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INTRODUCTION

Cancer is the second-leading cause of death in the United States.1 We can imagine a future where both germline and somatic genomics play an ever-increasing role in decreasing cancer deaths through (1) preemptive identification of germline cancer risk, (2) early-stage genomic cancer diagnoses, and (3) genome-based individually tailored therapeutics.

The term “precision medicine” was coined by U.S. President Barack Obama in the 2015 State of the Union address.2 The “All of Us” research program is a key NIH Precision Medicine initiative that seeks to enroll at least one million persons in the United States in an observational cohort complete with DNA sequencing that both accelerates biomedical research and improves health.3 Precision medicine, like “individualized medicine” or “personalized medicine,” seeks to shift from a “one-size-fits-all” approach to one that takes into account differences in an individual’s “genes, environments, and lifestyles.” With advances in genomic sequencing technologies, the promise of care that is routinely informed by an individual’s genetic code appears within reach. In the era of genomic medicine, sequence data will be used as both a screening and a diagnostic tool. Implementation of genome-based care, fueled by both falling costs and growing evidence, will continue to become increasingly accessible to patients and clinicians.4–6

Genomics will be a key tool but not the only tool in the advancing application of precision medicine in oncology. While cancer genomics focuses on variations in human DNA, other tools focus on other data sources: transcriptomics (RNA), proteomics (proteins), metabolomics (bioactive molecules), epigenomics (DNA modifications), as well as commensal bacterial communities (microbiomics). The clinical implementation of these other tools will advance both separately and in combination with genomics in the decades ahead.7,8 In addition to the three key roles for genomics already listed, these other tools are also important areas to expect advances in the management of cancer.

PREEMPTIVE IDENTIFICATION OF GERMLINE CANCER RISK

Identifying Germline Cancer Risk

The capacity of clinical laboratories to interpret an individual’s germline DNA variants has improved significantly in the last decade. This improved interpretation builds on (1) the extraordinary amount of sequence data that is being generated, (2) the development of a framework for clinical interpretation of variants, and (3) the availability of public-facing resources that make consensus variant interpretations broadly available.

The standards and guidelines for the interpretation of sequence variants published in 2015 established a framework for the clinical interpretation of variants.9 This framework, a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, is criteria-based and has been widely accepted by clinical laboratories to categorize variants using standard terminology, namely pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. It is clear that these categorizations, while incredibly useful for care, are made based on evidence at a single point in time and ...

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