title: Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas.
abstract: BACKGROUND
  MUTYH-associated polyposis (MAP) is a recessively inherited disorder which predisposes biallelic carriers for a high risk of polyposis and colorectal carcinoma (CRC). Since about one third of the biallelic MAP patients in population based CRC series has no adenomas, this study aimed to identify specific clinicopathological characteristics of MAP CRCs and compare these with reported data on sporadic and Lynch CRCs.
  
  
  METHODS
  From 44 MAP patients who developed > or = 1 CRCs, 42 of 58 tumours were analyzed histologically and 35 immunohistochemically for p53 and beta-catenin. Cell densities of CD3, CD8, CD57, and granzyme B positive lymphocytes were determined. KRAS2, the mutation cluster region (MCR) of APC, p53, and SMAD4 were analyzed for somatic mutations.
  
  
  RESULTS
  MAP CRCs frequently localized to the proximal colon (69%, 40/58), were mucinous in 21% (9/42), and had a conspicuous Crohn's like infiltrate reaction in 33% (13/40); all of these parameters occurred at a higher rate than reported for sporadic CRCs. Tumour infiltrating lymphocytes (TILs) were also highly prevalent in MAP CRCs. Somatic APC MCR mutations occurred in 14% (5/36) while 64% (23/36) had KRAS2 mutations (22/23 c.34G>T). G>T transversions were found in p53 and SMAD4, although the relative frequency compared to other mutations was low.
  
  
  CONCLUSIONS
  MAP CRCs show some similarities to micro-satellite unstable cancers, with a preferential proximal location, a high rate of mucinous histotype and increased presence of TILs. These features should direct the practicing pathologist towards a MAP aetiology of CRC as an alternative for a mismatch repair deficient cause. High frequent G>T transversions in APC and KRAS2 (mutated in early tumour development) but not in P53 and SMAD4 (implicated in tumour progression) might indicate a predominant MUTYH effect in early carcinogenesis.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. M.Nielsen@lumc.nl
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
authors.forename: Noel F C C
authors.initials: NF
authors.lastname: de Miranda
authors.forename: Marjo
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.forename: Anneke
authors.initials: A
authors.lastname: Middeldorp
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D000328:Adult; D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D009154:Mutation; D046888:Tissue Array Analysis
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase