Vollan Hans Kristian Moen, Rueda Oscar M, Chin Suet-Feung, Curtis Christina, Turashvili Gulisa, Shah Sohrab, Lingjærde Ole Christian, Yuan Yinyin, Ng Charlotte K, Dunning Mark J, Dicks Ed, Provenzano Elena, Sammut Stephen, McKinney Steven, Ellis Ian O, Pinder Sarah, Purushotham Arnie, Murphy Leigh C, Kristensen Vessela N, Brenton James D, Pharoah Paul D P, Børresen-Dale Anne-Lise, Aparicio Samuel, Caldas Carlos
Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK; Department of Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway; Department of Oncology, Division for Surgery, Cancer and Transplantation, Oslo University Hospital, The Norwegian Radium Hospital, Montebello, 0310 Oslo, Norway.
Cancer Research UK, Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Mol Oncol. 2015 Jan;9(1):115-27. doi: 10.1016/j.molonc.2014.07.019. Epub 2014 Aug 8.
Complex focal chromosomal rearrangements in cancer genomes, also called "firestorms", can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer. Copy number alteration (CNA) data from 1950 breast carcinomas (METABRIC cohort) and 508 high-grade serous ovarian carcinomas (TCGA dataset) were analyzed. Cases were classified as CAAI positive if at least one complex focal event was scored. Complex alterations were frequently localized on chromosome 8p (n = 159), 17q (n = 176) and 11q (n = 251). CAAI events on 11q were most frequent in estrogen receptor positive (ER+) cases and on 17q in estrogen receptor negative (ER-) cases. We found only a modest correlation between CAAI and the overall rate of genomic instability (GII) and number of breakpoints (r = 0.27 and r = 0.42, p < 0.001). Breast cancer specific survival (BCSS), overall survival (OS) and ovarian cancer progression free survival (PFS) were used as clinical end points in Cox proportional hazard model survival analyses. CAAI positive breast cancers (43%) had higher mortality: hazard ratio (HR) of 1.94 (95%CI, 1.62-2.32) for BCSS, and of 1.49 (95%CI, 1.30-1.71) for OS. Representations of the 70-gene and the 21-gene predictors were compared with CAAI in multivariable models and CAAI was independently significant with a Cox adjusted HR of 1.56 (95%CI, 1.23-1.99) for ER+ and 1.55 (95%CI, 1.11-2.18) for ER- disease. None of the expression-based predictors were prognostic in the ER- subset. We found that a model including CAAI and the two expression-based prognostic signatures outperformed a model including the 21-gene and 70-gene signatures but excluding CAAI. Inclusion of CAAI in the clinical prognostication tool PREDICT significantly improved its performance. CAAI positive ovarian cancers (52%) also had worse prognosis: HRs of 1.3 (95%CI, 1.1-1.7) for PFS and 1.3 (95%CI, 1.1-1.6) for OS. This study validates CAAI as an independent predictor of survival in both ER+ and ER- breast cancer and reveals a significant prognostic value for CAAI in high-grade serous ovarian cancer.
癌症基因组中的复杂局灶性染色体重排,也被称为“风暴”,可通过DNA拷贝数数据进行评分。复杂臂水平畸变指数(CAAI)是一种评分,用于捕捉在肿瘤中表现为局灶性复杂事件的DNA拷贝数改变,在乳腺癌中具有潜在的预后价值。本研究旨在验证这种基于DNA的乳腺癌预后指数,并首次测试其在卵巢癌中的潜在预后价值。分析了来自1950例乳腺癌(METABRIC队列)和508例高级别浆液性卵巢癌(TCGA数据集)的拷贝数改变(CNA)数据。如果至少有一个复杂局灶性事件被评分,则病例被分类为CAAI阳性。复杂改变经常定位于8号染色体短臂(n = 159)、17号染色体长臂(n = 176)和11号染色体长臂(n = 251)。11号染色体长臂上的CAAI事件在雌激素受体阳性(ER +)病例中最常见,而17号染色体长臂上的CAAI事件在雌激素受体阴性(ER -)病例中最常见。我们发现CAAI与基因组不稳定性(GII)的总体发生率和断点数量之间只有适度的相关性(r = 0.27和r = 0.42,p < 0.001)。在Cox比例风险模型生存分析中,将乳腺癌特异性生存(BCSS)、总生存(OS)和卵巢癌无进展生存(PFS)用作临床终点。CAAI阳性的乳腺癌(43%)死亡率更高:BCSS的风险比(HR)为1.94(95%CI,1.62 - 2.32),OS的风险比为1.49(95%CI,1.30 - 1.71)。在多变量模型中,将70基因和21基因预测指标的表现与CAAI进行了比较,CAAI具有独立显著性,ER +疾病的Cox调整后HR为1.56(95%CI,1.23 - 1.99),ER -疾病的Cox调整后HR为1.55(95%CI,1.11 - 2.18)。在ER -亚组中,没有基于表达的预测指标具有预后价值。我们发现,一个包含CAAI和两个基于表达的预后特征的模型优于一个包含21基因和70基因特征但不包括CAAI的模型。将CAAI纳入临床预后工具PREDICT显著提高了其性能。CAAI阳性的卵巢癌(52%)预后也较差:PFS的HR为1.3(95%CI,1.1 - 1.7),OS的HR为1.3(95%CI,1.1 - 1.6)。本研究验证了CAAI作为ER +和ER -乳腺癌生存的独立预测指标,并揭示了CAAI在高级别浆液性卵巢癌中的显著预后价值。