Novel Common Genetic Susceptibility Loci for Colorectal Cancer.

TitelNovel Common Genetic Susceptibility Loci for Colorectal Cancer.
MedientypJournal Article
Jahr der Veröffentlichung2019
AutorenSchmit SL, Edlund CK, Schumacher FR, et al.
JournalJ Natl Cancer Inst
Volume111
Ausgabe2
Pagination146-157
Datum der Veröffentlichung2019 Feb 01
ISSN1460-2105
Zusammenfassung

<p><b>BACKGROUND: </b>Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.</p><p><b>METHODS: </b>We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.</p><p><b>RESULTS: </b>The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.</p><p><b>CONCLUSIONS: </b>This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.</p>

DOI10.1093/jnci/djy099
Alternate JournalJ. Natl. Cancer Inst.
PubMed ID29917119
PubMed Central IDPMC6555904
Grant ListR01 CA197350 / CA / NCI NIH HHS / United States
R01 CA188214 / CA / NCI NIH HHS / United States
R01 CA195789 / CA / NCI NIH HHS / United States
K01 DK110267 / DK / NIDDK NIH HHS / United States
R01 CA238087 / CA / NCI NIH HHS / United States
U24 CA074794 / CA / NCI NIH HHS / United States
U01 CA074794 / CA / NCI NIH HHS / United States
U01 CA167551 / CA / NCI NIH HHS / United States
P30 CA076292 / CA / NCI NIH HHS / United States
R01 CA081488 / CA / NCI NIH HHS / United States
R01 CA207371 / CA / NCI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
10119 / / Cancer Research UK / United Kingdom
U01 CA152756 / CA / NCI NIH HHS / United States
P30 CA071789 / CA / NCI NIH HHS / United States
U19 CA148107 / CA / NCI NIH HHS / United States
10124 / / Cancer Research UK / United Kingdom