Year: 2013
Type: letter
Abstract: In a recent article, Dr Weischer and colleagues evaluated the association of peripheral leukocyte telomere length (TL) with cancer risk and cancer survival in 47102 Danish participants ( 1 ). Participants were followed for up to 20 years (median = 6 years), during which time 3142 individuals developed a first cancer, and of these, 1730 died. They concluded that “short telomere length is associated with reduced survival after cancer but not with cancer risk.” This excellent study has many strengths, including large sample size, prospective and population-based study design, long-term follow-up, and precise assay technique. However, we have reservations about the conclusion that short TL was not associated with cancer risk. We propose that the data actually support the association of TL with cancer risks in a cancer site–specific manner: in some cancers, short TL confers increased risk, whereas in others, short TL confers reduced risk ( 1 ). When pooling data for all the cancer sites, the opposite associations cancel each other out, resulting in the null finding. For cancers of different etiology and risk factors, it is more prudent to analyze them separately. Although the general perception is that short TL confers increased risk in some cancers, with many supporting studies ( 2 ), multiple lines of evidence support the notion that short TL can actually confer reduced risks for other cancers. In this article, the strongest protective effect of short TL was on sarcoma (hazard ratio [HR] = 0.70; 95% confidence interval [CI] = 0.55 to 0.89; P = .003), consistent with our recent report that long TL was associated with increased risk of soft tissue sarcoma ( P < .001) ( 3 ), presumably because of the more prominent alternative lengthening of telomeres pathway than telomerase in sarcomas. The Weischer et al. article ( 1 ) also shows borderline statistical significance for melanoma (HR = 0.89; 95% CI = 0.77 to 1.03). In this regard, two recent case–control studies, one retrospective and one nested prospective, have both reported consistent statistically significant association of short TL with reduced risks of melanoma ( 4 , 5 ). There is also indirect evidence. A recent genome-wide association study identified seven loci affecting TL and analyzed their associations with disease ( 6 ). An interesting finding was that alleles associated with both shorter and longer TL showed associations with specific cancers, suggesting that variation in TL in either direction may contribute to the development of specific cancers. Furthermore, in another recent large fine-mapping study of the TERT locus, one of the seven TL-predisposing loci, multiple independent variants were associated with TL and risks of breast and ovarian cancer ( 7 ). In particular, the minor allele of one variant, rs7705526, was associated with longer TL ( P = 2.3×10 −14 ), higher risk of both low-malignant-potential ( P = 1.3×10 −15 ) and invasive ovarian cancer ( P = 6.4×10 −7 ), and high promoter activity, indicating that longer TL may confer higher risk of ovarian cancer. This is consistent with the borderline statistically significant (HR = 0.85; 95% CI = 0.70 to 1.03) protective effect of short TL on ovarian cancer in the Weischer et al. article ( 1 ). In conclusion, the article of Weischer et al. ( 1 ) and the literature support that short leukocyte TL is associated with increased or reduced cancer risks in a cancer site– specific manner.
DOI: 10.1093/jnci/djt154
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2103132669