Individuals with &ITFANCM&IT biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility
Por:
Catucci, I, Osorio, A, Arver, B, Neidhardt, G, Bogliolo, M, Zanardi, F, Riboni, M, Minardi, S, Pujol, R, Azzollini, J, Peissel, B, Manoukian, S, De Vecchi, G, Casola, S, Hauke, J, Richters, L, Rhiem, K, Schmutzler, RK, Wallander, K, Torngren, T, Borg, A, Radice, P, Surralles, J, Hahnen, E, Ehrencrona, H, Kvist, A, Benitez, J, Peterlongo, P, SWE-BRCA
Publicada:
1 abr 2018
Resumen:
Purpose: Monoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.& para;& para;Methods: Breast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.& para;& para;Results: Five cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.& para;& para;Conclusion: Our data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.
Filiaciones:
Catucci, I:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Osorio, A:
Spanish Natl Canc Res Ctr CNIO, Madrid, Spain
Spanish Network Rare Dis, Madrid, Spain
Arver, B:
Karolinska Inst, Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden
Neidhardt, G:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Bogliolo, M:
Univ Autonoma Barcelona, Hosp Santes Creus & St Pau, Dept Genet, Dept Genet & Microbiol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Zanardi, F:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Riboni, M:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Minardi, S:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Pujol, R:
Univ Autonoma Barcelona, Hosp Santes Creus & St Pau, Dept Genet, Dept Genet & Microbiol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Azzollini, J:
Fdn IRCCS Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy
Peissel, B:
Fdn IRCCS Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy
Manoukian, S:
Fdn IRCCS Ist Nazl Tumori, Unit Med Genet, Dept Prevent & Predict Med, Milan, Italy
De Vecchi, G:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Cogentech, Canc Genet Test Lab, Milan, Italy
Casola, S:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Hauke, J:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Richters, L:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Rhiem, K:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Schmutzler, RK:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Wallander, K:
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden
Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden
Torngren, T:
Lund Univ, Dept Clin Sci, Divis Oncol, Lund, Sweden
Borg, A:
Lund Univ, Dept Clin Sci, Divis Oncol, Lund, Sweden
Radice, P:
Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, Milan, Italy
Surralles, J:
Univ Autonoma Barcelona, Hosp Santes Creus & St Pau, Dept Genet, Dept Genet & Microbiol, Barcelona, Spain
Ctr Invest Biomed Red Enfermedades Raras CIBERER, Barcelona, Spain
Hahnen, E:
Univ Hosp Cologne, Ctr Integrated Oncol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany
Univ Cologne, Ctr Mol Med Cologne, Cologne, Germany
Ehrencrona, H:
Off Med Serv, Dept Clin Genet, Lab Med, Lund, Sweden
Lund Univ, Dept Clin Genet, Lund, Sweden
Kvist, A:
Lund Univ, Dept Clin Sci, Divis Oncol, Lund, Sweden
Benitez, J:
Spanish Natl Canc Res Ctr CNIO, Madrid, Spain
Spanish Network Rare Dis, Madrid, Spain
Peterlongo, P:
FIRC Inst Mol Oncol, IFOM, Genome Diagnost Program, Milan, Italy
Bronze
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