Inherited genetic markers and cancer outcomes: personalized medicine in the postgenome era.

The report of Tsuchiya et al represents an area of research that has the potential to impact personalized genomic medicine; this area is the use of inherited genetic markers to predict clinical outcomes, including prognosis and recurrence, in cancer patients. Tsuchiya et al report that longer repeat polymorphisms in the IGF1 and/or CYP19 genes are significantly associated with poorer prostate cancer–specific survival among men with metastatic prostate cancer. This research complements other reports that inherited genetic markers predict prostate cancer outcomes, including associations with CYP3A4, SRD5A2, the androgen receptor gene (AR), and the vitamin D receptor gene (VDR). Numerous reports have also been made that relate inherited genetic markers and prognosis or recurrence with tumors at other sites. Prediction of clinical outcome by inherited genetic markers is likely to reflect the natural history of disease progression and, therefore, may involve genes and biochemical pathways that act along the continuum from disease causation, recurrence, and mortality (Fig 1). Indeed, IGF1, CYP19, CYP3A4, SRD5A2, AR, and VDR have all been implicated in prostate cancer etiology and outcomes. Inherited genetic markers may also provide predictive or prognostic information in addition to somatic tumor markers or inherited genetic markers of treatment response and toxicity (eg, pharmacogenetic markers; Fig 1). Despite reports associating inherited genetic markers with clinical outcomes, the existing literature is probably insufficient to warrant clinical translation of these markers at this time. What evidence must be gathered before inherited genetic markers could be applied in a clinical setting? Establishing a causal relationship between risk factor and outcome is a minimal requirement, and a variety of criteria for establishing causal inferences has been proposed. As outlined in the following sections, additional factors must be considered before an inherited genetic marker can be applied to predict cancer prognosis, recurrence, or other clinical outcomes.