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Sökning: WFRF:(Newcomb Polly A.) > (2015-2019) > Genome-wide associa...

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FältnamnIndikatorerMetadata
00004990naa a2200577 4500
001oai:DiVA.org:umu-160320
003SwePub
008190617s2018 | |||||||||||000 ||eng|
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1603202 URI
0247 a https://doi.org/10.1158/1538-7445.AM2018-2292 DOI
040 a (SwePub)umu
041 a engb eng
042 9 SwePub
072 7a vet2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Harrison, Tabitha A.4 aut
2451 0a Genome-wide association study by colorectal carcinoma subtype
264 1b American Association for Cancer Research,c 2018
338 a print2 rdacarrier
520 a Over 50 genetic variants have been associated with colorectal cancer (CRC) risk through genome-wide association studies (GWAS), yet these variants represent only a fraction of the total estimated heritability. CRC is a heterogenous disease with diverse tumor etiology. Assessing genetic risk in molecular subtypes may help to identify novel loci and characterize genetic risk among tumor subtypes. We used microsatellite instability (MSI), an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for GWAS analyses. We conducted a case-case analysis to estimate odds ratios (OR) and 95% confidence intervals (CI) for association of genome-wide variants with microsatellite stable (MSS) versus unstable (MSI) carcinomas. We ran an inverse-variance weighted fixed-effects meta-analysis across GWAS in a discovery set of 4,163 population-based CRC cases with harmonized microsatellite instability (MSI) marker and imputed genotype data. For each analysis, we used log-additive logistic regression, adjusting for age, sex, and principal components to account for population substructure. We then followed up with replication of 102 SNPs that reached p-values less than 5x10-6 in 1,698 cases. A total of 845 (20.3%) cancer cases were microsatellite unstable in the discovery population and 174 (10.2%) were unstable in the replication population. No variants reached the genome-wide significance level of 5x10-8 in the discovery set. However, we identified two variants that reached a Bonferroni corrected p-value of 4.0x10-4 in the replication set. This included one variant in MLH1 (Replication: OR=1.74, 95% CI=1.53-1.98, p=1.63x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76x10-11) and one variant in LOC105377645 (Replication: OR=1.70, 95% CI=1.49-1.94, p=5.13x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76 x 10-11). The MLH1 gene is a DNA mismatch repair gene implicated in Lynch Syndrome, the hallmark of which is microsatellite instability. This is the first genome-wide scan to identify a common variant in MLH1 that is associated with CRC. This variant (minor allele frequency, MAF = 23% in this all European ancestry population) is located in the 5'-untranslated region of MLH1 and is thought to act as a long-range regulator of DCLK3, a potential tumor driver gene. The second variant, located in LOC105377645 with an MAF of 22%, is in an uncharacterized region of the genome and has not previously been implicated in cancer development. These findings suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk. We plan to run polytomous regression analyses, increase our sample size, and further investigate CRC subtypes by CIMP, BRAF mutation, KRAS mutation status.
650 7a MEDICIN OCH HÄLSOVETENSKAPx Klinisk medicinx Cancer och onkologi0 (SwePub)302032 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Clinical Medicinex Cancer and Oncology0 (SwePub)302032 hsv//eng
7001 a Lu, Yiwen4 aut
7001 a Zeng, Chenjie4 aut
7001 a Qu, Flora4 aut
7001 a Anderson, Kristin4 aut
7001 a Brenner, Hermann4 aut
7001 a Buchanan, Daniel D.4 aut
7001 a Campbell, Peter T.4 aut
7001 a Chan, Andrew T.4 aut
7001 a Chang-Claude, Jenny4 aut
7001 a Giles, Graham G.4 aut
7001 a van Guelpen, Bethanyu Umeå universitet4 aut0 (Swepub:umu)beyvan99
7001 a Hoffmeister, Michael4 aut
7001 a Jenkins, Mark A.4 aut
7001 a Lindor, Noralane M.4 aut
7001 a Milne, Roger L.4 aut
7001 a Newcomb, Polly A.4 aut
7001 a Nishihara, Reiko4 aut
7001 a Woods, Michael O.4 aut
7001 a Ogino, Shuji4 aut
7001 a Potter, John D.4 aut
7001 a Slattery, Martha L.4 aut
7001 a Sun, Wei4 aut
7001 a Thibodeau, Stephen N.4 aut
7001 a Hsu, Li4 aut
7001 a Peters, Ulrike4 aut
7102 a Umeå universitet4 org
7730 t Cancer Researchd : American Association for Cancer Researchg 78:13q 78:13x 0008-5472x 1538-7445
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-160320
8564 8u https://doi.org/10.1158/1538-7445.AM2018-229

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