Germline biallelic BRCA2 pathogenic variants and medulloblastoma: an international cohort study

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...

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Published in:	Journal of hematology and oncology Vol. 17; no. 1; pp. 26 - 5
Main Authors:	Kastellan, Svenja, Kalb, Reinhard, Sajjad, Bia, McReynolds, Lisa J, Giri, Neelam, Samuel, David, Milde, Till, Elbracht, Miriam, Holzhauer, Susanne, Niewisch, Marena R, Kratz, Christian P
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 29-04-2024 BioMed Central BMC
Subjects:	Alleles Analysis Anemia Bone marrow Brain cancer BRCA2 BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Cerebellar Neoplasms - genetics Cerebellar Neoplasms - mortality Cerebellar Neoplasms - pathology Cerebellum Chemotherapy Child, Preschool Clinical trials Cohort analysis Cohort Studies Correspondence Diagnosis Esophageal cancer Fanconi anemia Fanconi Anemia - genetics Fanconi syndrome Fanconi's anemia Female Genes Genetic counseling Germ-Line Mutation Health aspects Humans Infant Male Medical prognosis Medulloblastoma Medulloblastoma - genetics Medulloblastoma - mortality Medulloblastoma - pathology Medulloblastoma - therapy Metastasis Mutation Ovarian cancer Pancreatic cancer Patients Prostate cancer Radiation Radiotherapy Risk factors Signal transduction Squamous cell carcinoma Tumors United States > US Fanconi anemia BRCA2 Medulloblastoma
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Correspondence-2 content type line 23
ISSN:	1756-8722 1756-8722
DOI:	10.1186/s13045-024-01547-4