Abstract 2716: Cancer study of germline carriers of Inborn Errors of Metabolism (IEMs) related genes

Abstract

Abstract Inborn Errors of Metabolism (IEMs) are a hereditary disorder in which a gene fails to operate correctly as a result of a mutation in a metabolic-related gene passed down from the parents. Majority of IEMs are inherited in autosomal recessive manner. Recent research has been undertaken on mutations in numerous metabolic genes, including IEMs and cancer development. This study used Next Generation Sequencing (NGS) data to confirm the link between metabolic-related genes and cancer development in heterozygous carriers. The PCAWG (Pan-Cancer Analysis of Whole Genomes) cancer patient cohort and the 1000G (1000 Genomes) healthy cohort were used in this work, with the TCGA (The Cancer Genome Atlas) cancer patient cohorts being used for validation analysis. A regression analysis was used to determine the statistical significance of the cancer patient group versus the normal cohort. We analyzed RNA-seq data by separating heterozygous carrier and non-carrier groups of IEM related genes. The proportion of IEM gene heterozygote carriers was higher in cancer patients than in the normal population. We chose genes showing similar patterns of occurrence with statistical significance across several cancer patient cohorts. Accordingly, the most important gene, phenylalanine hydroxylase (PAH), has been established, and the carrier frequency was consistently high in lung squamous cell carcinoma (LUSC). RNA analysis results revealed that the PAH heterozygous carrier group was enriched with various immune response pathways suggesting inflammation related carcinogenesis in PAH related LUSC. Our finding suggest that heterozygote carrier status of IEM genes may lead to generation of aberrant metabolites and the breakdown of metabolic networks, which eventually leads to cancer. Citation Format: Seokhyeon Kim, Seulki Song, Youngil Koh, Sung-Soo Yoon. Cancer study of germline carriers of Inborn Errors of Metabolism (IEMs) related genes [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 2716.