Using somatic mutation data to test tumors for clonal relatedness

TL;DR

This paper introduces a new statistical test for determining whether two tumors from the same patient are clonally related, addressing challenges posed by mutation profile complexities and limited prior knowledge.

Contribution

It proposes a novel method for testing tumor clonality based on somatic mutation profiles, accounting for mutation frequency disparities and limited prior data.

Findings

The test performs well in simulations, showing promising properties.

Application to literature examples demonstrates practical utility.

Addresses methodological challenges in mutation profile comparison.

Abstract

A major challenge for cancer pathologists is to determine whether a new tumor in a patient with cancer is a metastasis or an independent occurrence of the disease. In recent years numerous studies have evaluated pairs of tumor specimens to examine the similarity of the somatic characteristics of the tumors and to test for clonal relatedness. As the landscape of mutation testing has evolved, a number of statistical methods for determining clonality have developed, notably for comparing losses of heterozygosity at candidate markers, and for comparing copy number profiles. Increasingly tumors are being evaluated for point mutations in panels of candidate genes using gene sequencing technologies. Comparison of the mutational profiles of pairs of tumors presents unusual methodological challenges: mutations at some loci are much more common than others; knowledge of the marginal mutation probabilities is scanty for most loci at which mutations might occur; the sample space of potential mutational profiles is vast. We examine this problem and propose a test for clonal relatedness of a pair of tumors from a single patient. Using simulations, its properties are shown to be promising. The method is illustrated using several examples from the literature.