Colorectal cancer (CRC) is the third most frequent cancer in the world and has become a major issue for public health. Around 5% of CRC are inherited: the Familial Adenomatous Polyposis (FAP), Lynch syndrome (LS) and the MAP syndrome (MUTYH-Associated Polyposis). Implication of MAP syndrome in adenomatous polyposis: Among 31 patients with a polyposis with no mutation found in APC, 6 (20%) had biallelic mutation in MUTYH. Transversions were observed in Kras or APC in 5 patients (83%). Prevalence of the c.1185_1186dup mutation in MAP: Among a group of 36 families with a proven biallelic mutation in MUTYH, 11 had an homozygous biallelic mutation c.1185_1186dup. This mutation was significantly observed more frequently in patients with North African origin (79% vs. 5%, p<0.0001). Search for a funder effect using 10 microsatellites around MUTYH showed a common haplotype of at least 1.3 cM in every patients with c.1185_1186dup mutation. Rare variants (RV) in Cyclin D1: comparison of the frequency of RV in Cyclin D1 was performed between cases (112 undetermined polyposis and 44 early onset CRC) and 866 controls. VR were more frequently observed in cases. When combining VR, an increased in the risk of polyposis was observed in cases (OR= 2.2); 95%CI, 1.1-4.4; P=0,03). In silico analysis showed that the majority of rare variants had a functional effect. Role of rare variants: 70 variants among 17 genes were analyzed in the same set of patients. 21 were RV (frequency < 1%) and 4 were more frequently observed in cases (EXO1-12, MLH1-1, CTNNB1-1 and BRCA2-37, p<0,05). When combining all RV with a frequency below 0.5%, a risk of 3.2 was observed (95%CI=1.1-9.5; p=0.04)
