Telomere Length and Genetic Anticipation in Lynch Syndrome

Abstract

Telomere length variation has been associated with increased risk of several types of tumors, and telomere shortening, with genetic anticipation in a number of genetic diseases including hereditary cancer syndromes. No conclusive studies have been performed for Lynch syndrome, a hereditary colorectal cancer syndrome caused by germline mutations in the DNA mismatch repair genes. Here we evaluate telomere length in Lynch syndrome, both as a cancer risk factor and as a mechanism associated with anticipation in the age of cancer onset observed in successive generations of Lynch syndrome families. Leukocyte telomere length was measured in 244 mismatch repair gene mutation carriers from 96 Lynch syndrome families and in 234 controls using a monochrome multiplex quantitative PCR method. Cancer-affected mutation carriers showed significantly shorter telomeres than cancer-free mutation carriers. In addition, cancer-affected carriers showed the most pronounced shortening of telomere length with age, compared with unaffected carriers. The anticipation in the age of cancer onset observed in successive generations was not associated with telomere shortening, although, interestingly, all mother-son pairs showed telomere shortening. In conclusion, cancer-affected mismatch repair gene mutation carriers have distinct telomere-length pattern and dynamics. However, anticipation in the age of onset is not explained by telomere shortening. Pending further study, our findings suggest that telomere attrition might explain the previously reported dependence of cancer risk on the parent-of-origin of mismatch repair gene mutations.

Telomere Shortening Is Associated with Genetic Anticipation in Chinese Von Hippel–Lindau Disease Families

“…To date, anticipation has been found in two types of hereditary diseases, neurologic diseases such as fragile X syndrome, X-linked spinal and bulbar muscular atrophy, myotonic dystrophy and Huntington disease, and hereditary cancer syndromes such as dyskeratosis congenita, hereditary breast cancer, Li-Fraumeni syndrome, and hereditary nonpolyposis colorectal cancer syndrome (Lynch syndrome). Two molecular changes may be involved in the anticipation, expanding of trinucleotide repeats found in the anticipation in neurologic diseases, and shortening of telomere detected in the anticipation of hereditary cancer syndromes (13)(14)(15)(16)(17)(18)(19)(20)(21). The gradual decrease of telomere length with aging is attributed to the decrease of telomerase function or mutations accumulated in the DNA repair system besides aging (22).…”

Longer Telomeres Are Associated with Cancer Risk in MMR-Proficient Hereditary Non-Polyposis Colorectal Cancer

“…The results were compared to the results we published in a previous study of 144 cancer-affected MMR gene mutation carriers, 100 unaffected MMR gene mutation carriers and 234 controls [16].…”

“…Regarding hereditary CRC, our group recently reported that cancer-affected MMR gene mutation carriers had shorter telomeres and showed faster telomere attrition with age, measured in blood, than controls and cancer-free MMR gene mutation carriers [16]. Nevertheless, the role of telomere length as cancer risk modifier in LS could not be asserted since it had been argued that the shortened telomeres observed in retrospectively collected samples from cancer-affected individuals might be a consequence of the disease [8], [14].…”

“…Nevertheless, the role of telomere length as cancer risk modifier in LS could not be asserted since it had been argued that the shortened telomeres observed in retrospectively collected samples from cancer-affected individuals might be a consequence of the disease [8], [14]. However, the fact that cancer-free mutation carriers had longer telomeres than cancer-free controls provided additional evidence in support to the hypothesis that telomere length might act as a cancer risk modifier in LS [16].…”

DNA excision repair at telomeres

“…Analysis of Lynch syndrome families shows that telomere lengths in leukocytes of cancer patients carrying MMR gene mutations are significantly shorter than symptom-free mutation carriers and healthy controls [84]. In addition, cancer patients with MMR gene mutations show the most pronounced telomere attrition with age [84]. However, it is entirely unknown whether the shorter telomere length in cancer patients reflects the effects of MMR deficiency or merely represents a consequence of the cancer syndrome.…”