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Functional Effects of Four or Fewer Critical Genes Linked To Lung Cancers and New Subtypes Detected by a New Machine Learning Classifier

Zhengjun Zhang

Finding genes biologically directly or indirectly related to lung cancer has been drawing much attention, and many genes directly related to lung cancer have been reported. However, it has not been confirmed whether those published 'key' genes are truly critical to lung cancer formation, i.e., they may be with very limited useful information. As a result, finding essential genes remains a challenging lung cancer research problem. Using a recently developed competing linear factor analysis method in differentially expressed gene detection, we advance the study of lung cancer critical genes detection to a uniformly informative level. A set of common four genes and their functional effects are detected to be differentially expressed in tumor and non- tumor samples with 100% sensitivity and 100% specificity in one study of lung adenocarcinoma (LUAD) and one study of squamous cell lung cancers (LUSC) (two North American cohorts with 20429 genes, 576 and 552 samples respectively). Two additional analyses also gain accuracy of 97.8% sensitivity and 100% specificity in one study of non-small cell lung carcinomas (NSCLC, a European cohort with 20356 genes and 156 samples), and an accuracy of 100% sensitivity and 95% specificity (1 out of 20 non-tumor samples) in one study of ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas (LUAD, a Japanese cohort with 20356 genes and 224 samples). There are some common genes, but different functional effects, within each set of four genes among two North American cohorts and a European cohort and among North American cohorts and the Japanese cohort. These results show the four-gene-based classifiers are robust with different types of lung cancers and different race cohorts and accurate. The functional effects of four genes disclose significantly other mechanisms (mysteries) between LUAD and LUSC. These sets of four genes and their functional effects are considered to be essential for lung cancer studies and practice. These genes' functional effects naturally classify patients into different groups (more than seven subtypes). Subtype information is useful for personalized therapies. The new findings can motivate new lung cancer research in more focused and targeted directions to save lives, protect people, and reduce enormous economic costs in research and lung cancer treatments.