Fortunato Angelo, Mallo Diego, Cisneros Luis, King Lorraine M, Khan Aziz, Curtis Christina, Ryser Marc D, Lo Joseph Y, Hall Allison, Marks Jeffrey R, Hwang E Shelley, Maley Carlo C
Arizona Cancer Evolution Center and Biodesign Center for Biocomputing, Security and Society, Arizona State University, 727 E. Tyler St., Tempe, AZ 85281, USA.
School of Life Sciences, Arizona State University, 427 East Tyler Mall, Tempe, AZ 85287, USA.
medRxiv. 2024 Aug 16:2024.08.15.24311949. doi: 10.1101/2024.08.15.24311949.
Progression from pre-cancers like ductal carcinoma (DCIS) to invasive disease (cancer) is driven by somatic evolution and is altered by clinical interventions. We hypothesized that genetic and/or phenotypic intra-tumor heterogeneity would predict clinical outcomes for DCIS since it serves as the substrate for natural selection among cells. We profiled two samples from two geographically distinct foci from each DCIS in both cross-sectional (N = 119) and longitudinal cohorts (N = 224), with whole exome sequencing, low-pass whole genome sequencing, and a panel of immunohistochemical markers. In the longitudinal cohorts, the only statistically significant predictors of time to non-invasive DCIS recurrence were the combination of treatment (lumpectomy only vs mastectomy or lumpectomy with radiation, HR = 12.13, = 0.003, Wald test with FDR correction), ER status (HR = 0.16 for ER+ compared to ER-, = 0.0045), and divergence in SNVs between the two samples (HR = 1.33 per 10% divergence, = 0.018). SNV divergence also distinguished between pure DCIS and DCIS synchronous with invasive disease in the cross-sectional cohort. In contrast, the only statistically significant predictors of time to progression to invasive disease were the combination of the width of the surgical margin (HR = 0.67 per mm, = 0.043) and the number of mutations that were detectable at high allele frequencies (HR = 1.30 per 10 SNVs, = 0.02). These results imply that recurrence with DCIS is a clinical and biological process different from invasive progression.
从导管原位癌（DCIS）等癌前病变发展为浸润性疾病（癌症）是由体细胞进化驱动的，并会因临床干预而改变。我们假设，肿瘤内的遗传和/或表型异质性可以预测DCIS的临床结果，因为它是细胞间自然选择的基础。我们通过全外显子测序、低深度全基因组测序以及一组免疫组化标志物，对来自每个DCIS的两个地理上不同病灶的样本进行了分析，横断面队列（N = 119）和纵向队列（N = 224）均如此。在纵向队列中，非侵袭性DCIS复发时间的唯一具有统计学意义的预测因素是治疗方法的组合（仅行肿块切除术与乳房切除术或肿块切除加放疗，HR = 12.13，P = 0.003，经FDR校正的Wald检验）、雌激素受体（ER）状态（ER + 与ER - 相比，HR = 0.16，P = 0.0045）以及两个样本之间单核苷酸变异（SNV）的差异（每10%差异HR = 1.33，P = 0.018）。在横断面队列中，SNV差异也区分了单纯DCIS和与浸润性疾病同时存在的DCIS。相比之下，进展为浸润性疾病时间的唯一具有统计学意义的预测因素是手术切缘宽度（每毫米HR = 0.67，P = 0.043）和在高等位基因频率下可检测到的突变数量（每10个SNV HR = 1.30，P = 0.02）。这些结果表明，DCIS复发是一个与浸润性进展不同的临床和生物学过程。
