title: The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes.
abstract: Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer predisposition syndromes. We analyzed the frequency and genotype-phenotype correlations of microdeletions in 12 genes (BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1, and VHL) representing seven tumor predisposition syndromes in 5,897 individuals (2,611 families) from our center. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04-Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next-generation sequencing.
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Smith
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Centre for Imaging Sciences, University of Manchester, Manchester, M13 9PY, UK.
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Harkness
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Miles
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Bowers
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Byers
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Bulman
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Gokhale
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wallace
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, M13 9WL, UK.
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009154:Mutation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D016159:Tumor Suppressor Protein p53; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein
keywords: Gorlin syndrome; Lynch syndrome; breast cancer; familial adenomatous polyposis; neurofibromatosis; von Hippel Lindau; whole gene deletion