Technological innovation and rapid reduction in sequencing costs have enabled the genomic profiling of hundreds of cancer-associated genes as a component of routine cancer care. Tumour genomic profiling can refine cancer subtype classification, identify which patients are most likely to benefit from systemic therapies and screen for germline variants that influence heritable cancer risk. Here, we discuss ongoing efforts to enhance the clinical utility of tumour genomic profiling by integrating tumour and germline analyses, characterizing allelic context and identifying mutational signatures that influence therapy response. We also discuss the potential clinical utility of more comprehensive whole-genome and whole-transcriptome sequencing and ultra-sensitive cell-free DNA profiling platforms, which allow for minimally invasive, serial analyses of tumour-derived DNA in blood.
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The authors thank M. F. Berger, H. Al-Ahmadie, C. Ho, S. Sethi, A. Zehir and S. Nandakumar for their invaluable contributions to the figures. They are also grateful to the Molecular Diagnostics Service and the OncoKB team, particularly M. Ladanyi, H. Zhang and R. Kundra, for their assistance and insightful suggestions.
D.B.S. serves on the Scientific Advisory Board for Loxo Oncology at Eli Lilly, Pfizer, Scorpion Therapeutics, BridgeBio and Vividion Therapeutics, owned stock at Loxo Oncology at Eli Lilly and Scorpion Therapeutics, and received honoraria from Illumina and Eli Lilly. D.C. declares no competing interests.
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- Precision oncology
The process of using molecular data from the analysis of a patient’s tumour or healthy cells to inform treatment selection.
- Companion diagnostics
Within the context of precision oncology, companion diagnostics are medical devices designed to identify the subset of patients most likely to respond to and benefit from a targeted or other systemic or local therapy.
- Next-generation sequencing
(NGS). Massively parallel high-throughput sequencing methods designed to analyse DNA or RNA more rapidly and at higher resolution than older methods such as Sanger sequencing.
- Cell-free DNA
(cfDNA). In the context of this article, circulating tumour DNA, that is, DNA fragments shed by the tumour into the blood.
- Basket trials
A clinical trial design that prospectively accrues patients with a specific molecular alteration irrespective of tumour type.
- Mutational signatures
Patterns of base pair substitutions or structural abnormalities that are often characteristic of exogenous or endogenous mutational processes (such as tobacco smoking or DNA repair pathway mutations).
- Somatic mutations
Non-heritable mutations that may arise in any cell except germ cells (sperm or ova). Although somatic mutations have classically been defined as those found specifically in tumour but not in healthy cells, accumulation of somatic mutations is common in non-transformed, histologically normal-appearing cells as patients age.
Mutations that enhance tumour cell fitness by providing a growth or survival advantage.
Biologically inert mutations with no impact on tumour cell fitness.
- Clinically actionable mutations
A subset of driver mutations that are predictive biomarkers of drug response or resistance.
- Synthetic lethal mechanism
An interaction between two genes whereby loss of function of both (due to mutation, epigenetic silencing or drug inhibition) results in tumour cell death, whereas loss of function or inhibition of either individual gene does not.
- Mutational hotspots
Mutations identified in a population of patients with cancer more frequently than expected by chance.
- Germline variants
Heritable mutations that were present in germ cells and consequently found in all cells of the descendants.
- Resistance mutations
Mutations that increase tumour cell fitness under the selective pressure of a systemic therapy.
A measure of the proportion of individuals with a mutant allele in a defined population who manifest the associated phenotype. For germline variants associated with increased cancer predisposition, the penetrance is the proportion of patients who develop the associated cancer type.
- Whole-exome sequencing
(WES). Sequencing of all protein-coding regions (or exons) in the genome.
- Whole-genome sequencing
(WGS). Sequencing of the entire genome including non-coding sequences.
- Clonal haematopoiesis
The acquisition of somatic genomic alterations in haematopoietic stem and/or progenitor cells, resulting in clonal expansion.
- Capture-based DNA sequencing
A method for selectively sequencing targeted regions of the genome using baits that hybridize with specific regions of DNA.
- Clonal mutations
Mutations present in all of a patient’s cancer cells.
- Subclonal mutations
Mutations present in only a fraction of a patient’s cancer cells.
- Cancer cell fraction
The estimated fraction of cancer cells that harbour a specific mutation.
- Variant allele frequency
The fraction of mutant versus total sequencing reads at the mutation locus.
- Allelic configuration
The number of mutant and wild-type alleles, which because of copy number gain or loss can be less than or greater than two.
- Knudsen’s two-hit hypothesis
The hypothesis, proposed by Alfred Knudsen in 1971, that for tumour suppressor genes that are recessive in nature, in order for a phenotype to manifest, both alleles must be inactivated (biallelic inactivation). This may be achieved through multiple mechanisms including deletions (either chromosomal or subchromosomal), epigenetic silencing or mutation.
- Loss of heterozygosity
A common form of allelic imbalance in which a heterozygous somatic alteration becomes homozygous following loss of the wild-type allele.
- Clonal fitness
The relative growth, survival or metastatic potential advantage of a cancer cell clone over other cancer cells within the tumour or non-cancer cells. The term fitness here derives its origins from the concept of natural selection in evolutionary biology.
- Integer copy number
The copy number of a gene or localized DNA segment represented as an integer value. For missense mutations, the number of mutated and wild-type alleles in the cell.
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Chakravarty, D., Solit, D.B. Clinical cancer genomic profiling. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-021-00338-8