Spectrum of Germline Mutations within Fanconi Anemia-Associated Genes across Populations of Varying Ancestry

Menée à partir de données portant sur 3 523 individus inclus dans 7 cohortes du "The Cancer Genome Atlas", cette étude analyse la présence et la fréquence de mutations constitutionnelles de 17 gènes impliqués dans l'anémie de Fanconi (maladie génétique prédisposant à des tumeurs solides et à des cancers hématologiques)

Résumé en anglais

Fanconi anemia (FA) is a rare genetic disorder associated with hematological disorders and solid tumor predisposition. Owing to phenotypic heterogeneity, some patients remain undetected until adulthood, usually following cancer diagnoses. The uneven prevalence of FA cases with different underlying FA gene mutations worldwide suggests variable genetic distribution across populations. Here, we aim to assess the genetic spectrum of FA-associated genes across populations of varying ancestries and explore potential genotype-phenotype associations in cancer. Carrier frequency and variant spectrum of potentially pathogenic germline variants in 17 FA genes (excluding BRCA1/FANCS, BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO) were evaluated in 3,523 Singaporeans and seven populations encompassing Asian, European, African and admixed ancestries from Genome Aggregation Database. Germline and somatic variants of 17 FA genes in seven cancer cohorts from The Cancer Genome Atlas (TCGA) were assessed to explore genotype-phenotype associations. Germline variants in FANCA were consistently more frequent in all populations. Similar trends in carrier frequency and variant spectrum were detected in Singaporeans and East Asians, both distinct from other ancestry groups particularly in the lack of recurrent variants. Our TCGA dataset exploration suggested higher germline and somatic mutation burden between FANCA and FANCC with head and neck and lung squamous cell carcinomas, as well as FANCI and SLX4/FANCP with uterine cancer, but the analysis was insufficiently powered to detect any statistical significance.Our findings highlight the diverse genetic spectrum of FA-associated genes across populations of varying ancestries, emphasizing the need to include all known FA-related genes for accurate molecular diagnosis of FA.