Constitutional heterozygous pathogenic variants in genes coding for some components of the Fanconi anemia-BRCA signaling pathway, which repairs DNA interstrand crosslinks, represent risk factors for common cancers, including breast, ovarian, pancreatic and prostate cancer. A high cancer risk is also a main clinical feature in patients with Fanconi anemia (FA), a rare condition characterized by bone marrow failure, endocrine and physical abnormalities. The mainly recessive condition is caused by germline pathogenic variants in one of 21 FA-BRCA pathway genes. Among patients with FA, the highest cancer risks are observed in patients with biallelic pathogenic variants in BRCA2 or PALB2. These patients develop a range of embryonal tumors and leukemia during the first decade of life, however, little is known about specific clinical, genetic and pathologic features or toxicities. Here, we present genetic, clinical, pathological and treatment characteristics observed in an international cohort of eight patients with FA due to biallelic BRCA2 pathogenic variants and medulloblastoma (MB), an embryonal tumor of the cerebellum. Median age at MB diagnosis was 32.5 months (range 7–58 months). All patients with available data had sonic hedgehog-MB. Six patients received chemotherapy and one patient also received proton radiation treatment. No life-threatening toxicities were documented. Prognosis was poor and all patients died shortly after MB diagnosis (median survival time 4.5 months, range 0–21 months) due to MB or other neoplasms. In conclusion, MB in patients with biallelic BRCA2 pathogenic variants is a lethal disease. Future experimental treatments are necessary to help these patients.

中文翻译：

---

种系双等位基因 BRCA2 致病性变异和髓母细胞瘤：一项国际队列研究

范可尼贫血-BRCA 信号通路（修复 DNA 链间交联）某些成分的编码基因中的宪法性杂合致病性变异代表了常见癌症（包括乳腺癌、卵巢癌、胰腺癌和前列腺癌）的危险因素。高癌症风险也是范可尼贫血 (FA) 患者的主要临床特征，这是一种以骨髓衰竭、内分泌和身体异常为特征的罕见疾病。主要的隐性病症是由 21 个 FA-BRCA 途径基因之一的种系致病变异引起的。在 FA 患者中，BRCA2 或 PALB2 双等位基因致病性变异患者的癌症风险最高。这些患者在生命的最初十年中会出现一系列胚胎肿瘤和白血病，然而，人们对具体的临床、遗传和病理特征或毒性知之甚少。在此，我们介绍了在由 8 名因双等位基因 BRCA2 致病性变异和髓母细胞瘤 (MB)（一种小脑胚胎肿瘤）引起的 FA 患者组成的国际队列中观察到的遗传、临床、病理和治疗特征。 MB 诊断时的中位年龄为 32.5 个月（范围 7-58 个月）。所有有可用数据的患者均患有 sonic hedgehog-MB。六名患者接受了化疗，一名患者还接受了质子放射治疗。没有记录到危及生命的毒性。预后很差，所有患者在 MB 诊断后不久就因 MB 或其他肿瘤而死亡（中位生存时间 4.5 个月，范围 0-21 个月）。总之，携带双等位基因 BRCA2 致病性变异的患者中的 MB 是一种致命性疾病。未来的实验性治疗对于帮助这些患者是必要的。