No abstract

Background The advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, identifying many cancer-associated genes. Although cancers in the same tissue are widely categorized in the same group, they demonstrate many differences concerning their mutational profiles. Hence, there is no definitive treatment for most cancer types. This reveals the importance of developing new pipelines to identify cancer-associated genes accurately and re-classify patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types. Results In this study, we propose a new machine learning pipeline to identify protein-coding genes mutated in many samples to identify cancer subtypes. We apply our pipeline to 12,270 samples collected from the international cancer genome consortium, covering 19 cancer types. As a result, we identify 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways. Conclusions This new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. Additionally, we analyze the mutational signatures for samples in each subtype, which provides important insight into their active molecular mechanisms. Some of the pathways we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rates of mutation in multiple cancer subtypes. In addition, our study on “gene-motif” suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer.

Background: The advent of high throughput sequencing has enabled researchers to systematically evaluate the genetic variations in cancer, resulting in the identification of many cancer-associated genes. Although cancers in a same tissue are widely categorized in the same group, they demonstrate many differences among them with respect to their mutational profiles. Hence there is no “silver bullet” for treatment of a cancer type. This reveals the importance of developing a pipeline to accurately identify cancer-associated genes and re-classify cancer patients with similar mutational profiles. Classification of cancer patients with similar mutational profiles may help discover subtypes of cancer patients who might benefit from specific treatment types. Results: In this study, we propose a new machine learning pipeline to identify protein-coding genes which are mutated in significant portion of samples to identify cancer subtypes. We applied our pipeline to 12270 samples collected from the International Cancer Genome Consortium (ICGC) which covered 19 cancer types. Here we identified 17 different cancer subtypes. Comprehensive phenotypic and genotypic analysis indicates distinguishable properties, including unique cancer-related signaling pathways, in which, for most of them, targeted treatment options are currently available. Conclusions: This new subtyping approach offers a novel opportunity for cancer drug development based on the mutational profile of patients. We also comprehensive study the causes of mutations among samples in each subtype by mining the mutational signatures which provides important insight into their active molecular mechanisms. Some of the pathways that we identified in most subtypes, including the cell cycle and the Axon guidance pathways, are frequently observed in cancer disease. Interestingly, we also identified several mutated genes and different rate of mutation in multiple cancer subtypes. In addition, our study on “gene-motif” suggests the importance of considering both the context of the mutations and mutational processes in identifying cancer-associated genes. The source codes for our proposed clustering pipeline and analysis are publicly available at: https://github.com/bcb-sut/Pan-Cancer.

Selective classification is the task of rejecting inputs a model would predict incorrectly on through a trade-off between input space coverage and model accuracy. Current methods for selective classification impose constraints on either the model architecture or the loss function; this inhibits their usage in practice. In contrast to prior work, we show that state-of-the-art selective classification performance can be attained solely from studying the (discretized) training dynamics of a model. We propose a general framework that, for a given test input, monitors metrics capturing the disagreement with the final predicted label over intermediate models obtained during training; we then reject data points exhibiting too much disagreement at late stages in training. In particular, we instantiate a method that tracks when the label predicted during training stops disagreeing with the final predicted label. Our experimental evaluation shows that our method achieves state-of-the-art accuracy/coverage trade-offs on typical selective classification benchmarks. For example, we improve coverage on CIFAR-10/SVHN by 10.1%/1.5% respectively at a fixed target error of 0.5%.