EURURO Vol. 72 No. 5

756 860

performed employing rigorous Mendelian randomization.
The results suggest that longer telomere length in
peripheral blood leukocytes is associated with a higher
risk of RCC development. Interestingly, the association is
comparable in the following subtypes: clear cell, papillary,
and chromophobe RCCs.
While it was true that papillary and chromophobe
tumors were under-represented, the fact that the authors
observed the same susceptibility for cancer development in
all tested subtypes begs the question of whether these
results are really specific for RCC, or if excess telomere
length–related variants in general are associated with
cancer development. Recent findings of the genomic
underpinnings of clear cell, papillary, and chromophobe
RCCs have confirmed not only the different originwithin the
kidney, but also the unique underlying genetic mechanisms
for the development of these different subtypes If RCC
subtypes are biologically distinct diseases, then the
suggestion captured by the variants proposed here can be
applied to more cancer types, as recently published by the
Telomeres Mendelian Randomization Collaboration and
other cancer-type specific studies.
Telomere variations and telomerase activity are capti-
vating biomarkers for cancer development, but the lack of
tumor specificity still represents a challenge in effective
risk-assessment and treatment strategies.
As the authors recognize, the telomere length of renal
epithelial cells may represent a more appropriate marker
for the prediction of tumorigenesis. The study of variants in
the vicinity of the tissue of origin of a tumor may not veer
away from the appealing vision of an affordable and
accessible scan, but can help identify SNPs with clear
functional implications that are relevant to mechanisms of
disease. Interestingly, only one of the presented variants is
located in the protein-coding region of the telomerase
enzyme (TERT). We, for instance, have shown that muta-
tions in the promoter region of TERT gene are the fifth most
common mutation in clear cell RCC and can putatively lead
to telomerase upregulation .
In future, the associations generated by GWASs must
prove to have a functional basis in order to yield precise
predictions and appropriate interventions applicable in
clinical care. Additionally, whether variants in telomerase
SNPs correlate with response to systemic therapy is
certainly a worthwhile exploration.
Conflicts of interest: The authors have nothing to disclose.
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