疑似Li-Fraumeni综合征的阿尔及利亚患者的临床病理和遗传学特征：对遗传筛查和检测的意义

Background: Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer predisposition syndrome. LFS is an autosomal dominant disease caused by heterozygous germline pathogenic variant in TP53 gene and frequently predisposes to a broad spectrum of cancers including early-onset cancers. Because of the rarity of LFS, data on clinical and genetic features in Algerian patients are limited. Our study aimed to report clinicopathological and genetic features in 25 families with suspected LFS. Patients and Methods The present study investigated 25 patients and 22 relatives from 25 families with suspected LFS. Patients and relatives were referred through Children's Cancer Center and medical oncology services in two University hospitals. Clinical and pathological information was extracted from medical records of the patients with particular attention to age of diagnosis and updated Chompret clinical criteria such presence of adult rare tumors, childhood rare tumors and early-onset breast cancer. Family history of LFS was obtained from interviews of adult patients and relatives, pedigree and chart review of patients. TP53 exons 2-11 were screened in 25 patients and 22 high risk relatives using PCR-Sanger sequencing, respectively. Results We identified various primary cancers in our study. The following“Core”cancers were observed in 25 patients, early- onset breast cancer, adult sarcomas and rare childhood tumors including: rhabdomyosarcoma, osteosarcoma and adrenocortical carcinoma, respectively. In addition, we observed early-onset colorectal cancer in relatives from 9 LFS families. Rhabdomysarcoma was most frequently observed (N=12) in children. The median age at diagnosis for early-onset breast cancer, adult sarcomas and childhood cancers was 30.5 years, 38 years and 6.8 years, respectively. The genetic analysis identified 11 individuals (23.4%) with TP53 germline variants. The TP53 common germline variant c.215C>G/p.Arg72Pro has been identified in eight patients. Interestingly, the rare germline TP53 c.314G>T/p.Gly105Val has been identified in 4-year old girl (the index case) who developed rhabdomyosarcoma at age 3 years and secondary cancer in the right lung at age 4 years after radiotherapy. Her mother is also a carrier of this rare variant, she developed an early-onset breast cancer at age 30 years. To date, the TP53 c.314G>T has been initially classified as a Variant of Uncertain Significance in the ClinVar database. Interestingly, our present study reclassifies the variant as"likely Pathogenic" (Class 4) based on ACMG criteria, which directly impacts patient care, risk assessment, and management. Conclusions Our study highlights the importance of understanding clinical features of LFS and germline genetic variants of TP53 gene in underrepresented populations, such as Algeria, where clinical and genomic features of LFS are largely unknown.