Departments of Surgery and Cell, Developmental and Cancer Biology, Oregon Health & Science University, Portland, Oregon.
Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, Oregon.
Cancer Res. 2024 Sep 16;84(18):2941-2943. doi: 10.1158/0008-5472.CAN-24-2730.
In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360-4.
1996 年，Goggins 及其同事证明了种系 BRCA2 致病性变异在明显散发性胰腺导管腺癌 (PDAC) 发展中的重要性。在此之前，该小组在 PDAC 中鉴定出 13q 区域的纯合缺失，从而能够鉴定出 BRCA2 基因。这篇 1996 年的文章首次揭示了种系和体细胞 BRCA2 缺失作为 PDAC 的关键驱动因素，当时仍有人怀疑 PDAC 是否具有遗传成分。与当时的主流观点相反，并非所有携带遗传性致病性 BRCA2 变异的个体都有癌症家族史。这项工作具有创新性，将床边研究与临床应用相结合，揭示了如果仅对符合家族史标准的个体进行基因检测，将错过这些变异的个体。因此，Goggins 及其同事主张，如果遗传检测仅限于符合家族史标准的个体，那么对胰腺癌进行普遍基因检测可能是必要的。23 年后，即 2019 年，美国将胰腺癌的普遍检测作为标准治疗方法。此外，Kern 实验室的这项工作和后续相关出版物为通过合成致死治疗方法靶向 BRCA2 和相关 DNA 修复突变奠定了基础。该团队在这篇出版物中发起的富有争议性的讨论至今仍在激励着该领域。在这篇开创性的出版物中，Goggins 及其同事深刻地影响了胰腺癌研究的方向，为设计更复杂的早期检测和精准治疗策略提供了方向。参见 Goggins 及其同事在 Cancer Res 1996;56:5360-4 上发表的相关文章。
