (median age at diagnosis, 36 [15-40] years) diagnosed with CRC at age 40 years or younger without a known hereditary cancer syndrome who were identified from the Colon Cancer Family Registry. Both population- and clinic-based patients from the United States, Canada, Australia and New Zealand enrolled in the registry from 1998 to 2007, and demographic, clinical and family history data were collected, as well as patient and family biospecimens, including microsatellite instability and DNA mismatch repair immunohistochemistry results. The researchers performed germline sequencing of the TP53 gene on archived genomic DNA and assessed identified alterations for pathogenicity based on existing literature.
“We ultimately found that a small fraction, 1.3% (95% CI, 0.5-2.8) of patients had some sort of alteration in their germline TP53 gene, not all of which were conclusively harmful mutations,” Yurgelun said. “So, for individuals who are undergoing a hereditary CRC workup that includes TP53 testing, there is a small but real fraction who will be found to have some sort of germline alteration in the TP53 gene.”
The only clinical and pathological differences between TP53 carriers and noncarriers were that four carriers had left-sided tumors (P = .01). Furthermore, none of the six carriers had clinical features of Li-Fraumeni syndrome, which Yurgelun said was surprising, as these features are typically what prompt germline TP53 testing.
“If more and more patients ultimately undergo germline testing for TP53 mutations, we are going to be finding mutations in patients where we don’t expect it because of a lack of other cancers related to Li-Fraumeni syndrome, and thus the clinical management of these patients is going to be a challenge,” Yurgelun said. “Do we manage them based on these germline findings or on their clinical histories, and at the same time how do we interpret some of these alterations in the TP53 gene where we’re not sure if it’s actually a harmful mutation or not?” – by Adam Leitenberger
Disclosure: Yurgelun reports he received research funding from Myriad Genetic Laboratories. The other researchers report no relevant financial disclosures.
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