Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility

Irene Catucci, Ana Osorio, Brita Arver, Guido Neidhardt, Massimo Bogliolo, Federica Zanardi, Mirko Riboni, Simone Minardi, Roser Pujol, Jacopo Azzollini, Bernard Peissel, Siranoush Manoukian, Giovanna De Vecchi, Stefano Casola, Jan Hauke, Lisa Richters, Kerstin Rhiem, Rita K Schmutzler, Karin Wallander, Therese TörngrenÅke Borg, Paolo Radice, Jordi Surrallés, Eric Hahnen, Hans Ehrencrona, Anders Kvist, Javier Benitez, Paolo Peterlongo

Research output: Contribution to journalArticle

Abstract

PurposeMonoallelic 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.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive 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.ConclusionOur 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.

Original languageEnglish
Pages (from-to)452-457
Number of pages6
JournalGenetics in Medicine
Volume20
Issue number4
DOIs
Publication statusPublished - Apr 2018

Fingerprint

Chromosome Fragility
Fanconi Anemia
Breast Neoplasms
Drug Therapy
Mutation
Phenotype
Genes
Bone Marrow
Neoplasms
Gene Order
Germ-Line Mutation
Neoplasm Genes
Menopause
DNA Damage

Keywords

  • Alleles
  • Antineoplastic Agents/pharmacology
  • Breast Neoplasms/diagnosis
  • Chromosome Fragility
  • Consanguinity
  • DNA Helicases/genetics
  • Drug Resistance, Neoplasm/genetics
  • Fanconi Anemia/diagnosis
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Male
  • Mutation
  • Pedigree
  • Phenotype
  • Risk Assessment
  • Risk Factors

Cite this

Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. / Catucci, Irene; Osorio, Ana; Arver, Brita; Neidhardt, Guido; Bogliolo, Massimo; Zanardi, Federica; Riboni, Mirko; Minardi, Simone; Pujol, Roser; Azzollini, Jacopo; Peissel, Bernard; Manoukian, Siranoush; De Vecchi, Giovanna; Casola, Stefano; Hauke, Jan; Richters, Lisa; Rhiem, Kerstin; Schmutzler, Rita K; Wallander, Karin; Törngren, Therese; Borg, Åke; Radice, Paolo; Surrallés, Jordi; Hahnen, Eric; Ehrencrona, Hans; Kvist, Anders; Benitez, Javier; Peterlongo, Paolo.

In: Genetics in Medicine, Vol. 20, No. 4, 04.2018, p. 452-457.

Research output: Contribution to journalArticle

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, Törngren, T, Borg, Å, Radice, P, Surrallés, J, Hahnen, E, Ehrencrona, H, Kvist, A, Benitez, J & Peterlongo, P 2018, 'Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility', Genetics in Medicine, vol. 20, no. 4, pp. 452-457. https://doi.org/10.1038/gim.2017.123
Catucci, Irene ; Osorio, Ana ; Arver, Brita ; Neidhardt, Guido ; Bogliolo, Massimo ; Zanardi, Federica ; Riboni, Mirko ; Minardi, Simone ; Pujol, Roser ; Azzollini, Jacopo ; Peissel, Bernard ; Manoukian, Siranoush ; De Vecchi, Giovanna ; Casola, Stefano ; Hauke, Jan ; Richters, Lisa ; Rhiem, Kerstin ; Schmutzler, Rita K ; Wallander, Karin ; Törngren, Therese ; Borg, Åke ; Radice, Paolo ; Surrallés, Jordi ; Hahnen, Eric ; Ehrencrona, Hans ; Kvist, Anders ; Benitez, Javier ; Peterlongo, Paolo. / Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility. In: Genetics in Medicine. 2018 ; Vol. 20, No. 4. pp. 452-457.
@article{bc461f8d62ba461fa0dd8ec4e4064473,
title = "Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility",
abstract = "PurposeMonoallelic 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.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive 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.ConclusionOur 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.",
keywords = "Alleles, Antineoplastic Agents/pharmacology, Breast Neoplasms/diagnosis, Chromosome Fragility, Consanguinity, DNA Helicases/genetics, Drug Resistance, Neoplasm/genetics, Fanconi Anemia/diagnosis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, Male, Mutation, Pedigree, Phenotype, Risk Assessment, Risk Factors",
author = "Irene Catucci and Ana Osorio and Brita Arver and Guido Neidhardt and Massimo Bogliolo and Federica Zanardi and Mirko Riboni and Simone Minardi and Roser Pujol and Jacopo Azzollini and Bernard Peissel and Siranoush Manoukian and {De Vecchi}, Giovanna and Stefano Casola and Jan Hauke and Lisa Richters and Kerstin Rhiem and Schmutzler, {Rita K} and Karin Wallander and Therese T{\"o}rngren and {\AA}ke Borg and Paolo Radice and Jordi Surrall{\'e}s and Eric Hahnen and Hans Ehrencrona and Anders Kvist and Javier Benitez and Paolo Peterlongo",
year = "2018",
month = "4",
doi = "10.1038/gim.2017.123",
language = "English",
volume = "20",
pages = "452--457",
journal = "Genetics in Medicine",
issn = "1098-3600",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility

AU - Catucci, Irene

AU - Osorio, Ana

AU - Arver, Brita

AU - Neidhardt, Guido

AU - Bogliolo, Massimo

AU - Zanardi, Federica

AU - Riboni, Mirko

AU - Minardi, Simone

AU - Pujol, Roser

AU - Azzollini, Jacopo

AU - Peissel, Bernard

AU - Manoukian, Siranoush

AU - De Vecchi, Giovanna

AU - Casola, Stefano

AU - Hauke, Jan

AU - Richters, Lisa

AU - Rhiem, Kerstin

AU - Schmutzler, Rita K

AU - Wallander, Karin

AU - Törngren, Therese

AU - Borg, Åke

AU - Radice, Paolo

AU - Surrallés, Jordi

AU - Hahnen, Eric

AU - Ehrencrona, Hans

AU - Kvist, Anders

AU - Benitez, Javier

AU - Peterlongo, Paolo

PY - 2018/4

Y1 - 2018/4

N2 - PurposeMonoallelic 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.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive 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.ConclusionOur 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.

AB - PurposeMonoallelic 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.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive 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.ConclusionOur 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.

KW - Alleles

KW - Antineoplastic Agents/pharmacology

KW - Breast Neoplasms/diagnosis

KW - Chromosome Fragility

KW - Consanguinity

KW - DNA Helicases/genetics

KW - Drug Resistance, Neoplasm/genetics

KW - Fanconi Anemia/diagnosis

KW - Female

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Mutation

KW - Pedigree

KW - Phenotype

KW - Risk Assessment

KW - Risk Factors

U2 - 10.1038/gim.2017.123

DO - 10.1038/gim.2017.123

M3 - Article

C2 - 28837162

VL - 20

SP - 452

EP - 457

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

IS - 4

ER -