Titel | Novel Common Genetic Susceptibility Loci for Colorectal Cancer. |
Medientyp | Journal Article |
Jahr der Veröffentlichung | 2019 |
Autoren | Schmit SL, Edlund CK, Schumacher FR, et al. |
Journal | J Natl Cancer Inst |
Volume | 111 |
Ausgabe | 2 |
Pagination | 146-157 |
Datum der Veröffentlichung | 2019 Feb 01 |
ISSN | 1460-2105 |
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> |
DOI | 10.1093/jnci/djy099 |
Alternate Journal | J. Natl. Cancer Inst. |
PubMed ID | 29917119 |
PubMed Central ID | PMC6555904 |
Grant List | R01 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 |