Abstract
BACKGROUND: Copy Number Alternations (CNAs) is defined as somatic gain or loss of DNA regions. The profiles of CNAs may provide a fingerprint specific to a tumor type or tumor grade. Low-coverage sequencing for reporting CNAs has recently gained interest since successfully translated into clinical applications. Ovarian serous carcinomas can be classified into two largely mutually exclusive grades, low grade and high grade, based on their histologic features. The grade classification based on the genomics may provide valuable clue on how to best manage these patients in clinic. Based on the study of ovarian serous carcinomas, we explore the methodology of combining CNAs reporting from low-coverage sequencing with machine learning techniques to stratify tumor biospecimens of different grades. RESULTS: We have developed a data-driven methodology for tumor classification using the profiles of CNAs reported by low-coverage sequencing. The proposed method called Bag-of-Segments is used to summarize fixed-length CNA features predictive of tumor grades. These features are further processed by machine learning techniques to obtain classification models. High accuracy is obtained for classifying ovarian serous carcinoma into high and low grades based on leave-one-out cross-validation experiments. The models that are weakly influenced by the sequence coverage and the purity of the sample can also be built, which would be of higher relevance for clinical applications. The patterns captured by Bag-of-Segments features correlate with current clinical knowledge: low grade ovarian tumors being related to aneuploidy events associated to mitotic errors while high grade ovarian tumors are induced by DNA repair gene malfunction. CONCLUSIONS: The proposed data-driven method obtains high accuracy with various parametrizations for the ovarian serous carcinoma study, indicating that it has good generalization potential towards other CNA classification problems. This method could be applied to the more difficult task of classifying ovarian serous carcinomas with ambiguous histology or in those with low grade tumor co-existing with high grade tumor. The closer genomic relationship of these tumor samples to low or high grade may provide important clinical value.