Since the endometrial surface is a highly proliferative tissue, according to the telomere hypothesis of carcinogenesis, one might expect that women with shorter RTL would be at greater risk of endometrial cancer. We did not find evidence to support an association with RTL as measured in peripheral blood leukocytes among 279 incident invasive endometrial cancer cases and 791 matched controls nested within the Nurses’ Health Study and Women's Health Study. Women in the shortest RTL quartile were not at significantly greater risk compared to women in the longest RTL quartile (OR = 1.20, 95% CI = 0.73 – 1.96; Ptrend = 0.37). Although, our power was limited by the small sample size having only 35% power to detect a significant trend.
DNA from 674 endometrial cancer cases and 1685 matched controls were genotyped for tag SNPs across gene loci containing the core proteins that localize to telomeres in order to shape and tightly regulate the length of telomeres27, 28
. An elevation in risk was observed among women carrying variant alleles of RS2736122 at the TERT
locus (P=0.03) and RS12412538 at the TNKS2
locus (P=0.05). However, after adjusting the significance level using either a Bonferroni correction or the less conservative False Discovery Rate procedure 29
, neither of these SNPs reached significance. RS153045 at the TERF2
locus displayed significant heterogeneity between the studies. This SNP was not associated with endometrial cancer risk in NHS, but showed a 45% increased risk per variant allele in WHS. We believe the heterogeneity was due to chance. After adjustment for multiple comparisons, Rafnar et al observed that RS401681 at the TERT-CLPTM1L
locus was significantly associated with basal cell carcinoma (OR=1.25), lung (OR=1.15), bladder (OR=1.12), prostate (OR=1.07), and cervical cancer (1.31), but not with breast (OR=0.98) or endometrial cancer (OR=1.21) 20
. We had 80% power to detect an OR=1.21 between RS401681 and endometrial cancer risk. Our study supports a null association between RS401681 and endometrial cancer risk. RTL was not associated with the SNPs analyzed in this study, which is not entirely surprising given the constraint on nucleotide diversity observed in these genes 30
This is the first population-based investigation of the relationship between RTL, telomere-related gene SNPs and endometrial cancer risk. Whereas some studies found evidence for telomere attrition within endometrial tumors compared to matched normal adjacent tissue5-7
, a recent report on telomere dynamics during uterine carcinogenesis did not find consistent telomere shortening among endometrial cancer samples compared to surrounding normal tissue. An increase in telomere length was observed in roughly a third of patients 8
. Additionally, Type I endometrial cancers, which make up the majority of endometrial tumors, generally lack defects in the p53 gene and associated chromosomal instability 31
, two key components of the telomere hypothesis of carcinogenesis 1
. Over 95% of cases in our study were classified as Type I endometrial tumors. Our results and observations from these prior studies suggest telomere shortening may not be a major mechanism of Type I endometrial carcinogenesis.
We observed statistically significant inverse correlations with age, BMI, and weight gain from age 18. Telomere length decreases with age as a result of the end replication problem. Obesity, a state of chronic inflammation and oxidative stress 25
, is believed to contribute to telomere attrition 32
, which has been observed in some prior studies of women 33-36
. We also observed a significant association between longer RTL and later age at menarche (Ptrend
< 0.001). We do not have a plausible biological reason to believe the onset of menarche would have a direct effect on telomere length or vice versa. The positive correlation between RTL and age at menarche was attenuated slightly, but still significant after adjusting for BMI at diagnosis (data not shown). Since adolescent body fatness has been inversely associated with age at menarche 37, 38
, the observed RTL association with age at menarche may actually reflect an association with adolescent body size.
We cannot be certain that RTL measured in blood reflects telomere length in endometrial tissue. However, telomere lengths are highly synchronized in fetal tissues 39
and at birth among white blood cells, umbilical artery cells, and skin cells40, 41
. Though variation in telomere length increases with age, studies that have compared telomere length of blood DNA with that of matched skin 42, 43
, synovial tissue 43
, or fibroblasts 44
in older participants have found significant correlations between the pairs of tissues. Interindividual variation in telomere length far exceeds the variation between different tissues from the same individual40, 41
. This suggests blood serves as an adequate proxy for non-malignant endometrial tissue.
Our analyses benefit from the nested case-control design as cases and controls were drawn from well-characterized relatively homogeneous populations limiting selection bias. To prevent invalid risk estimates due to the limitations of retrospective case-control studies, such as cancer treatment and/or the disease itself influencing telomere length, we restricted telomere length analyses to endometrial cancer cases diagnosed after blood collection. Cases were followed for a median of 5.9 years prior to diagnosis (range: 1 month to 14.3 years). Estimates were similar after excluding cases diagnosed within 12 months of blood draw (n=30).
Due to recent evidence suggesting racial differences in telomere length dynamics 40
, we restricted our analyses to white women as most women in the NHS and WHS are Caucasian, limiting the generalizability of our results. Recent studies have also demonstrated differences in telomere attrition rates between individuals, which were mainly dictated by baseline telomere length40, 45-47
. We were not able to assess telomere attrition rate as a risk factor since we were only able to measure telomere length at one point in time. Nevertheless, Nordfjäll et al. 47
found comparable telomere attrition rates among individuals who later developed cancer and those who did not. Since RTL distributions were similar among cases and controls within our study, we have reason to believe attrition rates between these two groups would be alike as well.
In summary, we did not observe a significant elevation in endometrial cancer risk associated with shorter telomere lengths. We observed a nominal elevation in endometrial cancer risk associated with genetic variants at the TERT and TNKS2 loci. Overall, our data provide little support for leukocyte RTL as a biomarker of endometrial cancer risk among white women. Additional prospective epidemiologic studies are needed to confirm our findings as well as explore the relationship of telomere length dynamics in other racial and ethnic groups.