Genetics, genomics, and cancer risk assessment: State of the Art and Future Directions in the Era of Personalized Medicine

Abstract

Scientific and technologic advances are revolutionizing our approach to genetic cancer risk assessment, cancer screening and prevention, and targeted therapy, fulfilling the promise of personalized medicine. In this monograph, we review the evolution of scientific discovery in cancer genetics and genomics, and describe current approaches, benefits, and barriers to the translation of this information to the practice of preventive medicine. Summaries of known hereditary cancer syndromes and highly penetrant genes are provided and contrasted with recently discovered genomic variants associated with modest increases in cancer risk. We describe the scope of knowledge, tools, and expertise required for the translation of complex genetic and genomic test information into clinical practice. The challenges of genomic counseling include the need for genetics and genomics professional education and multidisciplinary team training, the need for evidence-based information regarding the clinical utility of testing for genomic variants, the potential dangers posed by premature marketing of first-generation genomic profiles, and the need for new clinical models to improve access to and responsible communication of complex disease risk information. We conclude that given the experiences and lessons learned in the genetics era, the multidisciplinary model of genetic cancer risk assessment and management will serve as a solid foundation to support the integration of personalized genomic information into the practice of cancer medicine.

FIGURE 1

Timeline of cancer genetics to genomic discovery. Depicted is a snapshot of scientific developments capturing a century of experience in the translation of research in genetics and genomics to the practice of cancer medicine.

FIGURE 2

Phenotypic effect size and frequency of occurrence. In humans, mutations in highly penetrant cancer susceptibility genes are rare whereas mutations in genes conferring low-to-moderate cancer risks are common. (*) Named genes only reflect the most likely candidate genes to be implicated by the marker single nucleotide polymorphisms (SNPs) identified from the genome-wide association studies. From Stadler ZK, Thom P, Robson ME, et al., Genome-Wide Association Studies of Cancer. J Clin Oncol Vol. 28(27), 2010. 4255–4267. Reprinted with permission. © 2010 by American Society of Clinical Oncology. All rights reserved.

FIGURE 3

Clinical utility of genetic and genomic tests. When considering the future development of germline genetic testing in oncologic care, it is useful to think of tests with regard to their position along two axes. The first axis identifies whether or not the test can be said to have accepted clinical utility. The second axis describes whether the test was obtained through the mediation of a health care provider (HCP) with whom the individual being tested had an ongoing relationship, or through a direct-to-consumer (DTC) channel. To date, most genetic testing for cancer susceptibility can be categorized as professionally mediated and of accepted clinical utility (quadrant 1). As the fields of oncology and genetics continue to progress and become increasingly intertwined, HCPs will need to develop a working knowledge of tests that fall under the other three quadrants. From Robson ME, Storm CD, Weitzel J, Wollins DS and Offit K. J Clin Oncol Vol. 28(5)2010:893–901. Reprinted with permission. © 2010 by American Society of Clinical Oncology. All rights reserved.

FIGURE 4

Genome Wide Association Studies for Cancer. The left axis represents the odds ratio (OR). The horizontal axis depicts the frequency of minor alleles. As shown, the OR associated with developing cancer for most of the alleles is low. Exceptions are the marker SNPs mapping to KITLG in testicular germ cell cancer and JAK2 in myeloproliferative neoplasms, which have ORs of approximately 3.0, with allele frequencies ranging from 20% to 40%. Adapted from data in Stadler ZK, Thom P, Robson ME, et al., Genome-Wide Association Studies of Cancer. J Clin Oncol Vol. 28(27), 2010. 4255–4267.