title: The effect of genotypes and parent of origin on cancer risk and age of cancer development in PMS2 mutation carriers.
abstract: OBJECTIVE
  Lynch syndrome (LS), a heritable disorder with an increased risk of primarily colorectal cancer (CRC) and endometrial cancer (EC), can be caused by mutations in the PMS2 gene. We wished to establish whether genotype and/or parent-of-origin effects (POE) explain (part of) the reported variability in severity of the phenotype.
  
  
  METHODS
  European PMS2 mutation carriers (n = 381) were grouped and compared based on RNA expression and whether the mutation was inherited paternally or maternally.
  
  
  RESULTS
  Mutation carriers with loss of RNA expression (group 1) had a significantly lower age at CRC diagnosis (51.1 years vs. 60.0 years, P = 0.035) and a lower age at EC diagnosis (55.8 years vs. 61.0 years, P = 0.2, nonsignificant) compared with group 2 (retention of RNA expression). Furthermore, group 1 showed slightly higher, but nonsignificant, hazard ratios (HRs) for both CRC (HR: 1.31, P = 0.38) and EC (HR: 1.22, P = 0.72). No evidence for a significant parent-of-origin effect was found for either CRC or EC.
  
  
  CONCLUSIONS
  PMS2 mutation carriers with retention of RNA expression developed CRC 9 years later than those with loss of RNA expression. If confirmed, this finding would justify a delay in surveillance for these cases. Cancer risk was not influenced by a parent-of-origin effect.Genet Med 18 4, 405-409.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Manon
authors.initials: M
authors.lastname: Suerink
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van der Klift
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sanne W
authors.identifier: http://orcid.org/0000-0001-6280-0087
authors.initials: SW
authors.lastname: Ten Broeke
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Olaf M
authors.initials: OM
authors.lastname: Dekkers
authors.affiliation: Surgical Gastroenterology Department, Aalborg University Hospital, Aalborg, Denmark.|Danish HNPCC Registry, Copenhagen, Denmark.
authors.forename: Inge
authors.initials: I
authors.lastname: Bernstein
authors.affiliation: Laboratori de Recerca Translacional, Catalan Institute of Oncology, Barcelona (ICO-IDIBELL), Spain.
authors.forename: Gabriel
authors.identifier: http://orcid.org/0000-0002-4669-7320
authors.initials: G
authors.lastname: Capellá Munar
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Encarna
authors.initials: E
authors.lastname: Gomez Garcia
authors.affiliation: Department of Clinical Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Clinical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Tom G W
authors.initials: TG
authors.lastname: Letteboer
authors.affiliation: Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Fred H
authors.initials: FH
authors.lastname: Menko
authors.affiliation: Department of Clinical Genetics, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Annika
authors.identifier: http://orcid.org/0000-0001-7675-7569
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Mensenkamp
authors.affiliation: Department of Medical Genetics, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway.
authors.forename: Pal
authors.initials: P
authors.lastname: Moller
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Theo A
authors.initials: TA
authors.lastname: van Os
authors.affiliation: Institut für Humangenetik und Anthropologie, Dusseldorf, Germany.
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Bert J W
authors.initials: BJ
authors.lastname: Redeker
authors.forename: M J W
authors.initials: MJ
authors.lastname: Olderode-Berends
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Maran
authors.initials: M
authors.lastname: Olderode
authors.affiliation: Department of Oncology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Anja
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012306:Risk
chemical_list: D000070976:Mismatch Repair Endonuclease PMS2