Department of Pediatrics, Baylor College of Medicine and Dan L. Duncan Cancer Center, Houston, TX, United States of America.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States of America.
PLoS One. 2020 Feb 10;15(2):e0228887. doi: 10.1371/journal.pone.0228887. eCollection 2020.
Telomere length is associated with risk for thyroid subsequent malignant neoplasm in survivors of childhood cancer. Here, we investigated associations between thyroid subsequent malignant neoplasm and inherited variation in telomere maintenance genes.
We used RegulomeDB to annotate the functional impact of variants mapping to 14 telomere maintenance genes among 5,066 five-or-more year survivors who participate in the Childhood Cancer Survivor Study (CCSS) and who are longitudinally followed for incidence of subsequent cancers. Hazard ratios for thyroid subsequent malignant neoplasm were calculated for 60 putatively functional variants with minor allele frequency ≥1% in or near telomere maintenance genes. Functional impact was further assessed by measuring telomere length in leukocyte subsets.
The minor allele at Protection of Telomeres-1 (POT1) rs58722976 was associated with increased risk for thyroid subsequent malignant neoplasm (adjusted HR = 6.1, 95% CI: 2.4, 15.5, P = 0.0001; Fisher's exact P = 0.001). This imputed SNP was present in three out of 110 survivors who developed thyroid cancer vs. 14 out of 4,956 survivors who did not develop thyroid cancer. In a subset of 83 survivors with leukocyte telomere length data available, this variant was associated with longer telomeres in B lymphocytes (P = 0.004).
Using a functional variant approach, we identified and confirmed an association between a low frequency intronic regulatory POT1 variant and thyroid subsequent malignant neoplasm in survivors of childhood cancer. These results suggest that intronic variation in POT1 may affect key protein binding interactions that impact telomere maintenance and genomic integrity.
端粒长度与儿童癌症幸存者发生甲状腺继发恶性肿瘤的风险相关。在此，我们研究了甲状腺继发恶性肿瘤与端粒维持基因遗传变异之间的关系。
我们使用 RegulomeDB 注释了在 5066 名参加儿童癌症幸存者研究（CCSS）且长期随访继发癌症发病率的五年或以上幸存者中，映射到 14 个端粒维持基因的变异在这些基因中的功能影响。对于位于端粒维持基因内或附近的 60 个假定功能变异（次要等位基因频率≥1%），计算了甲状腺继发恶性肿瘤的风险比。通过测量白细胞亚群中的端粒长度进一步评估了功能影响。
Protection of Telomeres-1（POT1）rs58722976 的次要等位基因与甲状腺继发恶性肿瘤的风险增加相关（调整后的 HR=6.1，95%CI：2.4，15.5，P=0.0001；Fisher's exact P=0.001）。该推断 SNP 存在于 110 名发生甲状腺癌的幸存者中的 3 名与 4956 名未发生甲状腺癌的幸存者中的 14 名中。在 83 名有白细胞端粒长度数据的幸存者亚组中，该变异与 B 淋巴细胞中较长的端粒相关（P=0.004）。
使用功能变异方法，我们在儿童癌症幸存者中确定并证实了一个低频率内含子调节 POT1 变异与甲状腺继发恶性肿瘤之间的关联。这些结果表明，POT1 内含子的变异可能会影响影响端粒维持和基因组完整性的关键蛋白结合相互作用。
