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Oulun yliopiston väitöskirjat

COLORECTAL CARCINOGENESIS VIA SERRATED ROUTE, ACTA UNIVERSITATIS OULUENSIS D Medica 1091

ISBN-13:	978-951-42-9398-6
Kieli:	englanti
Kustantaja:	Oulun yliopisto
Laitos:	Lääketieteellinen tiedekunta
Oppiaine:	Lääketiede,farmasia
Painosvuosi:	2011
Sidosasu:	pehmeäkantinen
Sijainti:	Print Tietotalo
Sivumäärä:	158
Tekijät:	STEFANIUS KAROLIINA

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Colorectal cancer is the third most common cancer in the developed countries. Originally,development of CRC was thought to proceed by a sequence of steps known as an adenoma-carcinoma sequence. At present CRC is recognized as a disease developing through diversepathways. Serrated adenocarcinoma represents an endpoint of tumors developing from serratedpathway. This thesis focuses on studying the molecular alterations in serrated adenocarcinoma. Microsatellite instability, hypermethylation of promoter region in DNA repair genes hMLH1and MGMT, frequency of KRAS and BRAF mutations and mutation spectrum of PTCH1 wasdetermined in serrated adenocarcinomas (n=42) and compared to non-serrated adenocarcinomas(n=75). MSI, particularly low level of MSI (p=0.02) and methylation of both hMLH1 and MGMTpromoters (p=0.004, p=0.026) were found to be more prevalent for serrated CRC. BRAF mutationwas frequent and specific to serrated adenocarcinomas (p<0.001) and KRAS mutations were morefrequent in serrated adenocarcinomas than in non-serrated cancers (p=0.002). A significantassociation between BRAF mutation, hMLH1 and MGMT methylation and MSI-H phenotype wasfound in serrated carcinomas. KRAS mutation was seen in association with MSS/MSI-Lphenotype; in fact, if serrated adenocarcinoma presents with MSI-L there always seems to be aKRAS mutation as well. Negative immunohistochemical staining of the hMLH1 enzyme was inassociation with methylation of the gene and proved reliable in the detection of MSI-H phenotype(p<0.0001). Sequencing analysis of the whole coding regions of the PTCH1 gene did not revealany truncating mutation to explain the previously detected downregulation of the gene in serratedCRCs. In conclusion, serrated adenocarcinomas proved to be an independent, but heterogeneoussubtype of CRCs. High combined mutation rate (79–82%) of KRAS and BRAF in serratedadenomas and adenocarcinomas indicates that MAPK activation is a crucial part of the serratedpathway. BRAF mutations are specific for serrated adenocarcinoma, and identify a subset ofserrated adenocarcinomas with gene methylation and a tendency for MSI-H. High frequency ofKRAS mutations in serrated adenocarcinomas suggests that a significant proportion of KRAS-mutated CRCs originate from serrated precursors.

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