Background: Familial colorectal cancer type X (FCCTX) fulfils clinical criteria defining Lynch syndrome (LS), but is not related to germline mutations in DNA mismatch-repair genes. Its aetiology remains unexplained and there is little evidence of involvement of the common colorectal carcinogenetic pathways. We aimed to identify susceptibility loci and gain insights into carcinogenic pathways involved FCCTX tumour development.
Methods: We performed a linkage analysis in 22 FCCTX families. We also constructed a tissue microarray in order to define an immunohistochemical (IHC) profile for FCCTX tumours (N = 27) by comparing them to three other types of colorectal tumors: LS (N = 18), stable early-onset (N = 31) and other sporadic disease (N = 80). Additionally, we screened for BRAF/KRAS mutations and determined CpG island methylator phenotype (CIMP) status for all FCCTX tumours.
Results: We found suggestive evidence of linkage at four chromosomal regions; 2p24.3, 4q13.1, 4q31.21 and 12q21.2-q21.31. We screened genes in 12q21 and ruled out the implication of RASSF9 and NTS, good candidates due to their potential involvement in carcinogenesis and colorectal epithelium development. Based on IHC profiles FCCTX tumours did not form a single, exclusive cluster. They were clearly different from LS, but very similar to stable early onset tumours. The CIMP and chromosomal instability pathways were implicated in one-third and one-quarter of FCCTX cases, respectively. The remaining cases did not have alterations in any known carcinogenic pathways.
Conclusions: Our results highlight the heterogeneity of FCCTX tumours and call into question the utility of using only clinical criteria to identify FCCTX cases.