Multidiciplinary Integrative Genomic Approach to Distinguish Lethal from Indolent Prostate Cancer in Men of Europena and African Ancestry

多学科综合基因组方法区分欧洲和非洲血统男性的致命性前列腺癌和惰性前列腺癌

• 批准号: 10253255
• 负责人: ANGELO Michael DE MARZO
• 金额: $ 64.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10253255
• 关键词: Address; Advocate; African; African American; Aging; Algorithms; American; Architecture; Automobile Driving; Autopsy; Baltimore; Bioinformatics; Biological Markers; Biometry; Biopsy; Cancer Etiology; Cancer Patient; Categories; Cessation of life; Clinical; Clinical Management; Collaborations; Collection; Coupled; DNA Methylation; DNA Sequence Rearrangement; DNA sequencing; Data Analyses; Data Set; Databases; Development; Diagnosis; Disease; Epidemiology; Equilibrium; Expression Profiling; Follow-Up Studies; Freezing; Frequencies; Genomic approach; Genomics; Gleason Grade for Prostate Cancer; Health; Health Professional; Immunohistochemistry; In Situ; In Situ Hybridization; Individual; Indolent; Intervention; Kinetics; Lesion; Localized Malignant Neoplasm; Longitudinal Studies; Longterm Follow-up; Malignant Neoplasms; Malignant neoplasm of prostate; Medical Oncology; Messenger RNA; Methods; Modernization; Molecular; Molecular Biology; Molecular Profiling; Monitor; Mutation; Nature; Neoplasm Metastasis; Nomograms; Organ; Outcome; PSA screening; Pathologic; Pathology; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phase; Phenotype; Physicians; Population; Progressive Disease; Prostate Adenocarcinoma; Race; Radical Prostatectomy; Recurrence; Research Personnel; Resources; Risk; Risk stratification; Screening for Prostate Cancer; Sum; Technology; Testing; Therapeutic Intervention; Urology; Validation; Variant; Visceral; Work; base; biobank; cancer therapy; caucasian American; cell type; cohort; computer science; design; epigenomics; exome sequencing; experience; genome sequencing; genome-wide; improved; interdisciplinary approach; men; minimally invasive; mortality; multidisciplinary; multimodality; neoplastic cell; next generation; novel; novel marker; outcome forecast; outcome prediction; overtreatment; predictive signature; prostate cancer risk; public health relevance; racial disparity; screening; tool; transcriptome sequencing; treatment strategy; tumor; unnecessary treatment; whole genome

 DESCRIPTION (provided by applicant): There are several critical unmet needs in the management of localized prostate cancer. Central among them is the development of minimally invasive tools to distinguish localized cancers that are truly indolent from cancers that are progressive and potentially lethal. To address this key need, we first propose to perform an integrated, multi-dimensional genomic, epigenomic and expression analysis to uncover novel molecular pathways that characterize indolent vs. aggressive prostate cancers. In this approach we define indolent tumors as those screen detected (e.g. PSA screening) lesions that are Gleason score 6 (or less) that are organ confined at radical prostatectomy. We consider these tumors indolent as they do not appear capable of metastasis. In contrast, we equate Gleason score 8-10 tumors as "interval" or symptomatic since, even with primary treatment, these tumors often recur and metastasize at high frequencies. Additionally, we will validate our key markers/pathways discovered in this project using additional populations with long term outcomes. We hypothesize that our multi-modality genomic-based integrated approach, contrasting these two divergent tumor types, will reveal signatures that distinguish cancers with dichotomous phenotypes. We also hypothesize that these signatures will vary based on race and thus in parallel we will comprehensively characterize African American prostate cancers to reveal molecular features driving racial disparities in outcomes. We will validate the signatures obtained using large cohorts of cases with established outcomes including: (1) the Johns Hopkins Active surveillance cohort and (2) Prostate cancer cases from the BLSA (Baltimore Longitudinal Study of Aging), an observational cohort of men followed since 1954 with autopsy documented indolent or aggressive/lethal disease. We also propose that these signatures will be able to predict outcomes of cancers with indeterminate kinetics and propose to test this through analysis of cases of intermediate risk prostate cancer with long-term follow-up and known outcomes from Johns Hopkins and in collaboration with colleagues from Harvard, from the Physician's Health and Health Professionals follow-up studies. Together this work will yield highly relevant information that can be directly applied to the clinical management of localized prostate cancer. Specifically, it will yield an integrated signature that distinguishes localized - indolent tumors from localized tumors with lethal potential. Additionally we believe these signatures will be critical in determining treatment strategies for individuals with prostate cancers of indeterminate kinetics.

 描述（由适用提供）：在局部前列腺癌的管理中有几种关键的未满足需求。其中的核心是开发微创工具的开发，以区分局部癌症，这些癌症与癌症的癌症确实是渐进的癌症。为了满足这一关键需求，我们首先建议执行综合的，多维的基因组，表观基因组和表达分析，以揭示表征纯种与侵略性前列腺癌的新型分子途径。在这种方法中，我们将无源肿瘤定义为在根治性前列腺切除术时组织的筛查（例如PSA筛选）课程（例如PSA筛选）课程。我们认为这些肿瘤是不可转移的，因为它们似乎无法转移。相比之下，我们等于8-10肿瘤的格里森评分与“间隔”或症状，因为即使在初级治疗中，这些肿瘤也经常在高频下复发并转移。此外，我们将使用具有长期成果的其他人群来验证该项目中发现的关键标记/途径。我们假设我们的多模式基于基因组的综合方法与这两种不同的肿瘤类型对比，将揭示具有区分二分法表型癌症的特征。我们还假设这些签名将根据种族而有所不同，因此，我们将全面地表征非裔美国人前列腺癌，以揭示分子特征在结果中推动赛车分布。我们将验证使用大量案例获得的签名，其中包括：（1）约翰·霍普金斯（Johns Hopkins）积极的监视队列和（2）（2）来自BLSA的前列腺癌病例（巴尔的摩的衰老纵向研究），自1954年以来的观察性人群，自动疾病以来，患有自动化的人，患有自动化的疾病/lentopalive/lethealive/letheal comperiality/letheal comperiality/letheal。我们还建议这些签名将能够预测具有不确定动力学的癌症的结果，并提出了通过分析中间风险前列腺癌病例来测试这一点，并具有长期的随访和约翰·霍普金斯（Johns Hopkins）的长期随访和已知结果，并与Harvard的同事合作，来自医生的健康和健康专业人士的研究。这项工作将共同产生高度相关的信息，可以直接应用于局部前列腺癌的临床管理。具体而言，它将产生一个综合签名，以区分本地化 - 来自具有致命潜力的局部肿瘤的懒惰肿瘤。此外，我们认为这些签名对于确定不确定动力学癌症患者的治疗策略至关重要。

项目成果

Transcriptional landscape of PTEN loss in primary prostate cancer.

• DOI: 10.1186/s12885-021-08593-y
• 发表时间: 2021-07-26
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Imada EL;Sanchez DF;Dinalankara W;Vidotto T;Ebot EM;Tyekucheva S;Franco GR;Mucci LA;Loda M;Schaeffer EM;Lotan T;Marchionni L
• 通讯作者: Marchionni L

Contemporary Incidence and Outcomes of Prostate Cancer Lymph Node Metastases.

• DOI: 10.1016/j.juro.2017.12.048
• 发表时间: 2018-06
• 期刊: The Journal of urology
• 作者: Bernstein AN;Shoag JE;Golan R;Halpern JA;Schaeffer EM;Hsu WC;Nguyen PL;Sedrakyan A;Chen RC;Eggener SE;Hu JC
• 通讯作者: Hu JC

Correlation of B7-H3 with androgen receptor, immune pathways and poor outcome in prostate cancer: an expression-based analysis.

• DOI: 10.1038/pcan.2016.49
• 发表时间: 2017-03
• 期刊: Prostate cancer and prostatic diseases
• 影响因子: 4.8
• 作者: Benzon B;Zhao SG;Haffner MC;Takhar M;Erho N;Yousefi K;Hurley P;Bishop JL;Tosoian J;Ghabili K;Alshalalfa M;Glavaris S;Simons BW;Tran P;Davicioni E;Karnes RJ;Boudadi K;Antonarakis ES;Schaeffer EM;Drake CG;Feng F;Ross AE
• 通讯作者: Ross AE

Risk of Pathological Upgrading and Up Staging among Men with Low Risk Prostate Cancer Varies by Race: Results from the National Cancer Database.

• DOI: 10.1016/j.juro.2016.08.095
• 发表时间: 2017-03
• 期刊: The Journal of urology
• 作者: Maurice MJ;Sundi D;Schaeffer EM;Abouassaly R
• 通讯作者: Abouassaly R

Use of the Prostate Health Index for detection of prostate cancer: results from a large academic practice.

• DOI: 10.1038/pcan.2016.72
• 发表时间: 2017-06
• 期刊: Prostate cancer and prostatic diseases
• 影响因子: 4.8
• 作者: Tosoian JJ;Druskin SC;Andreas D;Mullane P;Chappidi M;Joo S;Ghabili K;Agostino J;Macura KJ;Carter HB;Schaeffer EM;Partin AW;Sokoll LJ;Ross AE
• 通讯作者: Ross AE