Due to the rapid drop in the cost of DNA sequencing, a panel of multiple (25 to 125) cancer susceptibility genes can be now tested at a fraction of cost and time of what was needed earlier for testing only a handful of well-known cancer genes such as BRCA1 and BRCA2. As multi-gene panel tests are becoming accessible to increasingly broader population, more and more patients carrying pathogenic germline mutations of various genes are being identi?ed. This trend is creating a major paradigm shift in hereditary cancer risk assessment because the newly identi?ed mutation carriers need advise about approporiate management strategies such as targeted surveillance and preventive options. The counseling hinges crucially on accurate quantitative estimates of age-speci?c risks of developing cancers associated with a speci?c gene whose pathogenic mutation a patient carries, i.e., penetrance estimates. For several gene-cancer associations, a substantial amount of literature on risk estimation is available and new studies are also becoming available at a fast pace. Yet a synthesis of evidence from all relevant studies in the form of a robust meta-analysis of penetrance is generally lacking. A case in point is PALB2-breast cancer association for which several studies report risk measures, however, there is no meta- analysis of penetrance estimates. Thus there is an urgent need for meta-analysis of penetrances so that mutation carriers in PALB2 and many other genes can be counseled appropriately in light of their age-speci?c risks of developing various cancers. A major challenge in this task is that studies typically vary in design (e.g., family- or population-based) and hence type of risk measures reported (e.g., penetrance, relative risk, or odds ratio). Synthesis of such heterogeneous risk measures is not possible using the standard meta-analysis approaches. Moreover, for an accurate and robust estimation, the meta-analysis model should properly take into account various sources of uncertainties that arise in such kind of synthesis. To ?ll this gap, we propose a Bayesian hiererchical model for meta-analysis as it allows seamless integration of results of different types by borrowing information across the studies. At the same time, it accounts for uncertainties in a formal manner through hierarchical priors. Our ?rst speci?c aim is to develop this Bayesian meta-analysis methodology, investigate its properties, and compare it with existing approaches through simulations. The next speci?c aim is to apply this method to estimate the penetrance for PALB2 gene for breast cancer. Our ?nal aim is to develop an R package that implements the proposed Bayesian methodology and integrate it into the clinical decision support tool ASK2ME for immediate clinical use.
Due to the recent advances in molecular technologies, patients carrying mutations in a multitude of cancer genes are being identi?ed at an increasingly faster pace. To help in counseling them, we propose a novel statistical method for synthesis of relevant scienti?c literature on their age-speci?c risks of developing various cancers. With accurate risk estimates, appropriate management strategies can be suggested such as surveillance or preventive options, which can help reduce the cancer burden in the population.
