Returning genetic research panel results for breast cancer susceptibility

描述(申请人提供)：癌症易感性的基因筛查(例如BRCA1/2)已成为癌症预防的标准循证做法，并已被证明可以降低乳腺癌的发病率和死亡率。然而，大多数怀疑有遗传易感性的个人和家庭都没有BRCA1/2突变。采用下一代测序技术的研究表明，PALB2、CHEK2和ATM等其他基因的突变与乳腺癌风险的增加有关。因此，开发了多重面板来同时高效地筛选大量基因，包括不同外显率和癌症谱的基因，并对知情同意和遗传咨询提出了挑战。尽管没有明确的证据表明这些基因中的许多具有临床实用价值，但这些基因面板现在已经商业化，并得到越来越多的利用。随着储存DNA的大型前瞻性队列研究越来越多地被用来评估基因、环境和生活方式的影响，人们一直在争论是否有义务与研究参与者分享个人研究成果(IRR)。作为多路复用板 乳腺癌的易感性说明，一些基因研究结果将与健康结果相关，和/或可用于临床测试。然而，随着这些测试进入临床，对于是否、如何、何时以及哪些信息应该返回给研究参与者，还没有达成共识。此外，归还内部收益率的相关费用尚不清楚，谁应该承担这些活动的费用也没有得到解决。拟议的纵向多中心研究的总体目标是评估以下各项的风险、收益、效用和成本 将乳腺癌易感性的多重基因研究结果返回给地理和社会人口统计学上不同的研究人群。我们的理论模型建立在健康行为自我调节理论的基础上，旨在为短期和纵向结果的选择提供信息，并为这些结果的潜在调解人和调解人提供信息，为关于返还IRR的风险、好处和效用的辩论提供信息。此外，我们还扩大了基因组检测结果的“实际”效用的概念。在目标1中，我们将评估研究参与者对IRR的吸收(目标1a)，以及与吸收相关的因素(目标1b)。在目标2中，我们将评估短期(目标2a)和纵向(目标2b)的风险和收益(即患者对基因组的理解、反应、使用和感知的效用 信息)返回多重基因研究成果。我们还将评估这些结果的主持人(例如，内部收益率的回归对其或多或少有利的小组)。同样重要的是，我们将审查短期和纵向参与者成本、研究团队成本和医疗保健利用成本，以及具有回报或内部收益率的成本(目标3a)和这些成本的调节因素(目标3b)。我们期待这项研究为正在进行的辩论提供信息，并最终为返回个人基因组研究结果提供基于证据的指导方针。

DESCRIPTION (provided by applicant): Genetic screening for cancer susceptibility (e.g. BRCA1/2) has become a standard evidence-based practice in cancer prevention and has proven to reduce breast cancer morbidity and mortality. Yet, most individuals and families in whom genetic susceptibility is suspected do not have a BRCA1/2 mutation. Research employing next generation sequencing has revealed that mutations in other genes, such as PALB2, CHEK2 and ATM are associated with elevated risks of breast cancer. Thus, multiplex panels have been developed to efficiently screen a large number of genes simultaneously, including genes of varied penetrance and cancer spectrum and presenting challenges to informed consent and genetic counseling. Despite no clear evidence of clinical utility for many of these genes, these gene panels are now commercially available and increasingly utilized. As large prospective cohort studies with banked DNA have become increasingly utilized to evaluate the effects of genes, the environment and lifestyle, there has been debate over the obligations, if any, to share individual research results (IRR) with research participants. As multiplex panels for breast cancer susceptibility illustrate, some genetic research findings will be associated with health outcomes and/or become available for clinical testing. Yet, there is no consensus on if, how, when and what information should be returned to research participants as these tests become clinically available. Further, the associated costs of returning IRR are unknown, and who should bear the costs of these activities has not been resolved. The overall goal of the proposed longitudinal multi-center study is to evaluate the risks, benefits, utilities and costs of returning multiplex genetic research results for breast cancer susceptibility to geographically and sociodemographically diverse research populations. Our theoretical model grounded in the Self- Regulation Theory of Health Behavior was developed to inform the selection of the short-term and longitudinal outcomes and potential mediators and moderators of these outcomes to inform the debate over risks, benefits and utility of returning IRR. Additionally, we include a broadened conceptualization of the "actual" utility of genomic test results. In Aim 1, we will evaluate uptake of IRR among research participants (Aim 1a), and factors associated with uptake (Aim 1b). In Aim 2, we will evaluate the short-term (Aim 2a) and longitudinal (Aim 2b) risks and benefits (i.e. patients understanding, reactions to, use and perceived utility of genomic information) of returning multiplex genetic research results. We will also evaluate the moderators of these outcomes (e.g. subgroups for whom the return of IRR is more or less beneficial). Equally important we will examine the short-term and longitudinal participant costs, research team costs and medical care utilization and costs with return or IRR (Aim 3a) and moderators of these costs (Aim 3b). We expect this research to inform the ongoing debate and ultimately evidence based guidelines for return of individual genomic research results.