In an observational cohort study reported in The Lancet Oncology, de Andrade et al identified cancer incidence and patterns in individuals meeting criteria for Li-Fraumeni syndrome on the basis of presence of pathogenic or likely pathogenic germline TP53 variants.
As stated by the investigators, “Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual’s lifespan. We aimed to characterize and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.”
Study Details
The study included a cohort of 480 carriers of pathogenic/likely pathogenic germline TP53 variants from 143 families enrolled in the National Cancer Institute referral-based longitudinal Li-Fraumeni syndrome study between August 2011 and March 2020. Variants were categorized according to both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that in the general population using data from the Surveillance, Epidemiology, and End Results (SEER) registry from 1975 to 2017.
This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range–specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimize cancer screening and management for these individuals.— de Andrade et al
Tweet this quote
Key Findings
Overall, 305 (63.5%) of 480 individuals had at least one cancer, with a total of 619 cancers diagnosed among these individuals. Among the 619 cancers, the most common were female breast cancer (30.3%), soft-tissue sarcoma (20.0%), brain cancer (10.0%), osteosarcoma (6.6%), and hematologic malignancies (5.3%).
Compared with the general population, individuals in the cohort had a standardized incidence ratio for any cancer of 23.9 (95% confidence interval [CI] = 21.9–26.0). The highest comparative incidence was from childhood to age 30 years; however, the standardized incidence ratio remained elevated after age 50 years at 10.3 (95% CI = 7.9–13.2).
Among core Li-Fraumeni syndrome cancers, standardized incidence ratios were up to 1,000 for adrenal cancer, > 700 for osteosarcoma, > 200 for soft-tissue sarcoma, > 100 for brain cancer, and > 36 for breast cancer.
Of 276 individuals with complete data and a first cancer diagnosis, 129 (46.7%) developed second primary cancers. Among 582 cancers for which order was confirmed, breast cancer was the most common first malignancy (123 [56.9%] of 216) and second primary malignancy (40 [40.4%] of 99) in women. In men, brain cancer (27 [26.0%] of 104) was the most frequent first cancer, and soft-tissue sarcoma (9 [23.7%] of 38) the most frequent second cancer.
In analysis including breast cancer as a competing risk, the probability of a first diagnosis of a non–breast cancer malignancy for women decreased from 50.4% to 24.4% by age 33.7 years.
Overall, individuals with DNE-LOF and notDNE-LOF variants had an earlier median age at first and second cancers compared with individuals with notDNE-notLOF and DNE-notLOF variants. A difference in median age at first cancer of up to 30.9 years was observed between the notDNE-LOF vs DNE-notLOF groups.
Among individuals who developed second cancers, the interval between first and second cancer was shorter among those whose first cancer diagnosis was later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.
The investigators concluded, “This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range–specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimize cancer screening and management for these individuals.”
Payal P. Khincha, MBBS, of the Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health. For full disclosures of the study authors, visit thelancet.com.
