Disclosing Genomic Incidental Findings in a Cancer Biobank: An ELSI Experiment

描述(由申请者提供)：这个经验性和规范性的生物伦理学研究项目将指导关于基因组偶然发现(GIFD)披露的政策和实践，这是一个备受争议的话题。在多学科ELSI工作组的伦理指导下，我们将进行一项实验，旨在开发一种策略，向胰腺癌生物库中的先证者的家庭成员提供偶然发现。我们的方法将通过研究生物库研究参与者(包括亲属)的偏好来提供信息。据我们所知，以前没有研究涉及将偶然发现返回给家庭。然而，生物库面临着这个问题。我们迫切需要指导实践的建议。梅奥诊所已经在NCI资助的用于基因发现的孢子生物库中收集了胰腺癌先证者的胚系DNA。在寻找新的胰腺癌变种的同时，我们已经确定了73名先证者，他们是已知可增加胰腺癌以外疾病风险的基因突变的胚系携带者：BRCA2(乳腺癌和卵巢癌)、CDKN2A/p16(恶性黑色素瘤)和CFTR(子代囊性纤维化)。由于这些突变在临床实践中经常被披露，并具有严重的健康和/或生殖影响，因此考虑GIFD是合理的。考虑到大多数胰腺癌先证者都已经去世，许多人担心：既然先证者合法近亲的通知可能不能保证生物风险家庭成员得到通知，那么应该向谁提供这些发现？既然亲属没有参与最初的生物库知情同意过程，那么再次联系应该如何管理？什么披露程序最能满足家庭成员的关切？在决定研究人员何时有义务提供GIFD时，是否有道德门槛？3名PI之间的合作伙伴关系--一名领导孢子生物库的遗传流行病学家(Gloria Petersen)、一名经验研究员(Barbara Koenig)和一名生物伦理和法律学者(Susan Wolf)--结合了梅奥诊所和明尼苏达大学(UMN)的优势。这个项目利用了梅奥诊所的孢子生物库的基础设施和UMN的法律和价值观联盟关于NHGRI资助的偶然发现工作的历史。这个项目解决了翻译基因组学研究伦理中的一个关键问题。结合描述性和规范性目标的具体目标是：(1)通过a)访谈和b)调查来评估胰腺癌先证者及其家庭成员的偏好；(2)与专家法律和生物伦理学工作组一起进行深入的ELSI分析，以达成共识建议；(3)基于目标1和2的结果，设计和评估向携带胚系突变的先证者的家庭成员提供研究结果的程序；以及(4)制定“最佳实践”指南。该项目将生成关于先证者和家庭偏好的迫切需要的数据，对提出的法律和伦理问题进行详细分析，创建协商一致的建议，设计尊重偏好的方法，并推进健全的生物库治理。

DESCRIPTION (provided by applicant): This empirical and normative bioethics research project will guide policy and practice about the disclosure of genomic incidental findings (GIFD), a much-debated topic. With ethical guidance from a multidisciplinary ELSI Working Group, we will conduct an experiment designed to develop strategies for offering incidental findings to family members of probands in a biobank for pancreatic cancer. Our approach will be informed by studying the preferences of biobank research participants (including kin).To our knowledge, no previous research has addressed the return of incidental findings to families. Yet biobanks face this question. Recommendations to guide practice are sorely needed. Mayo Clinic has collected germline DNA of pancreatic cancer probands in an NCI-funded SPORE biobank created for gene discovery. While seeking novel pancreatic cancer variants, we have identified 73 probands who are germline carriers of mutations in genes known to confer increased risk of diseases other than pancreatic cancer: BRCA2 (breast & ovarian cancer), CDKN2A/p16 (malignant melanoma), and CFTR (cystic fibrosis in offspring). Because these mutations are routinely disclosed in clinical practice and have serious health and/or reproductive implications, consideration of GIFD is justified. Given that the majority of the pancreatic cancer probands are deceased, many concerns arise: Who should be offered the findings, given that notification of the proband's legal next of kin may not assure that biologically at-risk family members are informed? Since relatives were not involved in the original biobank informed consent process, how should re-contact be managed? What disclosure proce- dures best meet family members' concerns? Is there an ethical threshold for determining when the researcher is obligated to offer GIFD? A partnership among 3 PIs-a genetic epidemiologist who directs the SPORE biobank (Gloria Petersen), an empirical researcher (Barbara Koenig), and a bioethics and law scholar (Susan Wolf)-combines the strengths of Mayo Clinic and the University of Minnesota (UMN). This project leverages the infrastructure of the SPORE biobank at Mayo Clinic and UMN's Consortium on Law and Values' history of NHGRI-funded work on incidental findings. This project addresses a critical problem in translational genomics research ethics. The Specific Aims-which combine descriptive and normative objectives-are: (1) to assess preferences of pancreatic cancer probands and their family members using a) interviews and b) a survey; (2) to conduct an in-depth ELSI analysis with an expert law and bioethics Working Group, leading to consensus recommendations; (3) based on the findings from Aims 1 and 2, to prototype and evaluate a procedure for offering findings to family members of probands who carry germline mutations; and (4) to develop "best practice" guidelines. This project will generate much-needed data on proband and family preferences, produce detailed analyses of the legal and ethical issues raised, create consensus recommendations, devise methods for honoring preferences, and advance sound biobank governance.