Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Gastroenterology. 2021 May;160(6):2119-2132.e9. doi: 10.1053/j.gastro.2021.01.220. Epub 2021 Jan 30.
Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2.
We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.
Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetect cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance.
Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
除了 BRCA1、BRCA2 和 PALB2 种系改变之外，胰腺导管腺癌（PDAC）中的同源重组缺陷（HRD）仍未得到充分定义。
我们对 391 名患者的全基因组测序（WGS）数据进行了检测，其中包括 49 名种系 BRCA 和 PALB2 致病性变异（PV）携带者。将 HRD 分类器应用于数据集，包括（1）Myriad 的 MyChoice HRD 检测使用的基因组不稳定性评分（GIS）；（2）取代碱基特征 3（SBS3）；（3）HRDetect；和（4）结构变体（SV）负担。临床结局和对化疗的反应与 HRD 状态相关。
49 名种系携带者中有 43 名存在种系 BRCA 或 PALB2 的双等位基因肿瘤失活，确定为 HRD-PDAC。HRDetect（评分≥0.7）预测 gBRCA1/PALB2 缺陷的敏感性最高（98%），特异性最高（100%）。HRD 基因组肿瘤分类器表明，7%至 10%的 PDAC 不携带 gBRCA/PALB2，但具有 HRD 特征。在体细胞 HRDetect 病例中，69%归因于 BRCA1/2、PALB2、RAD51C/D 和 XRCC2 以及串联重复表型的改变。与 BRCA2 相关的 HRD-PDAC 相比，TP53 缺失更为常见。HRD 状态在可切除的 PDAC 中没有预后意义；然而，在晚期疾病中，GIS（P=0.02）、SBS3（P=0.03）和 HRDetect 评分（P=0.005）可预测铂类反应和生存优势。任何分类器均未显示 gATM（n=6）或 gCHEK2（n=2）中的种系 PV 导致 HRD-PDAC。在 4 名患者中，BRCA2 回复突变与铂类耐药相关。
PDAC 的种系和并行体细胞分析优于单独的种系检测，可更准确地识别 HRD-PDAC。另外 7%至 10%的无 gBRCA/PALB2 突变的患者可能受益于 DNA 损伤反应药物。
