title: Deleterious Germline BLM Mutations and the Risk for Early-onset Colorectal Cancer.
abstract: Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Richarda M
authors.initials: RM
authors.lastname: de Voer
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Marc-Manuel
authors.initials: MM
authors.lastname: Hahn
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Arjen R
authors.initials: AR
authors.lastname: Mensenkamp
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Henkes
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: van Zelst-Stams
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: C Marleen
authors.initials: CM
authors.lastname: Kets
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Verwiel
authors.affiliation: Department of Pathology, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Iris D
authors.initials: ID
authors.lastname: Nagtegaal
authors.affiliation: Department of Surgical Research, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstraße 74, 01307, Dresden, Germany.
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Ad Geurts
authors.initials: AG
authors.lastname: van Kessel
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.|Department of Pathology, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.affiliation: Department of Human Genetics, Radboud university medical center, Geert Grooteplein 10, 6525 GA, Nijmegen, The Netherlands.
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
mesh_terms: D000328:Adult; D017668:Age of Onset; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D066264:Datasets as Topic; D059472:Exome; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D018095:Germ-Line Mutation; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D059645:Mutation Rate; D010375:Pedigree; D011159:Population Surveillance; D053484:RecQ Helicases / Q000235:genetics*; D012306:Risk
chemical_list: C097151:Bloom syndrome protein; D053484:RecQ Helicases