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

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: Brain tumor; Cancer predisposition; Fanconi anemia; Genetic testing; Neuroblastoma; Wilms tumor.

Fig. 1.

Cases of FA due to FANCD1 and FANCN variants were identified from the literature and combined with four unpublished cases. There were 71 patients with FANCD1 variants and 16 with FANCN variants. The number of cancers in each genotype exceed the number of patients because some patients had multiple cancers. The types of cancer were the same in both groups.

Fig. 2.

The age at diagnosis of the D1-N associated cancers in FA due to FANCD1 and FANCN variants. No significant difference is seen (all p > 0.05). A) Brain Tumor. B) Wilms Tumor. C) Acute Leukemia, D) Neuroblastoma. Dark grey, FANCD1. Light grey, FANCN. X is the median.

Fig. 3.

The age at onset according to the genotypes of the D1-N associated cancers in FA due to FANCD1. A) Brain Tumor B) Wilms Tumor. C) Acute Leukemia. D) Neuroblastoma. N-N= Null-Null; N-H or H-H= Null-Hypomorph or Hypomorph-Hypomorph; N-B, H-B or H-VUS= Null-Benign, Hypomorph-Benign, Hypomorph-VUS; B-B or unknown= Benign-Benign or unknown alleles. No significant difference is seen comparing the variant allele groups. There is a non-significant trend to earlier onset of acute leukemia in the null-null group compared with all other variant groups (p = 0.92).