title: Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort.
abstract: OBJECTIVE
  Immunohistochemistry for DNA mismatch repair proteins is used to screen for Lynch syndrome in individuals with colorectal carcinoma (CRC). Although solitary loss of PMS2 expression is indicative of carrying a germline mutation in PMS2, previous studies reported MLH1 mutation in some cases. We determined the prevalence of MLH1 germline mutations in a large cohort of individuals with a CRC demonstrating solitary loss of PMS2 expression.
  
  
  METHODS
  This cohort study included 88 individuals affected with a PMS2-deficient CRC from the Colon Cancer Family Registry Cohort. Germline PMS2 mutation analysis (long-range PCR and multiplex ligation-dependent probe amplification) was followed by MLH1 mutation testing (Sanger sequencing and multiplex ligation-dependent probe amplification).
  
  
  RESULTS
  Of the 66 individuals with complete mutation screening, we identified a pathogenic PMS2 mutation in 49 (74%), a pathogenic MLH1 mutation in 8 (12%) and a MLH1 variant of uncertain clinical significance predicted to be damaging by in silico analysis in 3 (4%); 6 (9%) carried variants likely to have no clinical significance. Missense point mutations accounted for most alterations (83%; 9/11) in MLH1. The MLH1 c.113A> G p.Asn38Ser mutation was found in 2 related individuals. One individual who carried the MLH1 intronic mutation c.677+3A>G p.Gln197Argfs*8 leading to the skipping of exon 8, developed 2 tumours, both of which retained MLH1 expression.
  
  
  CONCLUSIONS
  A substantial proportion of CRCs with solitary loss of PMS2 expression are associated with a deleterious MLH1 germline mutation supporting the screening for MLH1 in individuals with tumours of this immunophenotype, when no PMS2 mutation has been identified.
authors.affiliation: Envoi Pathology, Brisbane, Queensland, Australia The School of Medicine, The University of Queensland, Brisbane, Queensland, Australia Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Christophe
authors.initials: C
authors.lastname: Rosty
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.affiliation: Department of Histopathology, Sullivan Nicolaides Pathology, Brisbane, Queensland, Australia.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Walsh
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Stine V
authors.initials: SV
authors.lastname: Eriksen
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
authors.affiliation: Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Winship
authors.affiliation: Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Finlay A
authors.initials: FA
authors.lastname: Macrae
authors.affiliation: Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Parkville, Victoria, Australia Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Alex
authors.initials: A
authors.lastname: Boussioutas
authors.affiliation: South Australian Clinical Genetics Service, SA Pathology at the WCH, North Adelaide, South Australia, Australia University Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Nicola K
authors.identifier: http://orcid.org/0000-0002-9372-3325
authors.initials: NK
authors.lastname: Poplawski
authors.affiliation: New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital, Auckland, New Zealand Department of Gastroenterology, Middlemore Hospital, Auckland, New Zealand.
authors.forename: Susan
authors.initials: S
authors.lastname: Parry
authors.affiliation: Department of Gastroenterology, Middlemore Hospital, Auckland, New Zealand.
authors.forename: Julie
authors.initials: J
authors.lastname: Arnold
authors.affiliation: Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia School of Medicine, University of Adelaide, Adelaide, South Australia, Australia SAHMRI Colorectal Node, Basil Hetzel Institute for Translational Research, Woodville, South Australia, Australia.
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA School of Public Health, University of Washington, Seattle, Washington, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA School of Public Health, University of Washington, Seattle, Washington, USA Centre for Public Health Research, Massey University, Wellington, New Zealand.
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.affiliation: Departments of Health Sciences Research, Biomedical Statistics and Informatics, Laboratory Medicine and Pathology, Medical Genetics, Medical Genomics Technology and Advanced Genomics Technology Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: DeRycke
authors.affiliation: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Baron
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D012042:Registries; D055815:Young Adult
chemical_list: C501486:MLH1 protein, human; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1
keywords: HISTOPATHOLOGY