PO-350 Case-case GWAS to identify germline metastasis risk variants in sporadic colorectal carcinomas

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and a leading cause of cancer mortality worldwide. Majority of mortality is due to metastasis to distal organs such as liver or lung. Stage IV CRC patients by definition have distant metastasis. Up to 50% of stage III (with node involvement) and 25% of early stage I/II CRC patients succumb to distal metastasis. Stage III as well as high risk stage II CRC patients are offered adjuvant therapy after surgery but not all patients benefit from the chemotherapy. In this study, we wish to look for genes and pathways that contribute to metastasis in CRC to better understand the mechanisms and to search for potential prognostic markers and therapeutic targets. Material and methods Samples from 2500 sporadic CRC patients age 50 years or more with no family history of CRC and with known cancer staging and metastasis status were subjected to whole genome microarray analysis using Affymetrix SNP6 array. Metastasis-positive status of the patients is confirmed based on distal organ involvement attributable to primary CRC, either from histopathological report or computed tomography/positron emission tomography (CT/PET) scan. Metastasis-negative status is confirmed with at least 5 years of follow-up with no distal organ involvement. DNA was extracted from fresh frozen mucosa collected at least 5 cm away from the tumours. Samples with genotyping call rate less than 95% were excluded and population stratification was examined based on principal component analysis. At the single nucleotide polymorphism (SNP) level, SNP with call rate <99% and minor allele frequency <0.01 were excluded. Whole genome Correlation/Trend test was performed by comparing patients with stages I/II that did not metastasize to patients from stage IV as well as stages I, II that succumbed to metastasis. Results and discussions Preliminary data of 622 patients shows two potential regions associated with metastasis, one implicating a gene in the Wnt signalling pathway while the other a gene in the Hippo pathway. Dysregulation of both pathways have been previously reported to play important roles in CRC tumour initiation, progression and metastasis. Analysis from a larger discovery panel to increase the genetic power of the study will be presented while an independent replication panel for validation is being recruited. Conclusion Initial screen implicated two genes in the Wnt and Hippo pathways associated with risk of metastasis in sporadic CRC.