Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2)

      Highlights

      • There is a unique genotype-cancer association in FANCD1 and FANCN Fanconi anemia.
      • FANCN and FANCD1 Fanconi anemia patients often develop embryonic tumors early in life.
      • Mouse embryonic stem cell-based functional testing improves FANCD1 variant curation.

      Abstract

      Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and a cancer predisposition disorder. Cancers in FA include acute leukemia and solid tumors; the most frequent solid tumor is head and neck squamous cell carcinoma. FA is a primarily autosomal recessive disorder. Several of the genes in which biallelic pathogenic variants cause FA are also autosomal monoallelic cancer predisposition genes e.g. FANCD1 (BRCA2) and FANCN (PALB2). We observed that patients with FA due to biallelic or homozygous pathogenic variants in FANCD1 and FANCN have a unique cancer association. We curated published cases plus our NCI cohort cases, including 71 patients in the FANCD1 group (94 cancers and 69 variants) and 16 patients in the FANCN group (23 cancers and 20 variants). Only patients in FANCD1 and FANCN groups had one or more of these tumors: brain tumors (primarily medulloblastoma), Wilms tumor and neuroblastoma; this is a genotype-specific cancer combination of tumors of embryonal origin. Acute leukemias, seen in all FA genotypes, also occurred in FANCD1 and FANCN group patients at young ages. In silico predictions of pathogenicity for FANCD1 variants were compared with results from a mouse embryonic stem cell-based functional assay. Patients with two null FANCD1 variants did not have an increased frequency of cancer nor earlier onset of cancer compared with those with hypomorphic variants. Patients with FA and these specific cancers should consider genetic testing focused on FANCD1 and FANCN, and patients with these genotypes may consider ongoing surveillance for these specific cancers.

      Keywords

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