The Mitochondrial and Autosomal Mutation Landscapes of Prostate Cancer

Background

Prostate cancer (PCa) is the most common cancer in men. PCa is strongly age associated; low death rates in surveillance cohorts call into question the widespread use of surgery, which leads to overtreatment and a reduction in quality of life. There is a great need to increase the understanding of tumor characteristics in the context of disease progression.

Objective

To perform the first multigenome investigation of PCa through analysis of both autosomal and mitochondrial DNA, and to integrate exome sequencing data, and RNA sequencing and copy-number alteration (CNA) data to investigate how various different tumor characteristics, commonly analyzed separately, are interconnected.

Design, setting, and participants

Exome sequencing was applied to 64 tumor samples from 55 PCa patients with varying stage and grade. Integrated analysis was performed on a core set of 50 tumors from which exome sequencing, CNA, and RNA sequencing data were available.

Outcome measurements and statistical analysis

Genes, mutated at a significantly higher rate relative to a genomic background, were identified. In addition, mitochondrial and autosomal mutation rates were correlated to CNAs and proliferation, assessed as a cell cycle gene expression signature.

Results and limitations

Genes not previously reported to be significantly mutated in PCa, such as cell division cycle 27 homolog (Saccharomyces cerevisiae) (CDC27), myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3), lysine (K)-specific demethylase 6A (KDM6A), and kinesin family member 5A (KIF5A) were identified. The mutation rate in the mitochondrial genome was 55 times higher than that of the autosomes. Multilevel analysis demonstrated a tight correlation between high reactive-oxygen exposure, chromosomal damage, high proliferation, and in parallel, a transition from multiclonal indolent primary PCa to monoclonal aggressive disease. As we only performed targeted sequence analysis; copy-number neutral rearrangements recently described for PCa were not accounted for.

Conclusions

The mitochondrial genome displays an elevated mutation rate compared to the autosomal chromosomes. By integrated analysis, we demonstrated that different tumor characteristics are interconnected, providing an increased understanding of PCa etiology.     

Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer

BackgroundBRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss.ObjectiveTo evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC.Design, setting, and participantsWe analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC.Outcome measurements and statistical analysisDifferences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models.Results and limitationsWe identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2–1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2–1.6; p < 0.001).ConclusionsCopy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and “CTC-only” losses. BRCA2 losses were supported by increases in genomic instability.Patient summaryCurrent testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.     

肿瘤抑制基因甲基化与胃癌

目的 探讨肿瘤抑制基因甲基化与胃癌的关系。方法 对近年来关于肿瘤抑制基因甲基化与胃癌关系的文献进行综述分析。结果 胃癌中，细胞周期调控基因、有丝分裂检测点基因、凋亡相关基因、错配修复基因、转移相关基因等多种肿瘤抑制基因发生甲基化而失活。结论 肿瘤抑制基因甲基化在胃癌的发生、发展过程中起重要作用，肿瘤抑制基因的甲基化有可能成为胃癌诊断、判断转移和评价预后的分子标记物，去甲基化干预有望成为胃癌治疗的新方法。     

Topographic genotyping of colorectal carcinoma: From a molecular carcinogenesis model to clinical relevance

Background: In recent years, as a result of refinement in molecular biology techniques, significant progress has been made in the understanding of colorectal carcinogenesis. Particular attention has been drawn to identification of genetic mutation that may predispose to colorectal carcinoma (familial syndromes) and may affect tumor behavior and prognosis (sporadic cases). Conclusions: Our method of topographic genotyping of human colonic carcinomas has shown a correlation between K-ras-2 and p53 mutations and stage- at diagnosis as well as long-term survival. Data from other investigators in this field confirm the importance of genetic analysis of human colorectal tumors. These findings are likely to impact management by allowing a more individualized therapeutic approach.     

Clinical Outcomes in Cyclin-dependent Kinase 12 Mutant Advanced Prostate Cancer

BackgroundCyclin-dependent kinase 12 (CDK12) loss occurs in 3–7% of metastatic prostate cancer patients and is characterized by a genomic instability signature, but the clinical implications of CDK12 loss are not well established.ObjectiveTo determine the clinical course of patients with CDK12 mutant advanced prostate cancer compared with other genomic subtypes.Design, setting, and participantsA retrospective analysis of data from three academic medical centers, including 317 patients with advanced prostate cancer and prior next-generation sequencing from tumor tissue (n = 172) or circulating tumor DNA (n = 145), was performed. Forty-six patients had CDK12 mutations; 34 had biallelic CDK12 loss (79%).Outcome measurements and statistical analysisPatients were stratified by mutation status (CDK12, homologous recombination deficiency [HRD; BRCA1/2 and ATM], TP53, and other cohort). The Kaplan-Meier method was used to evaluate time to event outcomes: time to development of metastatic disease, time to development of castration resistance, and time to prostate-specific antigen (PSA) progression after first-line androgen receptor pathway inhibitor (ARPI) therapy in a patient subset.Results and limitationsThe median follow-up was 66.6 mo. Patients with CDK12 mutant prostate cancer exhibited shorter time to metastasis (median = 34.9 mo, p = 0.004) and development of castration-resistant disease (median = 32.7 mo, p < 0.001), compared with other genomic subtypes, with shorter time to PSA progression on first-line ARPI treatment of metastatic castration-resistant disease (median = 3.6 mo, p = 0.0219). CDK12 mutant patients did not have overall shorter time on treatment compared with other mutation subgroups, and CDK12 status did not demonstrate statistical significance in multivariate analysis. Limitations include variable center-dependent practice patterns and heterogeneity due to combining tumor and liquid biopsy data.ConclusionsOur data suggest that advanced prostate cancers harboring CDK12 mutations display aggressive clinical behavior, underscoring the need to fully delineate the molecular and clinical characteristics, and appropriate therapeutic approaches for distinct subtypes of advanced prostate cancers.Patient summaryIn this report, we evaluate the clinical characteristics and outcomes of patients with prostate cancer and CDK12 mutation in their tumors. These patients seem to have more aggressive disease, with more high-grade Gleason ≥8 cancers and shorter time to developing metastatic cancer. Cases of advanced CDK12-mutated prostate cancer may warrant consideration of therapy intensification or combination approaches.     

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management

BackgroundClear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.ObjectiveTo comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.Design, setting, and participantsWe identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.Outcome measurements and statistical analysisNonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.Results and limitationsA higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).ConclusionsCCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.Patient summaryWe explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.     

抑癌基因P16在肺癌中的表达及意义

目的研究ｐ１６基因产物在人肺癌中的表达及其意义。方法用兔抗人ｐ１６多克隆抗体，以ＳＰ免疫组织化学方法检测肺癌组织中ｐ１６蛋白表达。结果ｐ１６在肺癌中表达阳性率为５８．５％（６２／１０６），在腺癌中的表达较鳞癌和小细胞癌高（Ｐ＜０．０５）。在鳞癌和腺癌中ｐ１６表达阳性率随着分化程度的降低而下降，高分化和低分化鳞癌之间ｐ１６阳性率有非常显著的差异（Ｐ＜０．０１）；鳞癌和腺癌中ｐ１６阳性率与有无淋巴结转移有密切关系（Ｐ＜０．０５）；与肺癌病理分期无明显关系。结论ｐ１６基因在不同类型肺癌的发生过程中作用不同，且与肺癌分化不良和有无淋巴结转移有密切关系。     

前列腺癌基因组学

前列腺癌在男性中发病率高,肿瘤晚期愈后差.目前前列腺癌生化检测指标依赖于PSA,受限于特异性,希望寻找新的生物标记物,用于检测、判断预后及指导治疗方案的选择.近来发展的前列腺癌基因组学有望成为理想的肿瘤生物标记物.     

The Influence of Prostate Volume on Prostate Cancer Detection

Objectives: The influence of prostate volume on the positive yield of the systematic sector biopsy is logical and has been demonstrated in numerous reports.Methods: Literature on prostate biopsy was reviewed and a selection of articles made. Keywords used for the Medline search included: Prostate cancer, Biopsy, Diagnosis.Results: Sextant biopsies have the highest positive biopsy rate (≤40 g) in small prostates (<20 g), whereas in large prostate (80–90 cc) it drops to 10% only.Conclusions: The present paper reviews the influence of total and peripheral zone volumes of the prostate on prostate cancer detection rates.     

Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention

ContextProstate cancer (PCa) is a leading cause of death and partially heritable. Genetic risk prediction might be useful for strategies to reduce PCa mortality through early detection and prevention.ObjectiveTo review evidence for genetic risk prediction for PCa.Evidence acquisitionA collaborative literature review was conducted using PubMed and Google Scholar. Search terms included genetic, risk, prediction, and “prostate cancer”. Articles addressing screening, early detection, or prevention were prioritized, as were studies involving diverse populations.Evidence synthesisRare pathogenic mutations (RPMs), especially in DNA damage repair genes, increase PCa risk. RPMs in BRCA2 are most clearly deleterious, conferring 2–8.6 times higher risk of PCa and a higher risk of aggressive disease. Common genetic variants can be combined into genetic risk scores (GRSs). A high GRS (top 20–25% of the population) confers two to three times higher risk of PCa than average; a very high GRS (top 1–5%) confers six to eight times higher risk. GRSs are not specific for aggressive PCa, possibly due to methodological limitations and/or a field effect of an elevated risk for both low- and high-grade PCa. It is challenging to disentangle genetics from structural racism and social determinants of health to understand PCa racial disparities. GRSs are independently associated with a lethal PCa risk after accounting for family history and race/ancestry. Healthy lifestyle might partially mitigate the risk of lethal PCa.ConclusionsGenetic risk assessment is becoming more common; implementation studies are needed to understand the implications and to avoid exacerbating healthcare disparities. Men with a high genetic risk of PCa can reasonably be encouraged to adhere to a healthy lifestyle.Patient summaryProstate cancer risk is inherited through rare mutations and through the combination of hundreds of common genetic markers. Some men with a high genetic risk (especially BRCA2 mutations) likely benefit from early screening for prostate cancer. The risk of lethal prostate cancer can be reduced through a healthy lifestyle.     

ING4基因与肿瘤研究新进展

ING4基因是肿瘤抑制因子家族的新成员,近来研究发现,ING基因在正常组织中表达丰富,但在多种恶性肿瘤组织,如乳腺癌、胶质瘤、肺癌等中表达明显下调,ING4可通过增强p53基因的活性、恢复细胞间接触抑制、抑制肿瘤血管生成、抑制HIF的活性而抑制肿瘤的生长,还能诱导细胞凋亡,增加肿瘤细胞对放化疗的敏感性,本研究对ING4基因与肿瘤研究的新进展进行综述。     

Clinical Outcome of Prostate Cancer Patients with Germline DNA Repair Mutations: Retrospective Analysis from an International Study

Background

Germline DNA damage repair gene mutation (gDDRm) is found in >10% of metastatic prostate cancer (mPC). Their prognostic and predictive impact relating to standard therapies is unclear.