Abstract 4108: Understanding the role of telomere biology gene variation in cancer etiology
Authors: Niewisch Marena R. , Kim Jung , Lunger Judith C. , McReynolds Lisa J. , Savage Sharon A. 
Published: June 2022

Abstract
Telomere biology disorders (TBDs) are cancer-prone syndromes associated with increased risk of acute myeloid leukemia (AML), head and neck squamous cell carcinoma (HNSCC), bone marrow failure, pulmonary fibrosis, and liver disease. Germline variants in at least 15 different telomere biology genes have been implicated (ACD, CTC1, TERT, TERC, STN1, NAF1, NOP10, NHP2, TINF2, RTEL1, PARN, ZCCHC8, DKC1, WRAP53, POT1) with autosomal dominant (AD), autosomal recessive (AR), or X-linked (XLR) inheritance as well as de novo occurrence. We hypothesize that TBDs may be more common than the currently estimated 1:1,000,000.
We analyzed the prevalence of germline variants in the 15 TBD-associated genes using 1) The Genome Aggregation Database [gnomAD v2.1.1 non-cancer] and 2) The Cancer Genome Atlas (TCGA). Germline TCGA variants were called using HaplotypeCaller, Freebayes, and UnifiedGenotyper. All variants with minor allele frequency (MAF) &lt;1% in gnomAD non-cancer were considered. They were classified as potentially deleterious based on ClinVar and/or loss of function classification and/or stringent in silico predictions utilizing REVEL, MetaSVM, CADD, BayesDel, Eigen for missense and a combination of spliceAI, spidex, and dbscSNV for splice site variants. For TERC (RNA telomerase template) variants in the pseudoknot/template region were considered deleterious. The known disease-causing inheritance pattern (AD, AR, XLR) for each gene was used to identify TCGA cases with a probable TBD.
There were 1215 potentially deleterious variants in TBD associated genes in the gnomAD v2.1.1 non-cancer dataset (n=134,187 samples) for a combined prevalence of 0.9%, without accounting for zygosity. In genes with AD/AR inheritance, variants were most common in: RTEL1 (249), TERT (104), and PARN (104). CTC1 and WRAP53, both associated with solely AR TBDs, also showed high variant frequencies (280 and 102, respectively). In the TCGA dataset, 9089 cancer cases (32 solid tumors and AML) were evaluated. We identified 227 cases (2.5%) with 161 mono- or biallelic rare, potentially deleterious variants in the 15 genes. Ninety-two cases had a probable underlying TBD [1% of total, 41 male, 51 female, median age at cancer diagnosis 46.5 (1-92) years]. Cancer diagnoses in these 92 cases included 24 solid tumors. The frequency of individuals with deleterious TBD-associated variants ranged from 0.4-2.8% in each of the 24 affected cancers. Notably, the heterozygous frequencies in lung squamous cell carcinoma and liver hepatocellular carcinoma were 1.6% and 2.2%, respectively. Our results show that the prevalence of TBDs may be noticeably higher than previously estimated, specifically in individuals with cancer. TBD-associated pathogenic germline variants may be implicated in the etiology of more solid tumor entities than previously recognized, warranting further studies.
Citation Format: Marena R. Niewisch, Jung Kim, Judith C. Lunger, Lisa J. McReynolds, Sharon A. Savage. Understanding the role of telomere biology gene variation in cancer etiology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4108.