title: Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations.
abstract: Colorectal serrated adenocarcinoma forms about 15-20% of colorectal carcinomas. We have previously shown that downregulation of PTCH1 is distinctive for this type of colorectal cancer. In several other tumor types, somatic inactivating PTCH1 mutations have been shown to lead to aberrant Hedgehog signaling, but in colorectal cancer the role of PTCH1 mutations has not been thoroughly studied. Here, we have analyzed the mutation status of PTCH1 in a series of 33 colorectal serrated adenocarcinomas by sequencing all 23 coding exons. We detected 11 previously known SNPs and eight new alterations. The latter included five synonymous changes and two previously unknown missense variations, somatic M319V, and germline V1231A. V1231A was also present in population controls and likely represents polymorphism. The somatic M319V variant does not appear to be an attractive candidate for a disease-associated mutation because in silico analyses did not support the pathogenic nature of the change. A somatic, intronic 1-bp deletion was detected in a short poly(T) stretch in two microsatellite unstable tumors. None of the three changes had predicted effect on splicing when analyzed in silico. Our results did not reveal any clearly deleterious inactivating PTCH1 mutations in our collection of colorectal serrated adenocarcinomas. This suggests that other mechanisms are involved in the observed downregulation of the PTCH1 gene. These might include, e.g., constantly active MAPK signaling by KRAS or BRAF mutations or silencing of PTCH1 by hypermethylation, and further studies are needed to reveal these mechanisms.
authors.affiliation: Department of Pathology, Institute of Diagnostics, University of Oulu, FI-90014, Oulu, Finland.
authors.forename: Karoliina
authors.initials: K
authors.lastname: Stefanius
authors.forename: Tiina
authors.initials: T
authors.lastname: Kantola
authors.forename: Anne
authors.initials: A
authors.lastname: Tuomisto
authors.forename: Pia
authors.initials: P
authors.lastname: Vahteristo
authors.forename: Tuomo J
authors.initials: TJ
authors.lastname: Karttunen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Mäkinen
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf