Alterations in Ca TRP ORAI and RYR channels have been

Alterations in Ca TRP, ORAI1 and RYR channels have been identified in cancer (Monteith et al., 2012; Ho et al., 2013; Love et al., 2012), and overexpression of CACNA1E are correlated with relapse in Wilms\' tumors (Natrajan et al., 2006), while CACNA2D1 plays a role in maintaining the properties of tumor-initiating cells in hepatocellular carcinoma (Zhao et al., 2013). Interestingly, Olivier et al. (2014) found that treatment of cells with BaP for 6days leads to mutations in CACNA1C and CACNA1G. We showed that in the 79 HPR NSCLCs, calcium signaling-related genes RYR2, RYR1, XIRP2, CACNA1E and ANK2 had high frequency mutations (29.1%–17.7%), compared to 1.2%–8.2% mutation rates in CR patients. In HPR NSCLCs, RYR1 and RYR2 had mutations of loss of function patterns, because the mutations were distributed throughout the entire genes and were either missense or nonsense in nature. CACNA1B-FAF1 fusion (Fig. S6D) could also damage CACNA1B\'s Ca channel function, because its C-terminal ion transmission and calcium channel domains were deleted. The 23 CACNA1E mutations in 15/79 (19%) HPR lung cancers were missense mutations and distributed throughout the entire gene. Among them, 10/23 (43.5%) mutations were found in the amino kv1.3 inhibitor 119–546 region, and 10/15 (67%) patients had one mutation in ion transmission, PKD channel or calcium channel domains (Fig. 3B). These mutations may interfere with the function of the calcium channel and the intracellular Ca concentration, the essential second messenger that can regulate nearly every aspect of cellular functions. Further investigation should be conducted to characterize the “driver mutation” aspects of these genes. The following are the supplementary data related to this article.
Author Contributions
Competing Interests
Acknowledgment This project has been funded by the National Natural Science Funds for Distinguished Young Scholar to G.B.Z. (81425025), National Key Program for Basic Research (2012CB910800), National Natural Science Foundation of China (81171925, 81201537), and grant from the Shanghai Municipal Science and Technology Commission (13431902000). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction Telomeres are tandem repeats of TTAGGG nucleotides at the ends of eukaryotic chromosomes that, along with telomere binding proteins, help maintain genomic stability (Ma et al., 2011). Studies show that blood telomere length (BTL) decreases with age and that environmental exposures causing oxidative stress and chronic inflammation accelerate this process (Jennings et al., 2000; von Zglinicki, 2002). Shortened telomeres are often involved in cellular senescence or apoptosis. However, if their shortening becomes critical, such biological responses can be inhibited, resulting in genomic instability (Kong et al., 2013; Frias et al., 2012) including chromosomal rearrangements, and both gains and losses of chromosomal segments (Lundblad and Szostak, 1989), all essential steps in carcinogenesis. For these reasons, telomeres have long been an object of study for potential early involvement in cancer development (Londono-Vallejo, 2008; DePinho, 2000). One major weakness to tissue-specific telomere length in tumors is that it is only measurable after disease development, and thus can be affected by both cancer and treatment. Blood leukocytes play an important role in carcinogenesis via inflammatory response and pro-apoptotic processes. Leukocyte infiltration is critical early in carcinogenesis and has been linked to many cancers including pancreatic (Schnekenburger et al., 2008) and colorectal (Ichikawa et al., 2011). Thus, studying BTL in DNA collected before cancer development can provide important information on its role in cancer etiology and serve a valuable predictive purpose. However, BTL has been extensively studied in relation to cancer risk with inconsistent results (Hou et al., 2012a; Willeit et al., 2010). One possible explanation is that most studies reporting shorter BTL in cancer patients relative to controls are retrospective studies in which BTL was measured post-diagnosis, a finding which could be a consequence of cancer development or treatment, not a cause (Hou et al., 2012a). For example, Unryn et al. showed that patients with neck and head tumors who went through eight weeks of chemotherapy had a mean telomere loss of 660 base pairs (Unryn et al., 2006). Results have also been inconsistent in prospective studies where BTL was measured pre-diagnostically, some reporting increased cancer risk in participants with shorter BTL, and others with longer (Hou et al., 2012a). Most studies examined BTL at a single time point only, and none to our knowledge measured BTL more than once before cancer diagnosis, making it difficult to examine the causal relationship between BTL attrition and cancer risk. Longitudinal studies of BTL with multiple pre-diagnostic measurements may be more informative about how BTL contributes to cancer risk, and provide critical information on the relationship between BTL and cancer development and diagnosis. Our objective is to examine BTL attrition over time in relation to risk of developing cancer, specifically: 1) How BTL changes with time affect, and are affected by, cancer development and 2) whether BTL measured prior to clinical diagnosis is associated with risk of developing cancer.