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

描述（由申请人提供）：这个经验和规范的生物伦理学研究项目将指导政策和实践有关披露基因组偶然发现（GIFD），一个备受争议的话题。在多学科ELSI工作组的伦理指导下，我们将进行一项旨在制定策略的实验，为胰腺癌生物库中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银行研究参与者（包括亲属）的偏好来了解。据我们所知，以前没有研究涉及将偶然发现归还给家庭。然而，生物银行面临着这个问题。迫切需要指导实践的建议。马约诊所已经收集了胰腺癌先证者的生殖系DNA，并将其存入了一个由国家癌症研究所资助的为基因发现而创建的孢子生物库。在寻找新的胰腺癌变异的同时，我们已经确定了73名先证者，他们是已知会增加胰腺癌以外疾病风险的基因突变的种系携带者：BRCA 2（乳腺癌和卵巢癌），CDKN 2A/p16（恶性黑色素瘤）和CFTR（后代囊性纤维化）。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。鉴于大多数胰腺癌先证者已经死亡，许多问题出现了：谁应该提供的结果，鉴于先证者的法律的近亲的通知可能无法确保生物风险的家庭成员被告知？由于亲属未参与最初的生物样本库知情同意过程，应如何管理再次联系？什么样的披露程序最能满足家庭成员的关切？是否有一个道德门槛来决定研究人员何时有义务提供GIFD？三位PI--一位指导SPORE生物库的遗传流行病学家（格洛丽亚彼得森）、一位经验研究者（芭芭拉·凯尼格）和一位生物伦理学和法律学者（苏珊·沃尔夫）--的合作结合了马约诊所和明尼苏达大学（UMN）的优势。该项目利用了马约诊所的SPORE生物库的基础设施和UMN的法律和价值观联盟的NHGRI资助的偶然发现工作的历史。本计画针对转译基因组学研究伦理的一个重要问题。联合收割机的具体目标是：（1）通过a）访谈和B）调查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进行深入的ELSI分析，得出共识建议;（3）根据目标1和2的发现，建立一个向携带生殖系突变的先证者家庭成员提供发现的程序原型并进行评估;（4）制定“最佳实践”指南。该项目将产生急需的先证者和家庭偏好数据，对提出的法律的和伦理问题进行详细分析，创建共识建议，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.