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
characterised effect heterogeneity at CRC risk loci using multinomial
modelling.
Results We identified 13 loci that reached genome-wide significance
(p<5x10(-8)) and that were not reported by previous GWASs 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 tumour