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：

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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


编码 Fanconi 贫血-BRCA 信号通路某些成分（修复 DNA 链间交联）某些成分的基因中的体质杂合致病性变异代表了常见癌症的危险因素，包括乳腺癌、卵巢癌、胰腺癌和前列腺癌。高癌症风险也是范可尼贫血 （FA） 患者的一个主要临床特征，范可尼贫血 （FA） 是一种以骨髓衰竭、内分泌和身体异常为特征的罕见疾病。主要隐性遗传是由 21 个 FA-BRCA 通路基因之一的种系致病性变异引起的。在 FA 患者中，在 BRCA2 或 PALB2 中具有双等位基因致病性变异的患者中观察到最高的癌症风险。这些患者在生命的最初十年中发展为一系列胚胎肿瘤和白血病，然而，人们对特定的临床、遗传和病理特征或毒性知之甚少。在这里，我们介绍了在由 8 名双等位基因 BRCA2 致病性变异和髓母细胞瘤 （MB）（一种小脑胚胎性肿瘤）引起的 FA 患者的国际队列中观察到的遗传、临床、病理和治疗特征。MB 诊断的中位年龄为 32.5 个月 （范围 7-58 个月）。所有有可用数据的患者都有 sonic hedgehog-MB。6 例患者接受化疗，1 例患者还接受质子放疗。没有记录到危及生命的毒性。预后较差，所有患者在 MB 诊断后不久 （中位生存时间 4.5 个月，范围 0-21 个月） 因 MB 或其他肿瘤而死亡。总之，双等位基因 BRCA2 致病性变异患者的 MB 是一种致命的疾病。未来的实验性治疗是必要的，以帮助这些患者。