medwireNews: People with Li-Fraumeni syndrome, who carry pathogenic or likely pathogenic germline TP53 variants, are 24 times more likely to develop cancer than people from the general population, research shows.
The findings from the longitudinal Li-Fraumeni syndrome study, which also looked at cancer diagnosis patterns, “could help in the future development of personalised cancer risk modelling and tailored screening approaches for individuals with Li-Fraumeni syndrome,” write Payal Khincha (National Cancer Institute, Bethesda, Maryland, USA) and co-authors in The Lancet Oncology.
They analyzed data for 480 individuals, from 143 families, who carried pathogenic or likely pathogenic germline TP53 variants and were followed up between 2011 and 2020. Of these, 63.5% had at least one cancer, with 619 cancers recorded in total.
Breast cancer was the most common diagnosis, accounting for 30.3% of all cases, followed by soft-tissue sarcomas (20.0%), brain cancer (10.0%), osteosarcoma (6.6%), and hematologic cancers (5.3%). The median age at first cancer diagnosis among the 457 individuals with complete information was 33.7 years for women and 45.0 years for men.
Khincha and team report that the incidence of cancer in the Li-Fraumeni cohort was 23.9 times higher than that expected in the general population based on Surveillance, Epidemiology, and End Results (SEER) 1975–2017 data.
The highest excess risk occurred among individuals under 30 years of age, for whom the standardized incidence ratio (SIR) relative to the general population was over 45, but the researchers note that the although the SIR reduced with age, incidence was still 10.3 times higher than expected in study participants aged 50 years and older.
Core Li-Fraumeni syndrome cancers had the highest SIRs, ranging from approximately 1000 for adrenal cancers to 36 for breast cancer.
The researchers also found that when breast cancers were treated as a competing risk, the likelihood of a woman being diagnosed with a first non-breast cancer malignancy by age 33.7 years halved, from 50.4% to 24.4%.
“These findings highlight the importance of early discussions between health-care providers and patients about cancer risk-reduction strategies, and the potentially significant impact that risk-reducing mastectomy might have in delaying cancer onset in women with Li-Fraumeni syndrome,” Khincha et al remark.
In addition, the team found that the type of TP53 variant affects age at first cancer. Specifically, individuals with both dominant-negative effect (DNE) and loss-of-function (LOF) mutations, and those with LOF mutations only, were diagnosed at a younger age than those with DNE variants only or those with other types of variants, with the difference reaching up to approximately 30 years in some cases.
Almost half (46.7%) of 276 individuals with complete data and a first cancer diagnosis developed second primary cancers, and the investigators estimated that the probability of developing a second cancer within 20 years of the first cancer was 66.0% for women and 45.4% for men, after accounting for death before second cancer as a competing risk.
However, the time between the first and second cancer was shorter among individuals who were diagnosed with their first cancer later in life than those with childhood cancer.
There was also a subgroup of individuals who were diagnosed with multiple cancers within a short timeframe, which the researchers suggest could be due to a “trigger effect” from “a combination of biological and therapy-related phenomena.”
Khincha and co-authors conclude: “By putting the cancer burden in Li-Fraumeni syndrome into context with that of the general population, examining genotype–phenotype associations based on TP53 variant functional group, and evaluating the temporality of subsequent malignancies in Li-Fraumeni syndrome, this study, together with the existing published literature, creates a foundation for the development of tailored cancer screening and personalised risk assessment in Li-Fraumeni syndrome.”
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