Abstract 1731P
Background
Li–Fraumeni syndrome (LFS) is a rare autosomal hereditary predisposition to multiples cancers, mainly affecting young individuals. It is characterized by a broad tumor spectrum, comprising early breast cancers (BC), sarcomas, adrenocortical tumors and brain tumors.
Methods
Retrospective study of clinical and genetic results of LFS patients with non-small-cell lung carcinoma (NSCLC).
Results
We reviewed medical reports of 194 LFS patients (105 index cases + 89 relatives) harboring 82 distinct TP53 germline variants with a follow-up at Gustave Roussy (1976-2021). We found 10 LFS patients with NSCLC, from 10 different families, 6M/4F, median age of 48y. These patients carried 10 distinct TP53 germline variants: p.(Val73fs), p.(Thr125=), p.(Arg196*), p.(His214fs), c.783-1G>A, p.(Arg267Gly), p.(Cys275Ser), p.(Arg282Gly), p.(Arg282Pro) and p.(Arg337His). For available personal and family cancers, Chompret criteria were fulfilled in 6/10, patients were non-smoker (5/6) with late onset advanced-stage disease (4/6) and adenocarcinoma subtype (6/6). BC was common among female patients. All six profiled tumors showed oncogenic somatic mutations in EGFR: p.(Leu858Arg) (1/6), exon 20 insertion(1/6), exon 19 deletion(4/6) with EGFR p.(Thr790Met) mutation in (3/6) cases and two of which had a concurrently PIK3CA mutation p.(Glu545Asp) and p.(His1047Arg).
Conclusions
NSCLC is known to occur in a rare proportion of LFS patients with frequently the variant p.(Arg337His) and with an enrichment of EGFR somatic alterations lung adenocarcinoma. Our study showed the diversity of germline TP53 variants associated with NSCLC and confirm the presence of the oncogenic dependency on EGFR somatic mutations. Face to a lung cancer, alterations in ATM, BRCA2 and EGFR gene p.(Thr790Met) in TKI-naïve patients with NSCLC should open the possibility of germline mutations with lung cancer predisposition. The TP53 gene is also a candidate for this risk.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.