Journal article
Genetic architectures of proximal and distal colorectal cancer are partly distinct
- Abstract:
-
Objective: an understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.
Design: to identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48,214 CRC cases and 64,159 controls of European ancestry. We characterized effect heterogeneity at CRC risk loci using multinomial modeling.
Results: We identified 13 loci that reached genome-wide significance (P<5×10-8) and that were not reported by previous GWAS for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.
Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumor.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, 924.1KB, Terms of use)
-
- Publisher copy:
- 10.1136/gutjnl-2020-321534
Authors
- Publisher:
- BMJ
- Journal:
- Gut More from this journal
- Volume:
- 70
- Issue:
- 7
- Pages:
- 1325-1334
- Publication date:
- 2021-02-25
- Acceptance date:
- 2020-12-18
- DOI:
- EISSN:
-
1468-3288
- ISSN:
-
0017-5749
- Language:
-
English
- Keywords:
- Pubs id:
-
1152577
- Local pid:
-
pubs:1152577
- Deposit date:
-
2021-01-08
Terms of use
- Copyright holder:
- Huyghe et al.
- Copyright date:
- 2021
- Rights statement:
- © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
If you are the owner of this record, you can report an update to it here: Report update to this record