Germline allele-specific expression of APC and MUTYH in mutation-negative patients with multiple colorectal adenomas and/ or colorectal cancer

In this study we analyzed whether the germline variations in APC and MUTYH ASE may be associated with low penetration familial cancers in APC mutation-negative colorectal cancer patients and whether the pathogenic APC and MUTYH mutations had impact on ASE. The study was carried out on DNA obtained from blood samples of 44 APC mutation-negative colorectal cancer patients, 13 APC mutation-positive FAP patients and 160 healthy donors from ‘‘SS. Annunziata’’ Chieti Hospital. DHPLC-based primer extension method was used to analyze APC and MUTYH ASE. In 25 out of 44 APC-negative patients we identified 6 heterozygous for the frequent APC coding SNP rs2229992. Two patients showed ASE values deviating more than 1SD from the mean ASE values measured in 121 individuals. Moreover, to assess the effect of germline APC mutations on ASE we analyzed 13 carriers of pathogenic variants. Six of these individuals were rs2229992 heterozygous and 1 of them, bearing the pathogenic APC p.Ser895X, showed a germline allelic loss by ASE analysis. Moreover, we are analyzing ASE of MUTYH among APC- negative patients. Six of them were heterozygous for the frequent MUTYH coding SNP rs3219489 (c.1005G [ C; p.Gln335His). One patient, APC- and MUTYH-negative, showed ASE values deviating more than 1SD from the mean ASE values measured in 31 individ- uals. Our preliminary results underline the importance of RNA-level studies in the molecular diagnosis of patients with colorectal cancer without detectable APC and/or MUTYH mutations.