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Targeted Next Generation sequencing identified novel gene variants involved in hereditary colorectal cancer

Ali, Ann-Therese
Master thesis
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Masteroppgave (1.560Mb)
URI
http://hdl.handle.net/11250/2373973
Date
2015
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  • Institutt for klinisk og molekylær medisin [2008]
Abstract
cancer (CRC) is one of the most common types of cancer both worldwide and in

Norway. Risk factors and mechanisms contributing to the disease are among dietary and

lifestyle and somatic and inherited mutations. CRC is divided in three groups 1. Sporadic

CRC where the patients have no family history and no identifiable mutations; 2. Familial

CRC where the majority of genetics are unknown but the patients have at least one blood

relative, but no specific germline mutation or clear inheritance pattern; 3. Hereditary CRC

syndromes where the patients have inherited a single gene mutation in highly penetrant cancer

susceptibility genes. The genes known to date to predispose to colorectal cancer are APC,

BMPR1A, POLE, SMAD4, the MMR genes among others and these genes are related to the

hereditary CRC syndromes. There are other genes which have been found in Genome-wide

association studies (GWAS), exome studies or with next-generation sequencing (NGS) to be

associated with CRC such as KLLN, AKT1, PIK3CA, OGG1, KIF23 among others. 123

genes some known to be involved in hereditary CRC syndromes and some associated with

CRC were sequenced in 95 patients using Haloplex targeted NGS. The purpose for this master

thesis was to identify pathogenic variants in these genes that could be of help to explain the

increased CRC risk in these patients.

The results from the NGS identified 1268 unique variants which were filtered with the

downstream analysis tool FILTUS. After the variants found in only one or two patients were

selected. 64 unique variants were left to be further evaluated using the prediction software

Alamut. From the 64 variants 25 variants were selected to further investigate because those

were found to have most prominent effects on the proteins. Four out of the 25 variants were

found to be involved in predisposition to hereditary CRC syndromes; two variants identified

in POLE, a variant in BMPR1A and a variant in PTEN. The other variants identified may be

involved in CRC predisposition, but further functional studies are needed to determine their

function in CRC involvement. There were identified a few false positive variants during the

use of Haloplex targeted NGS, but because the rate of these variants were not high this

method seems to be a reliable method to use in cancer research.
Publisher
NTNU

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