title: Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.
abstract: Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Pole Technique et biologie CHU Dijon, Dijon, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Degrolard-Courcet
authors.affiliation: Laboratoire de Génétique et INSERM U-954, CHU Nancy, Université de Lorraine, Nancy, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sokolowska
authors.affiliation: Département de Chirurgie, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Marie-Martine
authors.initials: MM
authors.lastname: Padeano
authors.affiliation: Département d'oncologie médicale, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Guiu
authors.affiliation: Laboratoire de Génétique et INSERM U-954, CHU Nancy, Université de Lorraine, Nancy, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Bronner
authors.affiliation: Laboratoire de Génétique et INSERM U-954, CHU Nancy, Université de Lorraine, Nancy, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Chery
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon et Université de bourgogne, Dijon, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Coron
authors.affiliation: Service d' Hepato-gastro-enterologie, CHU "Bocage Central", Dijon, France.
authors.forename: Côme
authors.initials: C
authors.lastname: Lepage
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Pole Technique et biologie CHU Dijon, Dijon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Chapusot
authors.affiliation: Département de Chirurgie, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Loustalot
authors.affiliation: Service d' Hepato-gastro-enterologie, CHU "Bocage Central", Dijon, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Jouve
authors.affiliation: Hepato-gastro-entérologie, Clinique Drevon, Dijon, France.
authors.forename: Cyril
authors.initials: C
authors.lastname: Hatem
authors.affiliation: Service d'Hématologie Clinique, Hôpital d'Enfants, CHU Dijon, Dijon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Ferrant
authors.affiliation: Service d'Anatomie et Cytologie Pathologiques, Pole Technique et biologie CHU Dijon, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martin
authors.affiliation: Département de Chirurgie, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Coutant
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon et Université de bourgogne, Dijon, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Baurand
authors.affiliation: Service de Pédiatrie 1, Hôpital d'Enfants, CHU Dijon, Dijon, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Couillault
authors.affiliation: Service de Radiologie, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Delignette
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon et Université de bourgogne, Dijon, France.
authors.forename: Salima
authors.initials: S
authors.lastname: El Chehadeh
authors.affiliation: Biologie Moléculaire, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Sarab
authors.initials: S
authors.lastname: Lizard
authors.affiliation: Anatomopathologie, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Arnould
authors.affiliation: Département d'oncologie médicale, Centre de lutte anti-cancereux Georges François Leclerc, Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.affiliation: Service de Cytogénétique, Pole Technique et biologie, CHU Dijon, Dijon, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Callier
authors.affiliation: Service de Cytogénétique, Pole Technique et biologie, CHU Dijon, Dijon, France.
authors.forename: Francine
authors.initials: F
authors.lastname: Mugneret
authors.affiliation: Laboratoire de Génétique et INSERM U-954, CHU Nancy, Université de Lorraine, Nancy, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Philippe
authors.affiliation: Inserm U1079 et Département de Génétique, CHU de Rouen, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Laboratoire de Génétique et INSERM U-954, CHU Nancy, Université de Lorraine, Nancy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Jonveaux
authors.affiliation: Centre de Génétique, Hôpital d'Enfants, CHU Dijon et Université de bourgogne, Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D019943:Amino Acid Substitution; D024682:BRCA2 Protein / Q000235:genetics*; D019457:Chromosome Breakage; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D009154:Mutation; D010375:Pedigree; D022821:RNA Splice Sites; D012326:RNA Splicing
chemical_list: D024682:BRCA2 Protein; D022821:RNA Splice Sites