Levels of oxidative stress and telomeres in Lynch syndrome-associated malignancies.

Abstract

582 Background: Lynch Syndrome (LS) is caused by germline mutations in mismatch repair genes (MMR) genes which are critical in maintaining cellular integrity. Failure of the MMR pathway in LS culminates in the hypermutable phenotype of Microsatellite Instability. LS confers an increased risk of malignancy of which colorectal cancer (CRC) is most common. Carriers exhibit significant phenotypic variation in the age of onset of malignancy which cannot be predicted. Telomere length attrition is considered an early step in carcinogenesis and may be accelerated by oxidative stress. We investigated an association between relative telomere length (RTL) and levels of DNA oxidative damage in LS affected carriers (AC), unaffected carriers (UAC) and in patients with MMR- proficient colorectal cancer (MPC). Methods: Peripheral blood mononuclear cells were isolated from patients within each group. DNA was extracted and RTL measured by quantitative polymerase chain reaction (PCR). Real-Time PCR was used to quantitate expression levels of TERT, TERC and DKC1 (telomerase components) from RNA. Serum levels of 8-hydroxydeguanosine (8-OHdG) were measured from patients using the ELISA technique. Pearson’s correlation was used to compare mean RTL, telomerase levels and 8-OHdG between groups. Results: RTL and telomerase components were measured in 27 AC (median age 50yrs) 27 UAC (median age 40yrs) and 27 MPC (median age 66yrs). Corresponding RTLs were 0.89, 0.91 and 1.69 respectively. AC had significantly shorter RTL compared to UAC (p = 0.03) and MPC (p < 0.0001). There we no differences in the mean expression of TERT, TERC or DKC between groups. Younger age of tumour onset was associated with shorter telomere length in both AC (p = 0.0006) and MPC (p < 0.0001). 8-OHdG levels have been measured in 17 AC, 19 UAC and 14 MPC. The mean levels of AC and UAC were not statistically different. However the mean MPC level was significantly less than UAC (p = 0.03) and AC (p < 0.0001). Conclusions: Shortened telomere length is an important step in carcinogenesis. Affected LS patients have shorter telomeres and evidence of higher levels of DNA oxidative stress than patients with MMR-proficient CRC.