Sanders J Alexa, Frasier Connor, Matulay Justin T, Steuerwald Nury M, Zhu Jason, Grigg Claud M, Kearns James T, Riggs Stephen B, Gaston Kris E, Brouwer Cory R, Burks R Tucker, Hartman Aaron L, Foureau David M, Burgess Earle F, Clark Peter E
Department of Bioinformatics & Genomics, University of North Carolina at Charlotte, Charlotte, NC, USA.
Bioinformatics Services Division, University of North Carolina at Charlotte, Kannapolis, NC, USA.
Transl Androl Urol. 2021 Jul;10(7):2998-3009. doi: 10.21037/tau-21-158.
Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes.
Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Baseline tumor samples were subjected to targeted DNA sequencing and whole-exome RNAseq. Genomic variants differing significantly between response groups were analyzed using Ingenuity Pathway Analysis (IPA) software. Variant selection was refined to target potential biomarker candidates for responsiveness to BCG.
Among 42 patients, the median follow-up was 51.7 months and 40.5% (n=17) were durable BCG responders. Deleterious mutations in the RNA sequence of , , , and were more common in non-durable responders. Mutations in and detected on targeted sequencing were more commonly found in durable responders. Of all deleterious DNA and RNA mutations identified, only was significantly associated with longer recurrence free survival (RFS) (P=0.031).
Differences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here, namely , are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.
膀胱内卡介苗（BCG）治疗是高危非肌层浸润性膀胱癌（NMIBC）的标准治疗方法，但总体疗效较低，目前尚无可靠的预测生物标志物来优化患者选择。我们对高级别（HG）T1期NMIBC进行了基因组分析，以确定某些突变和/或表达变化是否能预测治疗反应。
接受诱导性BCG治疗的HG T1期NMIBC患者按反应分为持久反应者和非持久反应者。对基线肿瘤样本进行靶向DNA测序和全外显子RNA测序。使用 Ingenuity Pathway Analysis（IPA）软件分析反应组之间有显著差异的基因组变异。对变异选择进行优化，以靶向BCG反应性的潜在生物标志物候选物。
在42例患者中，中位随访时间为51.7个月，40.5%（n = 17）为持久BCG反应者。在非持久反应者中，、、和的RNA序列中的有害突变更为常见。在靶向测序中检测到的和的突变在持久反应者中更常见。在所有鉴定出的有害DNA和RNA突变中，只有与更长的无复发生存期（RFS）显著相关（P = 0.031）。
对BCG显示持久反应的HG T1期NMIBC肿瘤与未显示持久反应的肿瘤之间存在基因组图谱差异。通过通路分析，这些差异表明反应者中几种相互关联的炎症通路上调。此处鉴定出的特定变异，即，是进一步研究的候选物，如果经过临床验证，未来可能作为有用的生物标志物。
