Abstract 111: Analysis of novel insertion polymorphisms of human endogenous retrovirus in lung cancer patients.
Authors: Kahyo Tomoaki , Mori Hiroki , Kurabe Nobuya , Funai Kazuhito , Ogawa Hiroshi , Tanioka Fumihiko , Tao Hong , Kono Suminori , Matsuo Keitaro , Shinmura Kazuya , Sugimura Haruhiko 
Published: August 2014

Abstract
Human endogenous retroviruses (HERVs) are members of the long terminal repeat (LTR) retrotransposon family accounting for about 8% of the human genome. A complete retroviral sequence includes promoter- and enhancer-active LTRs at both ends, but most HERV members appear to lack their mobility because of accumulated mutations within themselves. While the expression of HERV has long been a topic of cancer research, significant association between HERV insertion polymorphisms and cancers has never been reported. Here, we report the analysis of two novel polymorphic insertions of HERV solo LTR (accession no. AB728590 and AB728591) in lung cancer patients. To identify HERV insertion sites in the human genome, we firstly designed primer sequences targeting a conserved LTR region of HML-2, which is the most recently acquired HERV group and has the most intact retroviral sequence. Next, by using inverse PCR, a method amplifying unknown sequences flanking a primer target site, HERV-flanking sequences were amplified and cloned from lung cancer specimens. Finally, thirty two sequences were obtained from 178 clones. While twenty nine sequences were from known HERV loci, three sequences could not be assigned to any HERV loci in databases. Subsequent genomic analyses revealed that two sequences of those three sequences were located in 1p13.2 and 19q12 regions. In fact, we confirmed that HERV sequences were present in those genomic regions by the genotyping PCR and sequencing procedures. These two HERV insertions, HML-2_sLTR(1p13.2) and HML-2_sLTR(19q12), were solo LTRs and were also detected in normal tissues within the same individual, showing that they are polymorphic insertions. Furthermore, a retrospective cohort study indicated a significant prevalence of HML-2_sLTR(1p13.2) homozygosity (LTR/LTR genotype) among female never-smoking patients with lung adenocarcinoma (age =&gt; 60; in the west area of Shizuoka Prefecture; odds ratio, 1.97; 95% confidence interval, 1.02-3.81). Our results show that the insertion polymorphism of HML-2_sLTR(1p13.2) is involved in the susceptibility to lung adenocarcinoma in female never-smokers. Interestingly, acidic mammalian chitinase (CHIA), the product of which is known to show anti-apoptotic effects and to be secreted from lung epithelial cells, is located near HML-2_sLTR(1p13.2), suggesting that HML-2_sLTR(1p13.2) may regulate cell viability through the expression of CHIA. This report is the first to indicate an association between an insertion polymorphism of HERV and cancer and suggests that other HERV insertion polymorphisms related to cancer diseases may remain to be found in the human genome.
Citation Format: Tomoaki Kahyo, Hiroki Mori, Nobuya Kurabe, Kazuhito Funai, Hiroshi Ogawa, Fumihiko Tanioka, Hong Tao, Suminori Kono, Keitaro Matsuo, Kazuya Shinmura, Haruhiko Sugimura. Analysis of novel insertion polymorphisms of human endogenous retrovirus in lung cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 111. doi:10.1158/1538-7445.AM2013-111