Genomics of Cancer and a New Era for Cancer Prevention

A primary justification for dedicating substantial amounts of research funding to large-scale cancer genomics projects of both somatic and germline DNA is that the biological insights will lead to new treatment targets and strategies for cancer therapy. While it is too early to judge the success of these projects in terms of clinical breakthroughs, an alternative rationale is that new genomics techniques can be used to reduce the overall burden of cancer by prevention of new cases occurring and also by detecting them earlier. In particular, it is now becoming apparent that studying the genomic profile of tumors can help to identify new carcinogens and may subsequently result in implementing strategies that limit exposure. In parallel, it may be feasible to utilize genomic biomarkers to identify cancers at an earlier and more treatable stage using screening or other early detection approaches based on prediagnostic biospecimens. While the potential for these techniques is large, their successful outcome will depend on international collaboration and planning similar to that of recent sequencing initiatives.Since the publication of the initial human genome sequence in 2002, at a cost of around US$3 thousand million, DNA sequencing has advanced to the extent where whole genomes can be sequenced in days for around one millionth of the cost [1]. This has led to a scientific tour de force in projects that aim to understand the genetics of cancer. Large-scale initiatives such as the International Cancer Genome Consortium (ICGC) and the Cancer Genome Atlas (TCGA) for somatic variation, as well as the OncoArray Network for genome-wide studies of germline variation, have harnessed international expertise in oncology, genomics, and bioinformatics with very high levels of funding and have resulted in the coordinated genotyping, sequencing, and cataloging of many thousands of cancer cases [2]. Comprehensive genomic data from all completed cases are being made available to the research community, along with basic clinical information on some, allowing for extensive additional analyses. This initiative has led to a new understanding of how to define specific cancer subtypes and has vastly increased the pace of progress in elucidating the underlying biology of cancer [3].The most prominent visible outcome of the increased understanding of cancer biology is that targeted treatments have been developed or are being tested that aim to block specific molecules that spur the growth or spread of cancer. Although there are some exciting success stories such as the vastly improved survival with imatinib and chronic myelogenous leukemia (CML) or the increased efficacy of Herceptin treatment for women with Her2-positive breast cancer, most of this new generation of targeted treatments promise, at most, only a partial respite from the disease. The typical scenario is that the underlying cancer is not totally eradicated, remnants of the disease evolve and overcome any treatment, and the relapse is severe [4].New targeted therapies are also expensive to develop and to prescribe, some costing over US$100,000 for each patient per year, while being applicable for a smaller number of patients with the relevant subtype of disease. Disease resistance may be overcome through new strategies that combine therapies for specific pathways, and combination therapy of two or more drugs that target independent pathways is likely to hold even greater promise for improving response [5]. Other approaches such as combined use of immune checkpoint inhibitors are also providing exciting results [6], although there remain concerns that the strategy of developing targeted therapies for late-stage disease may be fundamentally flawed, given the inherent complexity and heterogeneity of such tumors [7,8]. A complementary approach would be to focus also on early detection of localized cancer, including the use of screening, when survival is usually a lot more favorable [3], as well as primary prevention in identifying the causes and minimizing exposure. The role of genomics in primary and secondary prevention of cancer has received less attention than treatment, although it is perhaps here that genomics will have its most important contribution in the long term.