Integrative Genomic Tests in Clinical Oncology

Abstract

Many clinical decisions in oncology practice rely on the presence or absence of an alteration in a single genetic locus, be it a pathogenic variant in a hereditary cancer gene or activating mutation in a drug target. In addition, there are integrative tests that produce continuous variables and evaluate complex characteristics of the entire tumor genome. Microsatellite instability (MSI) analysis identifies tumors with the accumulation of mutations in short repetitive nucleotide sequences. This procedure is utilized in Lynch syndrome diagnostic pipelines and for the selection of patients for immunotherapy. MSI analysis is well-established for colorectal malignancies, but its applications in other cancer types lack standardization and require additional research. Homologous repair deficiency (HRD) indicates tumor sensitivity to PARP inhibitors and some cytotoxic drugs. HRD-related "genomic scars" are manifested by a characteristic pattern of allelic imbalances, accumulation of deletions with flanking homology, and specific mutation signatures. The detection of the genetic consequences of HRD is particularly sophisticated and expensive, as it involves either whole genome sequencing (WGS) or the utilization of large next-generation sequencing (NGS) panels. Tumor mutation burden (TMB) can be determined by whole exome sequencing (WES) or middle-throughput NGS multigene testing. Although TMB is regarded as an agnostic indicator of tumor sensitivity to immunotherapy, the clinical utility of this test is proven only for a few cancer types.

Keywords: homologous repair deficiency; integrative tests; microsatellite instability; tumor mutation burden.

Figure 1

Integrative genomic tests. (a) Instability at short tandem repeats can be detected either by conventional PCR-based methods or by NGS. (b) Consequences of HR deficiency are usually determined by evaluating the level of chromosomal instability (e.g., HRD score (unweighted sum of LOH, LST, and TAI)) alone or in combination with specific mutational signatures. (c) TMB can be calculated from various NGS datasets, e.g., whole-genome, whole-exome, or targeted gene sequencing; colored circles designate various somatic mutations. Abbreviations: HRD, homologous repair deficiency; LOH, loss-of-heterozygosity; LST, large-scale state transition; MMR-D, mismatch repair deficiency; MSI, microsatellite instability; MSS, microsatellite stable; STR, short tandem repeats; TAI, telomeric allelic imbalance; TMB, tumor mutation burden; WES, whole-exome sequencing; WGS, whole-genome sequencing.