7012

TERC

DKCA1|SCARNA19|TR|TRC3|hTR;telomerase RNA component;TERC;telomerase RNA component

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3q26

miscRNA

Genetic anticipation is the increased incidence, earlier onset, or increased severity of a disease in successive generations. Before the biological basis of anticipation had been demonstrated, the phenomenon was thought to be due to sampling bias, epigenetic effects, gene conversion, or recombinant events. Sincethen, the biologic basis for anticipation in a number of neurodegenerative disorders has been shown to be attributable to trinucleotide repeat instability,with expansion of repeats clearly correlated with an earlier age of onset. Recently, telomere shortening has been suggested as the mechanism for anticipation in the autosomal dominant form of dyskeratosis congenita, attributable to mutations in the TERC gene, leading to dysfunctional telomeres (Vulliamy et al. 2004). However, the pattern of anticipation has been observed in other disorders, including cancers, for which no genetic defect has been identified. In this study, we assess the apparent generation effect on cancer incidence in ten extended families with P53 germline mutation, identified through probands diagnosed with childhood sarcoma. The probands were from two sets of systematically ascertained sarcoma patients treated at the University of Texas M. D. Anderson cancer Center between 1944 and 1982. From those overall studies, we have identified ten kindreds having germline P53 mutations in more than one generation. We compared the cancer incidence in members of successive generations of these families with P53 mutations (carriers) and with no P53 mutations (noncarriers). In carriers, cancer incidence increased in succeeding generations; there was no evidence for this effect in noncarriers; however, the noncarrier population was too small to rule it out. The apparent lack of increase in incidence in noncarriers argues against a cohort effect explaining the increase in carriers.

Telomeres are involved in maintaining chromosomal stability, cellular immortality and tumorigenesis. A recent genome-wide association study has identified an association between telomere length and two common variants (rs12696304 and rs16847897) at 3q26 that includes TERC. We hypothesized that the two variants and relative telomere length (RTL) would be predictors of the risk of childhood acute lymphoblastic leukemia (ALL). A case-control study of 570 cases and 673 cancer-free controls among Chinese children was performed. We found that there was a protective relationship between the second and third quartiles of RTL and risk of ALL [adjusted odds ratio (OR) with 95% confidence interval (95% CI) by quartile: 0.65 (0.47-0.91), 0.56 (0.40-0.79)], compared with the first quartile (shortest) RTL. Moreover, rs16847897 CG genotype increased the risk of childhoodALL by 29% compared with the CC genotype. Our findings indicate that extreme telomere length may be a potential predictor for future risk of ALL, and TERC rs16847897 may contribute to the development of childhood ALL.