Explore the vast range of titles available.

From a clinical, morphological and molecular perspective, prostate cancer is a heterogeneous disease. Primary prostate cancers are often multifocal, having topographically and morphologically distinct tumour foci. Sequencing studies have revealed that individual tumour foci can arise as clonally distinct lesions with no shared driver gene alterations. This finding demonstrates that multiple genomically and phenotypically distinct primary prostate cancers can be present in an individual patient. Lethal metastatic prostate cancer seems to arise from a single clone in the primary tumour but can exhibit subclonal heterogeneity at the genomic, epigenetic and phenotypic levels. Collectively, this complex heterogeneous constellation of molecular alterations poses obstacles for the diagnosis and treatment of prostate cancer. However, advances in our understanding of intra-tumoural heterogeneity and the development of novel technologies will allow us to navigate these challenges, refine approaches for translational research and ultimately improve patient care.This Review summarizes the manifestations of inter-tumoural and intra-tumoural heterogeneity in primary and metastatic prostate cancer, emphasizing the contribution of genomics studies and discussing the importance of phenotypic changes. The authors also critically discuss the implications for clinical management and research.

الفصل الأول عبارة عن مراجعة كاملة لاقل عدد من تعريفات وطرق المتجهات اللازمة لباقى الكتاب. وتطبيقات هذا الفصل التمهيدى عمل بها خلال هذا الكتاب أعطيت بعض الحلول بإستخام الحاسوب الألى ولكن أغلب المسائل يمكن حلها بالطرق الأخرى. موضوعات الفصول تناظر المادة التى تغطى فى مقررات الميكانيكا التمهيدية القياسية. كل فصل يبدأ بالنص على التعاريف والمبادئ والنظريات وثيقة الصلة بالموضوعات. ويتلو هذا النص مجموعات المسائل المحلولة والإضافية. المسائل المحلولة تخدم تصوير وإيضاح النظرية وتقديم طرق التحليل وعرض الأمثلة العملية ونضع أمام الطالب وبوضوح هذه النقط الدقيقة التى تمكنه من تطبيق المبادئ الأساسية بطريقة صحيحة ومؤكدة. وضعت فى المسائل المحلولة العديد من الإثباتات للنظريات و إستنتاجات المقادير. المسائل الإضافية العديدة تخدم كمراجعة كاملة للموضوعات المغطاة فى كل فصل.

Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.

Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.

Key Points Prostate cancer is the most common form of non-skin cancer in men in developed countries. The cause(s) of prostate cancer have not yet been clarified. Although heritable factors are implicated, immigration studies indicate that environmental exposures are also important. Chronic infection and inflammation cause cancer in several organs including the stomach, liver and large intestine. Data from histopathological, molecular histopathological, epidemiological and genetic epidemiological studies show that chronic inflammation might also be important in prostate carcinogenesis. The source of intraprostatic inflammation is often unknown, but might be caused by infection (for example, with sexually transmitted agents), cell injury (owing to exposure to chemical and physical trauma from urine reflux and prostatic calculi formation), hormonal variations and/or exposures, or dietary factors such as charred meats. The resultant epithelial cellular injury might cause a loss of tolerance to normal prostatic antigens, resulting in a self-perpetuating autoimmune reaction. Exposures to infectious agents and dietary carcinogens are postulated to directly injure the prostate epithelium, resulting in the histological lesions known as proliferative inflammatory atrophy (PIA), or proliferative atrophy. These lesions are postulated to be a manifestation of the 'field effect' caused by environmental exposures. Despite a strong genetic component to prostate cancer risk, no highly penetrant hereditary prostate cancer genes have been uncovered to date. Although complex, genetic variation in inflammatory genes is associated with prostate cancer risk. Several challenges remain regarding the inflammation hypothesis in prostate cancer, including the determination of the cause(s) of chronic inflammation in the prostate, an understanding of the cellular and molecular biology of the immune response in the prostate, whether inflammatory cells are truly causative in the process, and the determination of the target cell types within the proposed precursor lesions of prostate cancer. The refinement and application of new epidemiological approaches, including high-throughput genetic epidemiology, improved rodent models of prostate inflammation and cancer, and advances in the application of molecular techniques to histopathological studies should provide insights into the cause of prostate inflammation and its relevance to prostate carcinogenesis. Recent evidence indicates that both endogenous and environmental factors induce prostate inflammatory lesions that are proposed to increase the risk of cancer development. This Review explores different approaches aimed at clarifying whether inflammation drives prostate cancer and could be used to develop new prevention strategies. About 20% of all human cancers are caused by chronic infection or chronic inflammatory states. Recently, a new hypothesis has been proposed for prostate carcinogenesis. It proposes that exposure to environmental factors such as infectious agents and dietary carcinogens, and hormonal imbalances lead to injury of the prostate and to the development of chronic inflammation and regenerative 'risk factor' lesions, referred to as proliferative inflammatory atrophy (PIA). By developing new experimental animal models coupled with classical epidemiological studies, genetic epidemiological studies and molecular pathological approaches, we should be able to determine whether prostate cancer is driven by inflammation, and if so, to develop new strategies to prevent the disease.

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis. Studies of inherited susceptibility highlight the contributions of genes involved in prostate cell and tissue repair (BRCA1/2, ATM) and regeneration (HOXB13 and MYC). Social determinants of health appear to accentuate these genetic influences by fueling prostate inflammation and associated cell and genome damage. Molecular characterization of the prostate cancers that arise in Black versus White men further implicates this inflammatory microenvironment in disease behavior. Yet, when Black and White men with similar grade and stage of prostate cancer are treated equally, they exhibit equivalent outcomes. The central role of prostate inflammation in prostate cancer development and progression augments the impact of the social determinants of health on disease pathogenesis. And, when coupled with poorer access to high-quality treatment, these inequities result in a disparate burden of prostate cancer on African American men.

Epigenetic modification of DNA by cytosine methylation to produce 5-methylcytosine (5mC) has become well-recognized as an important epigenetic process in human health and disease. Recently, further modification of 5mC by the ten eleven translocated (TET) family of enzymes to produce 5-hydroxymethylcytosine (5hmC) has been described. In the present study, we used immunohistochemistry to evaluate the distribution of 5hmC in human brain during different periods of development and in a large series of gliomas (n=225). We found that during development, 5hmC levels are high in more differentiated compartments like the fetal cortex, but low in the periventricular progenitor cell regions. In adults, we found 5hmC levels to be highest in the cortex, but present in all intrinsic cell types in the brain including stromal elements. In brain tumors, 5hmC levels were high in low grade tumors and reduced in malignant glioma, but did not exhibit any correlation with IDH1 mutation status. Additionally, we identified a significant relationship between low levels of 5hmC and reduced survival in malignant glioma. This observation was further supported by in silico analysis showing differential expression of genes involved in 5hmC homeostasis in aggressive subsets of glioblastoma. Finally, we show that several genes involved in regulating the levels of 5hmC are also prognostic in malignant glioma. These findings suggest that 5hmC regulation in malignant glioma may represent an important determinant of tumor differentiation and aggressive behavior, as well as a potential therapeutic target.

Primary prostate cancer is genomically highly heterogeneous and is thought to derive from multiple independent clones of cancer cells. Using high-resolution genomic analyses, Bova et al . now show that, in contrast to primary tumors, metastases are monoclonal, originating from a single cancer cell. These findings call into question current views of the origins of primary prostate cancer and suggest that the genomic profile of prostate cancer metastases should inform therapeutic decisions. Many studies have shown that primary prostate cancers are multifocal 1 , 2 , 3 and are composed of multiple genetically distinct cancer cell clones 4 , 5 , 6 . Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis 7 and recent single-locus genetic data in prostate and other metastatic cancers 8 , 9 , 10 , these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer. Alterations in the tumour microenvironment (TME) can contribute to prostate cancer progression, but it is unclear how tumours mediate those changes. Here, analysis of human prostate cancer tissues and key stages of prostate cancer progression in a genetically engineered mouse model using single-cell RNA-sequencing reveals the central role of MYC signalling in reprogramming the TME.