Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome

Abstract

PURPOSE Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

Concomitant TP53 mutation in early-stage resected EGFR-mutated non-small cell lung cancer: a narrative approach in a genetically admixed Brazilian cohort

“…In our population, about 40% of patients harbored TP53 mutations. We found TP53 mutations in 21.4% of non-squamous cell carcinomas and 20% of squamous cell carcinomas, contrasting with studies reporting 40 and 51%, respectively ( 23 ). In the current study, TP53/EGFR co-mutation was found in 43.5% of patients with early-stage NSCLC.…”

“…However, regarding the TP53 gene, it is essential to relate it to the miscegenation of the Brazilian population. It is known that Li-Fraumeni syndrome (LFS), caused by the p.R337H variant in the TP53 gene, is rare in the world population but highly prevalent in the Brazilian population ( 23 ). Somatic variant databases rarely describe this variant.…”

Disruptive and Truncating TP53 Mutations Are Associated with African-Ancestry and Worse Prognosis in Brazilian Patients with Lung Adenocarcinoma

“…In Brazilian NSCLC patients, the frequency of p.(Arg337His) mutation ranges from 3.5% to 8.9%, and some studies suggest a higher frequency in mutant EGFR patients [41–43]. This germline mutation is associated with lower penetrance in the context Li-Fraumeni syndrome [44]. In our study, we evaluated the presence of TP53 in tumor tissue, and we could not confirm its germline nature.…”

Geographic differences in lung cancer: focus on carcinogens, genetic predisposition, and molecular epidemiology

“… 47 In Southeastern Brazilian populations, it is estimated that up to 0.3% of the population carries germline TP53 mutations. 48 This high frequency is attributed to a founder mutation, the TP53 p.R337H. Of particular interest is the established association between germline TP53 alterations and the development of lung cancer with somatic EGFR mutations.…”