title: Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer.
abstract: OBJECTIVE
  We report a patient of Indian descent with parental consanguinity, who developed 10 carcinomas and 35 adenomatous polyps at age 23 and duodenal adenocarcinoma at age 25. He also had dysmorphic features, mental retardation, and café-au-lait spots but no brain tumor. We aimed to establish his molecular diagnosis.
  
  
  METHODS
  Germ-line screening for APC and MYH/MUTYH mutations was normal as was immunohistochemistry for MLH1 and MSH2 proteins. Investigation by array-comparative genomic hybridization revealed deletion of a small region on chromosome 7. Using polymerase chain reaction, this region was refined to a 400-kilobase deletion, which included exons 9-15 of the PMS2 gene, and all coding regions of oncomodulin, TRIAD3, and FSCN1.
  
  
  RESULTS
  The deletion was confirmed as homozygous, and both parents were carriers. Immunohistochemistry showed absent PMS2 expression in all tumors and normal tissue. Most tumors showed microsatellite instability, more marked at dinucleotide than mononucleotide repeats. The tumors harbored no somatic mutations in APC, BRAF, AXIN2, or beta-catenin, but KRAS2 and TGFBR2 mutations were found.
  
  
  CONCLUSIONS
  Our patient represents a novel phenotype for homozygous PMS2 mutation and perhaps the most severe colorectal cancer phenotype-in terms of numbers of malignancies at an early age-described to date. PMS2 mutations-and perhaps other homozygous mismatch repair mutations-should be considered in any patient presenting with multiple gastrointestinal tumors, since our patient could not be distinguished clinically from cases with attenuated familial adenomatous polyposis or MUTYH-associated polyposis.
authors.affiliation: Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research, London, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Will
authors.forename: Luis G
authors.initials: LG
authors.lastname: Carvajal-Carmona
authors.forename: Patricia
authors.initials: P
authors.lastname: Gorman
authors.forename: Kimberley M
authors.initials: KM
authors.lastname: Howarth
authors.forename: Angela M
authors.initials: AM
authors.lastname: Jones
authors.forename: Guadalupe M
authors.initials: GM
authors.lastname: Polanco-Echeverry
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: Chinaleong
authors.forename: Thomas
authors.initials: T
authors.lastname: Günther
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.forename: Susan K
authors.initials: SK
authors.lastname: Clark
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000175:diagnosis; D018256:Adenomatous Polyps / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D004379:Duodenal Neoplasms / Q000235:genetics; D017809:Fatal Outcome; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006720:Homozygote; D006801:Humans; D044483:Intestinal Polyposis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D053842:Microsatellite Instability; D000070976:Mismatch Repair Endonuclease PMS2; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D012720:Severity of Illness Index; D018631:ras Proteins
chemical_list: D004268:DNA-Binding Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes