Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia-A Nationwide Register-Based Cohort Study in Germany.

PURPOSE: Fanconi anemia (FA) and ataxia-telangiectasia (AT) are rare inherited syndromes characterized by abnormal DNA damage response and caused by pathogenic variants in key DNA repair proteins that are also relevant in the pathogenesis of breast cancer and other cancer types. The risk of cancer in children with these diseases is poorly understood and has never been assessed in a population-based cohort before. METHODS: We identified 421 patients with FA and 160 patients with AT diagnosed between 1973 and 2020 through German DNA repair disorder reference laboratories. We linked patients' laboratory data with childhood cancer data from the German Childhood Cancer Registry. RESULTS: Among 421 patients with FA, we observed 33 cases of childhood cancer (15 cases of myelodysplastic syndrome; seven cases of acute myeloid leukemia; two cases of lymphoma, carcinoma, medulloblastoma, and nephroblastoma, respectively; and one case of rhabdomyosarcoma, acute lymphoblastic leukemia, and glioma, respectively) versus 0.74 expected (on the basis of population-based incidence rates in Germany). This corresponds to a 39-fold increased risk (standardized incidence ratio [SIR] = 39; 95% CI, 26 to 56). For all FA subgroups combined, the cancer-specific SIR for myeloid neoplasms was 445 (95% CI, 272 to 687). Among the 160 patients with AT, we observed 19 cases of childhood cancer (15 cases of lymphoma, three cases of leukemia, and one case of medulloblastoma) versus 0.32 expected. This corresponds to a 56-fold increased risk (SIR = 56; 95% CI, 33 to 88). The cancer-specific SIR for Hodgkin lymphoma was 215 (95% CI, 58 to 549) and for non-Hodgkin lymphoma 470 (95% CI, 225 to 865). CONCLUSION: Approximately 11% of patients with FA and 14% of patients with AT develop cancer by age 18 years.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype.

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n = 10) or multiple (n = 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

Fanconi anemia with sun-sensitivity caused by a Xeroderma pigmentosum-associated missense mutation in XPF.

BACKGROUND: Fanconi anemia (FA) is an inherited genomic instability disorder with congenital and developmental abnormalities, bone marrow failure and predisposition to cancer early in life, and cellular sensitivity to DNA interstrand crosslinks. CASE PRESENTATION: A fifty-one-year old female patient, initially diagnosed with FA in childhood on the basis of classic features and increased chromosomal breakage, and remarkable sun-sensitivity is described. She only ever had mild haematological abnormalities and no history of malignancy. To identify and characterise the genetic defect in this lady, who is one of the oldest reported FA patients, we used whole-exome sequencing for identification of causative mutations, and functionally characterized the cellular phenotype. Detection of the novel splice site mutation c.793-2A > G and the previously described missense mutation c.1765C > T (p.Arg589Trp) in XPF/ERCC4/FANCQ assign her as the third individual of complementation group FA-Q. Ectopic expression of wildtype, but not mutant, XPF/ERCC4/FANCQ, in patient-derived fibroblasts rescued cellular resistance to DNA interstrand-crosslinking agents. Patient derived FA-Q cells showed impaired nuclear excision repair capacity. However, mutated XPF/ERCC4/FANCQ protein in our patient's cells, as in the two other patients with FA-Q, was detectable on chromatin, in contrast to XP-F cells, where missense-mutant protein failed to properly translocate to the nucleus. CONCLUSIONS: Patients with FA characteristics and UV sensitivity should be tested for mutations in XPF/ERCC4/FANCQ. The missense mutation p.Arg589Trp was previously detected in patients diagnosed with Xeroderma pigmentosum or Cockayne syndrome. Hence, phenotypic manifestations associated with this XPF/ERCC4/ FANCQ mutation are highly variable.