Abstract LB014: The role of genetic alterations in metastatic development insights from a large-scale genomic database

Abstract

Abstract Metastasis remains a major challenge in cancer treatment, with somatic genetic alterations being a crucial feature in progression. This study harnesses the whole genome sequencing data in the Genomics England biobank (GEL), cataloging of somatic alterations in the context of cancer metastasis. Our research aims to uncover the genetic underpinnings that facilitate the spread of cancer from its primary site to secondary locations by analyzing clinicogenomic data from 3047 cancer patients with metastatic progression. In this study, we analyzed the complex relationship between somatic alterations and cancer progression to uncover significant interactions among these alterations in a broad distribution of common tumor types among well-established oncogenic and tumor suppressor genes. In our study, we employed a Bayesian network approach, enabling us to not only pinpoint crucial genetic contributors to metastasis but also to consider other clinical variables, including patient treatment, sex, age, tumor grade and cancer types. In our analysis, LILRB2 was found to directly increase metastatic risk in hematologic cancer, with prior evidence suggesting its potential as a therapeutic biomarker in colorectal cancer and adversely related to patient prognosis in lung cancer. Similarly, MYL1, initially linked to tumor metastasis and immune infiltration in head and neck squamous cell carcinoma, was also found to increase the risk of metastasis in renal cancer, while interacting with the transcription factor E2F4, marker of poor prognosis in hepatocellular carcinoma. Our study not only confirmed the numerous key somatic gene alterations significantly linked to metastatic behavior across various cancers, but also established their significant roles.Our work highlights the potential of leveraging extensive genomic databases such as GEL to enhance our understanding of cancer metastasis. GEL’s paired germline and somatic data allows us to not only identify mutations unique to cancer cells but also to uncover germline variants that are associated with an elevated risk of cancer and the presence of more aggressive tumor characteristics. By characterizing metastatic risk features, we can explore the opportunities to stratify high-risk patients in clinical trials, with similar effort has been applied to brain metastasis in lung adenocarcinoma. Although tumor heterogeneity poses a treatment challenge due to cell diversity, previous work has demonstrated value in targeting the metastatic potential. For instance, trastuzumab target HER2-positive breast cancers prone to metastasis, markedly improving patient outcomes. Similarly, vemurafenib effectively controls metastatic Melanoma progression by targeting specific mutations like BRAFV600E. Understanding the genetic basis of metastasis could help identify high risk patients and lead to personalized combination therapies addressing various tumor subpopulations. Future research based on these findings could lead to the development of personalized combination treatment strategies that improve patient outcomes. Citation Format: Songjun Xu, Danyang Yu, Shuwei Li, Christopher Moy, Julio Molineros. The role of genetic alterations in metastatic development insights from a large-scale genomic database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB014.