Impact of chemotherapy on telomere length in sporadic and familial breast cancer patients

Abstract

Recently, we observed that telomeres of BRCA1/2 mutation carriers were shorter than those of controls or sporadic breast cancer patients, suggesting that mutations in these genes might be responsible for this event. Given the contradictory results reported in the literature, we tested whether other parameters, such as chemotherapy, could be modifying telomere length (TL). We performed a cross-sectional study measuring leukocyte TL of 266 sporadic breasts cancer patients treated with first-line chemotherapy, with a median follow-up of 240 days. Additionally, we performed both cross-sectional and longitudinal studies in a series of 236 familial breast cancer patients that included affected and non-affected BRCA1/2 mutation carriers. We have measured in leukocytes from peripheral blood: the TL, percentage of short telomeres (<3 kb), telomerase activity levels and the annual telomere shortening speed. In sporadic cases we found that chemotherapy exerts a transient telomere shortening effect (around 2 years) that varies depending on the drug combination. In familial cases, only patients receiving treatment were associated with telomere shortening but they recovered normal TL after a period of 2 years. Chemotherapy affects TL and should be considered in the studies that correlate TL with disease susceptibility.

Figure 1

a) Correlation between telomere-length (t/s) and treatment time (r=−0.43; p=3.71E-05). b) Correlation between telomere-length (t/s) and time after treatment (r=0.17; p=0.02).

Figure 2

Telomere-length evolution during treatment and after treatment. Mann Whitney test was used to determine significant differences between controls and the different subgroups. The discontinuous lines represent significantly shortened telomeres compared to controls for all the patients together (black line) and for the two major drug schedules (red and green lines).

Figure 3

a) Distribution of telomere-length (t/s) values adjusted for age for the familial breast cancer groups according to mutational status. The Mann Whitney test was used to test for significant differences in telomere-length between controls and the different subgroups. b) Distribution of telomere-length (t/s) values adjusted for age for the familial breast cancer groups according to treatment status (Mann Whitney test). c) Comparative analysis of telomerase activity levels in the familial breast cancer series; Student’s unpaired t-test was used to determine significant differences among groups.

Figure 4

a) Comparative analysis regarding telomere-length (adjusted Kb) in the familial breast cancer series (Unpaired Student t-test). b) Comparative analysis regarding content of short telomeres (<3Kb) in the familial breast cancer series (Unpaired Student t-test).

Figure 5

Theoretical telomere-length (TL) evolution based on two telomere-length measurements along the time (average 6 years). We observed a similar behavior for controls, Healthy BRCA1/2 carriers and Post treatment affected patients carrying BRCA1/2 mutations regarding telomere shortening rate, ranging from 0.028 to 0.033 t/s per year. Strikingly patients with control samples during treatment and post treatment presented an opposite elongation pattern, of −0.086 t/s year.