GENES WITH SIGNIFICANT DEFICIT OF LOSS-OF-FUNCTION MUTATIONS IN LUNG TUMOR - ABSTRACT Studies aimed at the identification of cancer-related genes usually focus on the genes with an excess of somatic mutations. We hypothesized that genes with a lower-than-expected number of loss-of-function (LOF) mutations are also cancer-related. Indeed, genes whose function is essential for tumor cell survival and proliferation are expected to lack or have a deficit of LOF mutations since the loss of the function of an essential gene will lead to death of the tumor cell. As a result, genes essential for tumor cell survival are “prohibited” from having LOF somatic mutations and, therefore, can be identified through a deficit of LOF mutations. We tested this idea in a pan-cancer analysis. We applied a multiple regression model to predict how many LOF mutations one can expect in a given gene based on characteristics of the gene. Analysis of residuals was used to identify negative outliers—i.e., genes with a lower-than-expected number of mutations in them. After our pan-cancer analysis was published, the number of available mutations detected in tumors more than doubled, making it possible to conduct a lung cancer-specific analysis which is expected to be more powerful compared to the pan-cancer analysis. The cancer-essential genes identified in pan-cancer analysis fall into two categories: (1) genes that are essential in general - common housekeeping genes, and (2) genes that are nonessential in normal tissue but become essential after cells undergo malignant transformation. We will focus on the genes from the second category because they are expected to be a better therapeutic target than genes with housekeeping functions, as silencing the former is expected to have lower overall toxicity compared to the silencing of housekeeping genes. We propose the following specific aims: Aim 1: To identify genes with a significant deficit of loss-of-function mutations in lung tumors. Aim 2: To conduct pilot functional studies of the genes with a significant deficit of LOF mutations. To summarize, we will use existing somatic mutation data to identify genes in the human genome that are essential for survival of tumor cells in lung cancer. We will conduct pilot functional studies to demonstrate that silencing of the genes with a significant deficit of LOF mutations has antitumor effect. 1
