Telomeres and disease PM Lansdorp persist and stimulate the growth of abnormal cells (e.g. cells with defective DNA damage responses). The malignant pro- gression of such abnormal cells could be further facilitated by mutations induced by earlier treatment. In other words, normal stem cell numbers could indirectly suppress malig- nant transformation of cells, whereas loss of stem cells could predispose for malignant transformation. The difﬁculties related to the identiﬁcation of stem cells in vivo that were discussed above greatly complicate studies on the role of the number of stem cells in tumour development. However, it seems possible that a decline in the number of tissue-speciﬁc stem cells could contribute to the exponential increase in tumour development with age. Such a relationship is suggested by the paradoxical relationship between hypo- and hyperproliferative disorders. For example, Calado et al, reported in a recent paper that heritable hypomorphic muta- tions in the telomerase reverse transcriptase gene predispose for acute myeloid leukaemia (Calado et al, 2009). In this study of AML patients (n ¼ 594), a common variant of the telomerase reverse transcriptase gene hTERT, A1062T, was present three times more frequently in patients than in controls (n ¼ 1110, P ¼ 0.0009). The mutant telomerase allele was found to decrease the enzymatic activity of telomerase by B50% in the TRAP telomerase assay (Calado et al, 2009). However, the A1062T hTERT variant did not appear to compromise telomerase activity in another study (Alder et al, 2008), and the precise functional consequences of A1062T expression in human (stem) cells remain to be clariﬁed. As in most patients only one TERT allele was affected, telomerase activity in the stem cells of these patients is expected to be around 75% of normal levels. How reduced telomerase levels in these patients relate to the development of AML is not clear. One possibility is that telomeres were on average shorter at birth and that shorter telomeres limited normal stem cell proliferation with selection of abnormal cells as discussed above. Second, it is possible that full telomerase levels are critical in HSCs to maintain telomere function of critically short telomeres. Even a slight reduction in telomerase levels could increase the probability of cell death after, for example, oxidative damage to telomeric DNA in stem cells. Telomeres in the most primitive haematopoietic cells were found to have the lowest frequency of abruptly shortened telomeres in the haematopoietic system (Hills et al, 2009) and oxidative damage is a major cause of telomere attrition (von Zglinicki, 2002). Two recent studies have suggested that risk of developing lung cancer is associated with genetic markers (SNP’s) that map to the TERT locus (McKay et al, 2008; Wang et al, 2008). These results were conﬁrmed in a large SNP study, which also looked at a variety of other tumours (Rafnar et al, 2009). In this large study of over 30 000 cancer cases and 45 000 controls, a signiﬁcant association of SNP rs401681[C] within References Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, Vulto I, Xie M, Qi X, Tuder RM, Phillips III JA, Lansdorp PM, Loyd JE, Armanios MY (2008) Short telomeres are a risk factor for idiopathic pulmonary ﬁbrosis. Proc Natl Acad Sci USA 105: 13051–13056 Alter BP, Giri N, Savage SA, Rosenberg PS (2009) Cancer in dyskeratosis congenita. Blood (in press) the TERT locus on chromosome 5p15.33 was found with basal cell carcinoma, lung cancer and cancer of the urinary bladder, prostate and cervix. Interestingly, the same SNP seems to confer protection against cutaneous melanoma, and the cancers that are associated with this SNP all have a strong environmental component to their risk. Although the precise role of genetic variation within the TERT locus remains to be elucidated, it is tempting to speculate that this SNP is linked to hypomorphic TERT alleles similar to the A1062T variant that was found to be more frequently in patients with AML than normal controls. Concluding remarks Recent studies have put telomerase and telomere research square at the centre of cancer research. Not only is ampliﬁca- tion of the hTERT gene one of the most common genetic abnormalities in lung adenocarcinoma, one of the most common human cancers (Weir et al, 2007; Kang et al, 2008), it now is becoming clear that SNP’s within the TERT locus are among the most reproducible risk factors for the development of different types of cancer (McKay et al, 2008; Wang et al, 2008; Rafnar et al, 2009). The ﬁnding that hypomorphic TERT mutations increase the risk for the devel- opment of acute myeloid leukaemia (Calado et al, 2009), chronic lymphocytic leukaemia (Hills and Lansdorp, NYAS in press) and probably other cancers, together with the in- creased risk for leukaemia development associated with bone marrow failure in AA, MDS and DC, strongly implicates stem cell failure and reduced stem cell numbers as risk factors for tumour development. More direct measures of stem cell numbers in vivo are needed to examine the relation- ship between stem cell numbers and tumour development in patients with defective telomere maintenance as well as in normal individuals as a function of age. Measurements of the average telomere length as well as the length at individual chromosome ends in speciﬁc cells and tissues are expected to provide valuable information about the involvement of telo- meres in normal ageing and tumour biology. Acknowledgements Work in my laboratory is supported by grants from the Canadian Institutes of Health Research (MOP38075 and GMH79042) and the National Cancer Institute of Canada (with support from the Terry Fox Run). I thank Gerry Krystal and anonymous reviewers for critically reading the paper. Conﬂict of interest The author declares a ﬁnancial interest in Repeat Diagnostics Inc., a company specializing in leucocyte telomere length measurements using ﬂow FISH. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Grifﬁn CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW (2005) Haploinsufﬁciency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis con- genita. Proc Natl Acad Sci USA 102: 15960–15964 Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, Lawson WE, Xie M, Vulto I, Phillips III JA, Lansdorp PM, Greider 2538 The EMBO Journal VOL 28 | NO 17 | 2009 & 2009 European Molecular Biology Organization