Galante Pedro A F, Guardia Gabriela D A, Pisani Janina, Sandoval Renata L, Barros-Filho Mateus C, Gifoni Ana Carolina Leite Vieira Costa, Patrão Diogo F C, Ashton-Prolla Patricia, de Vasconcellos Vitor Fiorin, Freycon Claire, Levine Arnold, Hainaut Pierre, Achatz Maria Isabel
Centro de Oncologia Molecular, Hospital Sirio-Libanes, São Paulo, Brazil.
Department of Oncology, Hospital Sírio-Libanês, São Paulo, Brazil.
Lancet Reg Health Am. 2025 Jan 18;42:100982. doi: 10.1016/j.lana.2024.100982. eCollection 2025 Feb.
Li-Fraumeni Syndrome (LFS) is a predisposition associated with early onset malignant tumors caused by germline pathogenic variants in the gene. Although rare worldwide, LFS is prevalent in Southern Brazil due to the founder pathogenic variant R337H. Here, we assessed tumor patterns and temporal trends, cancer risk, and sex differences of adult R337H carriers and carriers of other LFS-associated variants.
We retrospectively analyzed 708 adults, combining data from two sources: the Brazilian Li-Fraumeni Syndrome Study cohort and the NCI TP53 database. We assessed the clinical characteristics of 303 adults with R337H and compared them with those associated with 405 carriers of other TP53 variants.
R337H carriers, compared to adult carriers of other variants typical of LFS, had a lower cumulative risk of developing cancer (54% vs 78%). Female R337H carriers were at a higher risk than males (65% vs 30%) and had a higher risk of developing a second primary cancer, underscoring a strong sex bias not observed in carriers of other variants. The most common cancers were breast cancer and soft tissue sarcoma in females, and soft tissue sarcoma and prostate cancer in males. Common second malignancies were breast cancer in females and lung cancer in males.
This study shows that R337H is associated with a lifetime risk of multiple LFS-spectrum cancers but with incomplete penetrance, particularly in males. Our findings suggest that R337H carriers would benefit from tailored surveillance and risk reduction strategies.
São Paulo Research Foundation, Conselho Nacional de Pesquisa, and Hospital Sírio-Libanês.
李-佛美尼综合征（LFS）是一种由该基因种系致病性变异导致的与早发性恶性肿瘤相关的易感性疾病。尽管在全球范围内较为罕见，但由于奠基者致病性变异R337H，LFS在巴西南部地区较为普遍。在此，我们评估了成年R337H携带者以及其他与LFS相关变异携带者的肿瘤模式和时间趋势、癌症风险及性别差异。
我们回顾性分析了708名成年人，数据来自两个来源：巴西李-佛美尼综合征研究队列和美国国立癌症研究所TP53数据库。我们评估了303名携带R337H的成年人的临床特征，并将其与405名其他TP53变异携带者的临床特征进行比较。
与其他典型LFS变异的成年携带者相比，R337H携带者患癌的累积风险较低（54%对78%）。女性R337H携带者的风险高于男性（65%对30%），且发生第二原发性癌症的风险更高，这突出了在其他变异携带者中未观察到的强烈性别偏见。女性最常见的癌症是乳腺癌和软组织肉瘤，男性是软组织肉瘤和前列腺癌。常见的第二原发性恶性肿瘤女性为乳腺癌，男性为肺癌。
本研究表明，R337H与多种LFS谱系癌症的终生风险相关，但具有不完全外显率，尤其是在男性中。我们的研究结果表明，R337H携带者将从量身定制的监测和风险降低策略中受益。
圣保罗研究基金会、巴西国家科学技术发展委员会和黎巴嫩叙利亚医院。
