Low-penetrance susceptibility variants in familial colorectal cancer.
BACKGROUND
Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC.


METHODS
The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases.


RESULTS
A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC.


CONCLUSIONS
This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC.


CONCLUSIONS
Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
Niittymäki
Iina
I
Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Kaasinen
Eevi
E
Tuupanen
Sari
S
Karhu
Auli
A
Järvinen
Heikki
H
Mecklin
Jukka-Pekka
JP
Tomlinson
Ian P M
IP
Di Bernardo
Maria Chiara
MC
Houlston
Richard S
RS
Aaltonen
Lauri A
LA
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D019683:Penetrance; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate