DataSheet_1_Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA.docx

BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher’s exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation.

已有研究证实，BRCA1突变型前列腺癌相较于BRCA2突变型前列腺癌，对聚(ADP-核糖)聚合酶（poly (ADP-ribose) polymerase, PARP）抑制剂的应答敏感性更低，目前该应答差异的潜在机制尚不明确。我们提出假设：这种对PARP抑制剂的敏感性差异，可通过BRCA1与BRCA2所共分离的基因存在截然不同的基因组特征加以解释。本研究纳入7707名接受循环游离脱氧核糖核酸（cell-free DNA, cfDNA）全面基因组分析（comprehensive genomic profiling, CGP）的晚期前列腺癌男性患者，其中614名患者携带BRCA1和/或BRCA2突变；通过费希尔精确检验（Fisher’s exact test）与概率图模型（probabilistic graphical models, PGMs），我们对共分离基因的基因组特征差异展开了探究。研究结果显示，BRCA1与其他6种基因存在显著的共分离关联，而BRCA2未与任何基因呈现显著关联；上述发现提示，BRCA2或为前列腺癌的主要驱动突变，而BRCA1突变往往与其他参与前列腺癌进展的分子通路中的突变共同存在，这些可产生研究假说的数据或可解释PARP抑制剂应答的异质性，并为BRCA1突变患者的联合用药方案开发提供指导。