摘要:DNA甲基化和遗传改变与非裔美国男性侵袭性前列腺癌有关

S. Ramakrishnan, Xuan Peng, Qianya Qi, Q. Hu, G. Azabdaftari, E. Pop, J. Mohler, K. Attwood, Li Yan, Jianmin Wang, A. Woloszynska-Read
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To increase analytical power, we included AA (n=22) and EA (n=172) patients from The Cancer Genome Atlas (TCGA) database. We found no significant difference in the average age between EA and AA men in the RPCI cohort, but the TCGA cohort consisted of AA men who had significantly lower average and median age compared to EA men (57 and 56 vs 61 and 62; p=0.019). We assessed baseline androgen receptor (AR) protein levels in matched benign and malignant AA (n=95) and EA (n=93) radical prostatectomy tissues from RPCI using immunohistochemistry. Gleason score 4+3 were classified as low and high aggressive tumors, respectively. Results: Unsupervised hierarchical clustering of DNA methylation levels in prostate cancers revealed 9 clusters. We focused on the 2 largest clusters, Cluster 1 (n=133) and Cluster 3 (n=73). Cluster 1 consisted predominantly of low aggressive disease (p=0.00002) with lower serum prostate specific antigen (PSA) values (8.97 vs 13.35 ng/ml) compared to Cluster 3. Following this trend, AA patients, but not EA patients, in Cluster 1 had better overall (57 vs 50 months, p=0.48) and disease-free time (47 vs 22 months, p=0.01) as compared to Cluster 3. ERG (ETS-related gene) fusion-positive prostate cancer is believed to be more aggressive than fusion-negative prostate cancer due to increased ERG gene transcription. We did not observe a difference in fusion status between the two DNA methylation clusters. However, overall DNA methylation was higher in fusion-negative samples as compared to fusion-positive samples in the TCGA dataset. ERG is known to bind to and reduce PSA, a direct downstream AR target. In the TCGA dataset, AA fusion-negative patients had higher average and median preoperative PSA values (18.38, 20.15 ng/ml) as compared with AA fusion-positive (7.51, 6.70 ng/ml), EA fusion-positive (9.43, 7.00 ng/ml), and EA fusion-negative patients (11.47, 7.50 ng/ml). There was no significant difference in the AR transcript and AR protein levels between fusion-positive and -negative AA and EA men. AR protein expression in RPCI cohort tissue microarrays showed that adjacent nontumor tissues from AA men had higher percent AR positive nuclei (p Conclusions: Analysis of the RPCI and TCGA cohorts indicated that DNA methylation separated low and high aggressive prostate cancer in AA men. Further analysis will include more patients as well as identify differences in specific CpG loci between Cluster 1 and Cluster 3. Our results suggest that DNA methylation alterations can be important in patients with ERG fusion-negative disease since these prostate cancers exhibit higher levels of overall DNA methylation. Lastly, our observations of higher AR expression in adjacent nontumor tissues suggest that there are underlying genetic variations that contribute to early-onset high aggressive prostate cancer in AA men compared to EA men. Citation Format: Swathi Ramakrishnan, Xuan Peng, Qianya Qi, Qiang Hu, Gissou Azabdaftari, Elena Pop, James Mohler, Kristopher Attwood, Li Yan, Jianmin Wang, Anna Woloszynska-Read. DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. 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引用次数: 0

摘要

背景:非裔美国人(AA)男性比欧洲裔美国人(EA)男性更常被诊断为早发性侵袭性前列腺癌。AA和EA男性之间的前列腺癌健康差异归因于两组之间存在的社会经济和生物学差异。本研究的目的是探讨遗传和表观遗传改变,特别是DNA甲基化,如何促进AA男性早发性侵袭性前列腺癌。方法:我们对Roswell Park癌症研究所(RPCI)治疗的AA (n=32)和EA (n=5)男性根治性前列腺切除术标本进行450K甲基化阵列和rna测序。为了提高分析能力,我们从癌症基因组图谱(TCGA)数据库中纳入了AA (n=22)和EA (n=172)患者。我们发现在RPCI队列中EA和AA男性的平均年龄没有显著差异,但TCGA队列中AA男性的平均和中位年龄明显低于EA男性(57岁和56岁vs 61岁和62岁;p = 0.019)。我们使用免疫组化技术评估了RPCI根治性前列腺切除术后的良性和恶性AA (n=95)和EA (n=93)配对组织的基线雄激素受体(AR)蛋白水平。Gleason评分4+3分为低侵袭性肿瘤和高侵袭性肿瘤。结果:前列腺癌DNA甲基化水平的无监督分层聚类显示了9个簇。我们专注于2个最大的集群,集群1 (n=133)和集群3 (n=73)。聚类1主要由低侵袭性疾病组成(p=0.00002),与聚类3相比,血清前列腺特异性抗原(PSA)值较低(8.97 vs 13.35 ng/ml)。根据这一趋势,第1组AA患者比第3组EA患者总体上(57 vs 50个月,p=0.48)和无病时间(47 vs 22个月,p=0.01)更好。ERG (ets相关基因)融合阳性前列腺癌被认为比融合阴性前列腺癌更具侵袭性,因为ERG基因转录增加。我们没有观察到两个DNA甲基化簇之间融合状态的差异。然而,与TCGA数据集中的融合阳性样本相比,融合阴性样本的总体DNA甲基化更高。已知ERG结合并降低PSA,这是AR的直接下游靶标。在TCGA数据集中,AA融合阴性患者的平均和中位术前PSA值(18.38,20.15 ng/ml)高于AA融合阳性患者(7.51,6.70 ng/ml), EA融合阳性患者(9.43,7.00 ng/ml)和EA融合阴性患者(11.47,7.50 ng/ml)。融合阳性和阴性AA和EA男性的AR转录物和AR蛋白水平无显著差异。RPCI队列组织芯片中AR蛋白表达显示,AA男性的邻近非肿瘤组织中AR阳性核的比例更高(p)。结论:RPCI和TCGA队列分析表明,DNA甲基化区分了AA男性的低侵袭性和高侵袭性前列腺癌。进一步的分析将包括更多的患者,并确定集群1和集群3之间特定CpG位点的差异。我们的研究结果表明,DNA甲基化改变在ERG融合阴性疾病患者中可能很重要,因为这些前列腺癌表现出更高水平的总体DNA甲基化。最后,我们观察到邻近非肿瘤组织中较高的AR表达表明,与EA男性相比,AA男性中存在潜在的遗传变异,导致早发性高侵袭性前列腺癌。引用格式:Swathi Ramakrishnan, Xuan Peng, Qianya Qi, Qiang Hu, Gissou Azabdaftari, Elena Pop, James Mohler, christopher Attwood, Li Yan, Jianmin Wang, Anna Woloszynska-Read。DNA甲基化和基因改变与非裔美国男性侵袭性前列腺癌有关。见:第十届AACR会议论文集:种族/少数民族和医疗服务不足人群的癌症健康差异科学;2017年9月25-28日;亚特兰大,乔治亚州。费城(PA): AACR;癌症流行病学杂志,2018;27(7增刊):摘要nr B72。
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Abstract B72: DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men
Background: African-American (AA) men are more often diagnosed with early-onset aggressive prostate cancer than European American (EA) men. Prostate cancer health disparities between AA and EA men are attributed to socioeconomic as well as biologic differences existing between the two groups. The purpose of this study is to investigate how genetic and epigenetic alterations, specifically DNA methylation, contribute to early-onset aggressive prostate cancer in AA men. Methods: We performed 450K methylation array and RNA-sequencing on radical prostatectomy specimens from AA (n=32) and EA (n=5) men treated at Roswell Park Cancer Institute (RPCI). To increase analytical power, we included AA (n=22) and EA (n=172) patients from The Cancer Genome Atlas (TCGA) database. We found no significant difference in the average age between EA and AA men in the RPCI cohort, but the TCGA cohort consisted of AA men who had significantly lower average and median age compared to EA men (57 and 56 vs 61 and 62; p=0.019). We assessed baseline androgen receptor (AR) protein levels in matched benign and malignant AA (n=95) and EA (n=93) radical prostatectomy tissues from RPCI using immunohistochemistry. Gleason score 4+3 were classified as low and high aggressive tumors, respectively. Results: Unsupervised hierarchical clustering of DNA methylation levels in prostate cancers revealed 9 clusters. We focused on the 2 largest clusters, Cluster 1 (n=133) and Cluster 3 (n=73). Cluster 1 consisted predominantly of low aggressive disease (p=0.00002) with lower serum prostate specific antigen (PSA) values (8.97 vs 13.35 ng/ml) compared to Cluster 3. Following this trend, AA patients, but not EA patients, in Cluster 1 had better overall (57 vs 50 months, p=0.48) and disease-free time (47 vs 22 months, p=0.01) as compared to Cluster 3. ERG (ETS-related gene) fusion-positive prostate cancer is believed to be more aggressive than fusion-negative prostate cancer due to increased ERG gene transcription. We did not observe a difference in fusion status between the two DNA methylation clusters. However, overall DNA methylation was higher in fusion-negative samples as compared to fusion-positive samples in the TCGA dataset. ERG is known to bind to and reduce PSA, a direct downstream AR target. In the TCGA dataset, AA fusion-negative patients had higher average and median preoperative PSA values (18.38, 20.15 ng/ml) as compared with AA fusion-positive (7.51, 6.70 ng/ml), EA fusion-positive (9.43, 7.00 ng/ml), and EA fusion-negative patients (11.47, 7.50 ng/ml). There was no significant difference in the AR transcript and AR protein levels between fusion-positive and -negative AA and EA men. AR protein expression in RPCI cohort tissue microarrays showed that adjacent nontumor tissues from AA men had higher percent AR positive nuclei (p Conclusions: Analysis of the RPCI and TCGA cohorts indicated that DNA methylation separated low and high aggressive prostate cancer in AA men. Further analysis will include more patients as well as identify differences in specific CpG loci between Cluster 1 and Cluster 3. Our results suggest that DNA methylation alterations can be important in patients with ERG fusion-negative disease since these prostate cancers exhibit higher levels of overall DNA methylation. Lastly, our observations of higher AR expression in adjacent nontumor tissues suggest that there are underlying genetic variations that contribute to early-onset high aggressive prostate cancer in AA men compared to EA men. Citation Format: Swathi Ramakrishnan, Xuan Peng, Qianya Qi, Qiang Hu, Gissou Azabdaftari, Elena Pop, James Mohler, Kristopher Attwood, Li Yan, Jianmin Wang, Anna Woloszynska-Read. DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B72.
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Abstract B63: Race and triple-negative breast cancer: Advances in noncoding RNA research together with a systems-biology-level analysis uncover key molecular differences Abstract B72: DNA methylation and genetic alterations contribute to aggressive prostate cancer in African American men Abstract B67: Overexpression of claudin-3 tight junction protein in endometrial cancer cell lines and tumor tissues derived from African American women Abstract B71: Biologic for the treatment of CRLF2 B-cell acute lymphoblastic leukemia to reduce pediatric cancer health disparities Abstract C46: Fruit and vegetable intake and lung cancer incidence among Black women according to cigarette smoking status
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