Abstract 2129: Proteogenomic analysis points to relationship between LINE-1 retrotransposon expression and copy number variation

Abstract

Abstract Changes in the DNA copy number of genes (copy number variation/CNV) are widespread in many cancers and affect the expression of tumor suppressors and oncogenes. Many of these CNVs arise from chromosomal aberrations that are the result of improperly repaired DNA damage. LINE-1 retrotransposons - genomic elements that cut DNA and then reverse transcribe themselves into the gap - are expressed in many cancers and likely contribute to DNA damage and CNV in cancer cells. Using multi-omic data from CPTAC, we developed cloud-based tools on the NCI funded Cancer Genomics Cloud to measure LINE-1 RNA, protein, phosphoprotein and insertion in five cancer types - breast, ovarian, endometrial, kidney and colon - and identified mutation, expression and phosphorylation correlates of LINE-1 expression. We found significant LINE-1 expression in all, but kidney cancer. LINE-1 expression was significantly correlated with global copy number variation in breast, endometrial and ovarian cancer, a trend that was reflected in the fact that we observed the highest LINE-1 expression in ovarian cancer, which is characterized by very high CNV, and the lowest LINE-1 expression in kidney cancer, which has less overall CNV. This correlation is mirrored in our finding that, in breast, ovarian and endometrial cancer, p53 mutants express more LINE-1, indicating that high LINE-1 expression occurs in a background that is tolerant of DNA damage and CNV. We also observed an association between LINE-1 expression and phosphorylation of 53BP1 in breast, colon and endometrial cancers. ATM phosphorylated 53BP1 localizes to double strand breaks and promotes repair by non-homologous end-joining (NHEJ). Taken together, this analysis supports the hypothesis that in many cancers LINE-1 contributes to DNA damage and copy number variation, perhaps involving mismatched repair by NHEJ. Funded by NCI Contract No. HHSN261200800001E Citation Format: Wilson H. McKerrow, Xuya Wang, Mark Grivainis, David Fenyö. Proteogenomic analysis points to relationship between LINE-1 retrotransposon expression and copy number variation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2129.