Using the "Hidden" genome to improve classification of cancer types. Academic Article uri icon

Overview

abstract

  • It is increasingly common clinically for cancer specimens to be examined using techniques that identify somatic mutations. In principle, these mutational profiles can be used to diagnose the tissue of origin, a critical task for the 3% to 5% of tumors that have an unknown primary site. Diagnosis of primary site is also critical for screening tests that employ circulating DNA. However, most mutations observed in any new tumor are very rarely occurring mutations, and indeed the preponderance of these may never have been observed in any previous recorded tumor. To create a viable diagnostic tool we need to harness the information content in this "hidden genome" of variants for which no direct information is available. To accomplish this we propose a multilevel meta-feature regression to extract the critical information from rare variants in the training data in a way that permits us to also extract diagnostic information from any previously unobserved variants in the new tumor sample. A scalable implementation of the model is obtained by combining a high-dimensional feature screening approach with a group-lasso penalized maximum likelihood approach based on an equivalent mixed-effect representation of the multilevel model. We apply the method to the Cancer Genome Atlas whole-exome sequencing data set including 3702 tumor samples across seven common cancer sites. Results show that our multilevel approach can harness substantial diagnostic information from the hidden genome.

publication date

  • September 21, 2020

Research

keywords

  • Neoplasms

Identity

PubMed Central ID

  • PMC8846548

Scopus Document Identifier

  • 85091270917

Digital Object Identifier (DOI)

  • 10.1111/biom.13367

PubMed ID

  • 32914442

Additional Document Info

volume

  • 77

issue

  • 4