Copy number aberrations using multicolour fluorescencein situhybridization (FISH) for prognostication in non-muscle-invasive bladder cancer (NIMBC)

BackgroundFinding effective prognostic signatures is of great urgency due to the high risk of recurrence and progression of bladder cancer (BC). Although a lot of genetic alterations are involved in the carcinogenesis, none of them were referred in the current risk group stratifications. In this study, we aimed to find significant copy number variations (CNVs) to predict prognosis for BC patients.MethodsCNVs with high aberration frequencies in BC were explored by array-based comparative genomic hybridization in 65 tumor samples. Candidates were validated in independent groups of BC tumor samples (n=219) and urine samples (n=123). 3D digital PCR was applied for detecting accurate gene copy numbers in BC urine. In order to explore the prognostic value of candidate CNVs, all enrolled patients were followed up for the disease-free survival (DFS). Cox proportional hazards regression analysis was performed to find the independent prognostic factors for DFS.ResultsCNVs of CEP63, FOSL2 and PAQR6 with high aberration frequencies (67.7%, 56.9% and 60.0%, respectively) were found in BC tumors. Copy numbers of CEP63, FOSL2 and PAQR6 were gained in 219 tumor samples. CNVs of CEP63 and FOSL2 were correlated with advanced tumor stage and high grade. Retrospective analysis (median follow-up time: 69 months) revealed that CNVs of CEP63 and FOSL2 were independent prognostic factors for DFS of non-muscle-invasive bladder cancer (NMIBC) patients, while CNVs of FOSL2 and PAQR6 were independent prognostic factors for DFS of muscle-invasive bladder cancer (MIBC) patients. Models for predicting DFS were constructed based on CNVs of three genes. Patients with high prognostic indexes tended to have poor DFS. Prognostic index can also help to identify those with worse outcomes among high risk NMIBC patients. Copy number gains of CEP63 and FOSL2 in urine were found to be significantly correlated with poor DFS of NMIBC patients.ConclusionsCNVs of CEP63, FOSL2 and PAQR6 were capable of predicting DFS and may serve as promising signatures for prognosis of BC.

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A genome-wide query of somatic copy number alterations to predict lymph node metastases and survival in patients with muscle-invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.325 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 325-325

Author(s):

Karla Lindquist ◽

Thomas Sanford ◽

Terence W. Friedlander ◽

Pamela Paris ◽

Sima P. Porten

Keyword(s):

Bladder Cancer ◽

Copy Number ◽

Treatment Decisions ◽

Invasive Bladder Cancer ◽

Copy Number Alterations ◽

Muscle Invasive Bladder Cancer ◽

Genome Wide ◽

A Genome ◽

Muscle Invasive ◽

One Year

325 Background: Patients with muscle-invasive bladder cancer (MIBC) have a poor prognosis if the cancer has metastasized to surrounding lymph nodes (LN). Adding tumor-based genomic tests that improve prediction of LN status and prognosis over clinical variables alone would be useful to clinicians in making treatment decisions, potentially improving outcomes for these patients. Methods: We performed a genome-wide query of copy number alterations (CNAs) in MIBC tumors from 237 patients in The Cancer Genome Atlas who had radical cystectomy and lymphadenectomy ( ≥ 10 nodes) without neoadjuvant treatment. We independently analyzed pathology reports and copy number data to confirm LN status and gene-level CNAs. Using elastic net and logistic regression models, we sought to identify a set of genes with CNAs that predict LN status. We also tested for association between CNAs and survival. Results: We identified 26 genes with CNAs that predicted LN status. Those located on chr3p25 and chr11p11 had gains associated with LN positivity after adjusting for age, gender, race, pathological tumor stage, histology, and number of nodes examined (p = 0.03). CNAs at these loci were also associated with one-year survival in the cohort overall (p < 0.01), as well as in LN-positive patients after adjusting for node stage, LN density, and extracapsular extension (p < 0.01). Conclusions: We have identified a small set of genes with CNAs in MIBC tumors that robustly predict LN status and one-year survival. A simple copy number-based test based on these genes could potentially improve preoperative LN status determination and help inform adjuvant treatment decisions to improve outcomes in MIBC patients.

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Germline DNA copy number polymorphism to predict the efficacy of BCG therapy for non-muscle invasive bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.431 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 431-431

Author(s):

Yoshiaki Yamamoto ◽

Sho Ozawa ◽

Masahiro Samoto ◽

Junichi Mori ◽

Ryo Inoue ◽

...

Keyword(s):

Bladder Cancer ◽

Copy Number ◽

Progression Free Survival ◽

Japanese Patients ◽

Intravesical Instillation ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Free Survival ◽

Bcg Therapy ◽

Muscle Invasive

431 Background: Bacillus Calmette-Guerin (BCG) intravesical instillation is the most effective immunotherapy for non-muscle-invasive bladder cancer (NMIBC), however there are few reliable markers to elucidate the efficacy of BCG therapy. Germline copy number polymorphisms (CNPs) are expected to affect various diseases including human malignancies, but the significance of CNPs in NMIBC treated with BCG therapy remains unclear. FAM81A located on 15q22.2 was reported as one of tumor-associated ETS shared target genes in prostate cancer. PCSK6 located on 15q26.3 was reported to regulate proliferation and tumor progression in several cancers. The purpose of this study is to determine the prognostic value of CNPs for NMIBC treated with BCG therapy. To our knowledge, this is the first report to confirm CNPs as a potential biomarker for assessing the efficacy of immunotherapy. Methods: Array comparative genomic hybridization (CGH) was performed to search for candidate whole genome-wide CNPs related to NMIBC susceptibility. Next, quantitative real-time polymerase chain reaction was carried out to evaluate the effect of BCG therapy for 57 Japanese patients with NMIBC treated with BCG intravesical instillation. Results: Eleven CNPs were associated with NMIBC risk in array CGH. FAM81A and PCSK6 copy number according to those CNPs examined showed significant relationship with disease progression in NMIBC treated with BCG. The means of the relative copy numbers of patients with CNP and those without it were 1.58 and 2.10 for FAM81A ( P < 0.0001), and 1.06 and 1.80 for PCSK6 ( P < 0.0001), respectively. Univariate Cox proportional hazards regression analysis showed that FAM81A ( P = 0.0022), and PCSK6 ( P = 0.0147) copy number had a significant effect on progression-free survival. In multivariate analyses, FAM81A copy number was an independent prognostic factor for progression-free survival ( P = 0.0419, RR = 7.59, 95% CI, 1.07–153.42). The combination of FAM81A or PCSK6 CNP was the most significant prognostic biomarker to predict the efficacy of BCG therapy for NMIBC ( P = 0.0002). Conclusions: Germline DNA CNPs may be a potential new biomarker for estimating the efficacy of BCG therapy in Japanese patients with NMIBC.

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