Prostate Carcinoma

Prostate carcinoma, commonly known as prostate cancer, is a prevalent malignancy affecting the prostate gland, a small organ located below the bladder in men. It is one of the most frequently diagnosed cancers and a leading cause of cancer-related death in men worldwide, making it a significant public health challenge.

The biological basis of prostate carcinoma involves the uncontrolled growth and division of cells within the prostate gland. This complex process is influenced by a combination of genetic predisposition, hormonal factors, and environmental exposures. Extensive research, particularly through genome-wide association studies (GWAS), has identified numerous genetic variants and specific susceptibility loci associated with an increased risk of developing prostate carcinoma. For instance, studies have pinpointed risk-associated sequence variants at 22q13, and common variants on 2p15 and Xp11.22 have been shown to confer susceptibility. Additionally, a number of novel prostate cancer predisposition loci have been identified through large-scale international collaborations^[1]. These genetic discoveries are crucial for understanding the inherited component of prostate cancer risk and the molecular pathways involved in its development.

Clinically, prostate carcinoma presents a wide spectrum, from slow-growing, indolent tumors that may never cause significant health issues to aggressive, fast-spreading metastatic disease. Early detection often relies on screening methods such as the prostate-specific antigen (PSA) blood test and digital rectal examination, with a prostate biopsy confirming the diagnosis. Treatment strategies are highly individualized, depending on the cancer’s stage, grade, and the patient’s overall health, and may include active surveillance, surgery (prostatectomy), radiation therapy, hormone therapy, chemotherapy, or targeted therapies.

The social importance of prostate carcinoma is profound. Its high prevalence means it impacts the lives of millions of men globally, affecting not only their physical health but also their emotional well-being and the dynamics of their families and communities. The ongoing efforts in research, from uncovering genetic predispositions to developing more effective diagnostic tools and treatments, are vital for improving patient outcomes, enhancing quality of life, and ultimately reducing the global burden of this disease.

Limitations

Understanding the full scope of prostate cancer risk and its underlying biological mechanisms faces several limitations, despite significant progress in genetic research. These challenges stem from the inherent complexity of the disease, the design of current studies, and the interpretative hurdles in translating genetic findings into clinical insight.

Incomplete Genetic Architecture and Missing Heritability

Despite the identification and consistent replication of numerous prostate cancer risk variants through genome-wide association studies, these genetic markers collectively explain only a small fraction of the total genetic variance associated with prostate cancer risk^[1]. For example, specific highly significant single nucleotide polymorphisms at 17q12 were estimated to account for less than 1% of the genetic variance in a Swedish population^[1]. This “missing heritability” highlights a substantial gap in understanding the complete genetic architecture of the disease, suggesting that many other genetic factors, including rarer variants or complex interactions, remain undiscovered.

Furthermore, many of the identified risk variants are situated in intergenic regions or within genes not previously implicated as important in prostate carcinogenesis ^[1]. While these findings offer novel avenues for exploring disease etiology, their precise functional mechanisms and contribution to molecular pathways in prostate cancer are largely unknown. This lack of clear functional annotation limits the immediate utility of these variants for enhanced prediction, earlier detection, or a comprehensive understanding of the disease’s underlying biological processes, pointing to ongoing knowledge gaps in molecular mechanisms^[1].

Methodological and Interpretative Challenges

Current genome-wide association studies, while powerful, face inherent methodological limitations that can constrain the full identification of prostate cancer susceptibility loci. The scope of these studies is often limited by available sample sizes and the breadth of single nucleotide polymorphism (SNP) coverage, suggesting that further large-scale meta-analyses and replication efforts are necessary to uncover additional risk variants^[2]. Moreover, the use of stringent statistical thresholds for genome-wide significance, while crucial for minimizing false positives, may inadvertently lead to overlooking variants with smaller but genuine effect sizes, thereby limiting the comprehensive capture of all genetic contributions to risk ^[3].

Interpreting the functional impact of identified genetic variants presents another significant challenge. Many variants are not directly coding, and common regulatory variations can influence gene expression in a complex, cell type-dependent manner ^[4]. This complexity means that the biological mechanisms linking a risk SNP to prostate cancer development are often not immediately clear, requiring extensive follow-up functional studies. Without a deeper understanding of how these variants perturb cellular processes, their full implications for disease pathology and therapeutic targeting remain largely speculative, underscoring a critical interpretative gap in the research.

Variants

Genetic variants play a crucial role in influencing an individual’s susceptibility to prostate carcinoma, often through subtle alterations in gene function or expression. Many of these variants have been identified through genome-wide association studies (GWAS) and are found in or near genes involved in prostate development, hormone regulation, cellular proliferation, and DNA repair.

The HNF1B (HNF1 Homeobox B) gene, also known as TCF2, is a critical transcription factor essential for the proper development of various organs, including the prostate. Single nucleotide polymorphisms (SNPs) within this gene, such asrs11263763 , rs4430796 , and rs11649743 , have been consistently linked to an increased risk of prostate cancer, is a malignant growth originating within the prostate gland. Its definitive diagnosis necessitates histopathological confirmation, typically achieved through the examination of biopsy specimens^[5]. For both clinical and research purposes, specific criteria delineate the disease, classifying aggressive prostate cancer by a clinical stage of T3/T4 or a Gleason Score of 7 or higher based on the biopsy findings^[1]. Conversely, certain studies may deliberately exclude tumors with very low-grade features, such as those with Gleason scores below 5, to prioritize the investigation of more clinically significant disease manifestations^[5].

Key Variants

RS ID	Gene	Related Traits
rs72725854 rs77541621 rs7463326	PCAT1	prostate carcinoma prostate cancer response to radiation drug use measurement, prostate cancer radiation injury
rs11263763 rs4430796 rs11649743	HNF1B	endometrial endometrioid carcinoma endometrial carcinoma prostate carcinoma cancer Drugs used in diabetes use measurement
rs10993994	MSMB	prostate carcinoma prostate specific antigen amount cancer biomarker measurement protein measurement beta-microseminoprotein measurement
rs11228580 rs7130881 rs7931342	SMIM38 - MYEOV	prostate cancer prostate carcinoma family history of prostate cancer
rs60681470 rs6983561 rs76595456	PCAT1, CASC19	prostate carcinoma
rs1160267 rs4872175 rs13265330	SINHCAFP3 - NKX3-1	prostate carcinoma prostate specific antigen amount
rs72725879	CASC19, PCAT1, PRNCR1	prostate specific antigen amount prostate carcinoma prostate cancer urinary system disease
rs4646284 rs651164	SLC22A1 - SLC22A2	prostate carcinoma prostate cancer
rs62113212 rs76765083 rs17632542	KLK3	prostate carcinoma prostate specific antigen amount prostate cancer
rs1447295 rs4871798 rs1447293	CASC8	prostate carcinoma cancer

Clinical Classification and Prognostic Grading

The classification of prostate carcinoma heavily relies on the Gleason grading system, a crucial tool for assessing prognosis based on the architectural patterns of cancer cells observed in biopsy samples. A Gleason Score of 7 or higher is a common threshold used to identify aggressive forms of prostate cancer^[1], differentiating them from less aggressive cases and informing subsequent treatment strategies. This system facilitates a categorical approach to disease severity, which is vital for patient management and for defining cohorts in research, where specific grades often serve as inclusion or exclusion criteria^[5]. Beyond histological grading, prostate-specific antigen (PSA) levels are also considered in the comprehensive assessment and monitoring of prostate cancer, often in conjunction with investigations into genetic polymorphisms^[6].

Genetic Susceptibility and Research Nomenclature

Research into prostate carcinoma extensively utilizes terminology related to genetic predisposition and susceptibility to the disease. Terms such as “prostate cancer-susceptibility genes”^[1]and “prostate cancer predisposition loci”^[7]refer to specific genomic regions or genes that are associated with an elevated risk of developing prostate cancer. These genetic markers are frequently identified through genome-wide association studies (GWAS)^[3], a methodological approach that systematically scans the entire human genome for single nucleotide polymorphisms (SNPs)^[5] linked to the trait. In such studies, a stringent statistical threshold, commonly a p-value less than 5 × 10^-8, is applied to establish genome-wide significance for newly identified susceptibility loci ^[3], including those relevant to familial prostate cancer^[8].

Signs and Symptoms

Prostate carcinoma often presents with variable clinical features, with its definitive diagnosis relying heavily on pathological confirmation and detailed grading. The detection and understanding of this cancer are further influenced by patient-specific factors, such as age at diagnosis.

Pathological Confirmation and Tumor Grading

The definitive diagnosis of prostate carcinoma is established through histopathological confirmation, representing a critical objective assessment method. This process involves the microscopic examination of prostate tissue samples, providing an unequivocal identification of malignant cells^[5]. A crucial measurement approach within this diagnostic framework is the assignment of a Gleason score, which evaluates the architectural patterns and differentiation of tumor cells to quantify cancer aggressiveness. The diagnostic significance of the Gleason score is substantial, with studies frequently focusing on cases exhibiting scores of 5 or higher, as the exclusion of tumors with Gleason scores < 5 suggests these lower-grade cancers may represent less aggressive clinical phenotypes or require different management approaches^[5].

Age is a significant factor contributing to the variability and heterogeneity observed in prostate carcinoma diagnoses. Research studies frequently incorporate age-related criteria, such as including cases diagnosed specifically at less than 70 years of age, with sampling often stratified by age at diagnosis^[5]. This approach highlights age-related changes in the clinical presentation or detection patterns of the disease, suggesting that prostate carcinoma diagnosed in younger individuals may represent distinct clinical phenotypes or have different prognostic indicators compared to those diagnosed later in life. While specific age-related symptoms are not detailed, the emphasis on age in study design underscores its diagnostic significance in understanding disease patterns and potential inter-individual variation.

Causes of Prostate Carcinoma

The development of prostate carcinoma is a complex process influenced by a combination of genetic predispositions and other contributing factors. Research indicates a strong hereditary component, alongside age-related changes, in the etiology of this disease.

Genetic and Inherited Susceptibility

Prostate carcinoma risk is significantly influenced by genetic factors, with numerous inherited variants contributing to an individual’s susceptibility. Genome-wide association studies (GWAS) have been instrumental in identifying multiple prostate cancer susceptibility loci, including sequence variants at 22q13, 2p15, and Xp11.22^[1]. Further large-scale studies have confirmed these findings and pinpointed additional loci, illustrating a polygenic risk architecture where the cumulative effect of several common genetic variants can significantly impact an individual’s disease risk^[5].

Familial predisposition is a strong indicator of inherited risk, with studies employing genomewide linkage scans across numerous families to identify specific prostate cancer-susceptibility genes^[9]. Beyond individual single nucleotide polymorphisms (SNPs), the overall genetic background and potential gene-gene interactions contribute to the complex etiology of the disease. For instance, the ICAM gene region has been identified as a susceptibility locus for prostate cancer, further highlighting the multifactorial genetic landscape that underpins varying risk profiles among individuals^[10].

Age stands as a prominent, non-modifiable risk factor for prostate carcinoma, with the incidence of the disease increasing significantly in older men. Research studies frequently stratify cases by age at diagnosis, such as focusing on individuals diagnosed at less than 70 years of age, to better understand age-specific disease characteristics and progression^[5]. This demographic pattern suggests that the gradual accumulation of cellular damage, age-related hormonal changes, and alterations in the prostate microenvironment over a lifetime likely contribute to the initiation and advancement of prostate carcinoma.

Biological Background of Prostate Carcinoma

Prostate carcinoma, commonly known as prostate cancer, is a significant health concern affecting the male reproductive system. It originates in the prostate gland, a small, walnut-sized gland located below the bladder that produces seminal fluid. The development and progression of prostate cancer involve a complex interplay of genetic, molecular, and cellular changes that disrupt the normal homeostatic mechanisms within the gland. Understanding these biological underpinnings is crucial for diagnosis, prognosis, and therapeutic interventions.

Prostate Gland Biology and Homeostasis

The prostate gland undergoes precise developmental processes and maintains specific homeostatic balances throughout a man’s life. Normal prostate organogenesis, the process of its formation and development, is tightly regulated by various genes and signaling pathways. For instance, the homeobox gene Nkx3.1 plays a critical role in the normal development of the prostate gland, ensuring proper tissue structure and function ^[11]. Disruptions in these fundamental developmental programs can set the stage for cellular abnormalities and uncontrolled growth, leading to the initiation of carcinoma. The maintenance of a healthy prostate tissue environment relies on a delicate balance of cell proliferation, differentiation, and apoptosis, which, when disturbed, can contribute to disease progression.

Genetic and Epigenetic Underpinnings

Prostate carcinoma is strongly influenced by genetic factors, with numerous susceptibility loci identified through large-scale genome-wide association studies (GWAS). Research has uncovered common sequence variants in specific chromosomal regions, such as 22q13, 2p15, and Xp11.22, which confer an increased susceptibility to prostate cancer^[1]. Additionally, several new prostate cancer susceptibility loci have been identified, further highlighting the polygenic nature of the disease^[5]. These genetic variations can impact the function of genes, alter regulatory elements, and influence gene expression patterns in a cell type-dependent manner, thereby contributing to disease risk^[12].

Beyond inherited genetic variants, epigenetic modifications also play a role in prostate carcinogenesis. These changes, which include DNA methylation and histone modifications, can alter gene expression without changing the underlying DNA sequence. Genes like Nkx3.1, while crucial for normal prostate development, also exhibit altered expression or function in prostate carcinogenesis, indicating its involvement in both physiological and pathological processes^[11]. Furthermore, genes such as the prostate stem cell antigen (PSCA) gene, though studied for its association with bladder cancer susceptibility, are inherently linked to prostate cellular biology and may contribute to the tissue’s overall susceptibility to oncogenic transformation^[13].

Molecular and Cellular Dysregulation in Carcinogenesis

The transition from normal prostate cells to cancerous cells involves profound molecular and cellular dysregulation. This includes alterations in critical signaling pathways that control cell growth, survival, and differentiation. Uncontrolled cell proliferation, a hallmark of cancer, often results from disruptions in growth factor signaling cascades, leading to sustained proliferative signaling. Metabolic processes within prostate cancer cells are also frequently reprogrammed to support rapid growth and division, shifting towards increased glycolysis even in the presence of oxygen, a phenomenon known as the Warburg effect. These altered cellular functions are often driven by the cumulative effects of genetic variants and epigenetic modifications, disrupting the intricate regulatory networks that maintain cellular integrity and tissue homeostasis.

Key Biomolecules and Their Roles

A range of critical biomolecules plays pivotal roles in the development and progression of prostate carcinoma. Transcription factors, such as the Nkx3.1 homeobox protein, are essential regulatory components that control gene expression programs vital for prostate cell identity and differentiation; its dysregulation can contribute to the malignant phenotype^[11]. Hormones, particularly androgens like testosterone, are well-known drivers of prostate growth and are crucial for the development and progression of prostate cancer, acting through androgen receptors to promote cell survival and proliferation. Enzymes involved in metabolic pathways or DNA repair, and various cell surface receptors that mediate cellular communication and growth signals, are frequently altered or hyperactivated in prostate cancer cells. The identification of these key biomolecules and understanding their precise mechanisms of action provides targets for therapeutic intervention and opportunities for early detection.

Genetic Variation and Regulatory Control

Prostate carcinoma development is influenced by a complex interplay of genetic factors, with numerous susceptibility loci identified through genome-wide association studies. Variants at locations such as 22q13, 2p15, Xp11.22, and the TERT-CLPTM1L locus have been associated with increased prostate cancer risk^[1]. A key mechanism through which these genetic variations contribute to disease susceptibility involves their impact on gene expression. Common regulatory variations can alter gene expression in a cell type-dependent manner, thereby modulating the levels of proteins essential for prostate cell function and potentially leading to dysregulation^[12].

These regulatory mechanisms can involve changes in transcription factor binding, enhancer activity, or epigenetic modifications, ultimately influencing the production of specific proteins. Such modifications can lead to either an overexpression or underexpression of genes, disrupting cellular homeostasis ^[12]. For instance, variants affecting genes involved in cell cycle control or DNA repair could compromise genomic integrity, increasing the likelihood of malignant transformation. This highlights how subtle genetic differences can perturb fundamental regulatory circuits, setting the stage for disease initiation and progression.

Impact on Cellular Signaling Pathways

The genetic variations influencing gene expression can subsequently affect the activity and balance of various cellular signaling pathways critical for prostate cell growth, survival, and differentiation. While specific pathway components are not detailed, altered expression of receptors, intracellular signaling molecules, or transcription factors due to genetic predisposition would profoundly impact signal transduction ^[12]. Such dysregulation could lead to unchecked cell proliferation, reduced apoptosis, or enhanced metastatic potential, all hallmarks of cancer. Feedback loops within these pathways could also be compromised, preventing cells from responding appropriately to internal or external cues and contributing to uncontrolled growth.

For example, altered levels of proteins involved in growth factor receptor signaling could lead to constitutive activation of downstream cascades, even in the absence of external stimuli. This sustained signaling drives cellular processes that promote tumor development, such as cell cycle progression and angiogenesis. The overall effect is a disruption of normal cell communication and control, favoring cancerous characteristics.

Network Interactions and Disease Susceptibility

The identification of multiple distinct susceptibility loci for prostate cancer, often with individual modest effects, suggests a complex, systems-level integration of genetic risk factors^[14]. These numerous genetic variants likely exert their influence not in isolation, but through intricate pathway crosstalk and network interactions within the cellular machinery. The collective impact of these variations, even when individually subtle, can lead to emergent properties at the cellular or tissue level that significantly increase prostate cancer susceptibility. Such network perturbations can also involve compensatory mechanisms, where cells attempt to adapt to initial dysregulations, potentially leading to new vulnerabilities or altered disease trajectories.

Understanding these network-level interactions is crucial for comprehending the full spectrum of prostate carcinoma development, moving beyond single-gene defects to a more holistic view of disease etiology. This integrative perspective highlights that the overall risk may arise from the cumulative burden of multiple small genetic alterations affecting interconnected biological systems rather than a single dominant pathway.

Clinical Relevance

Genetic Risk Stratification and Personalized Screening

Genome-wide association studies (GWAS) have significantly advanced the understanding of prostate carcinoma etiology by identifying numerous common sequence variants that confer susceptibility to the disease^[1]. These discoveries, including variants on chromosomes 22q13, 2p15, Xp11.22, and other loci, provide crucial tools for refining individual risk assessment ^[1]. Clinically, this allows for the identification of individuals at higher genetic risk, enabling more personalized and targeted screening strategies rather than a uniform approach. Such stratification can optimize screening intervals and initiation ages, potentially reducing overdiagnosis in low-risk groups while ensuring timely detection in those most likely to benefit from early intervention.

Integrating these genetic markers into risk prediction models can enhance the accuracy of distinguishing individuals with varying propensities for prostate carcinoma development. This personalized medicine approach holds promise for improving the efficiency and effectiveness of screening programs, guiding preventive discussions, and informing lifestyle modifications for high-risk populations. The identification of these susceptibility loci, confirmed by large international consortia, underscores their clinical utility in moving towards more precise prevention and diagnostic pathways^[5].

Prognostic Assessment and Treatment Optimization

Beyond initial risk assessment, the understanding of genetic susceptibility for prostate carcinoma can contribute to prognostic evaluation and guide therapeutic decisions. While the identified genetic variants primarily indicate risk of developing the disease, they may also correlate with specific disease characteristics, such as aggressiveness or likelihood of progression^[5]. Such insights could inform clinicians about the potential trajectory of an individual’s prostate cancer, helping to differentiate indolent from aggressive forms.

This genetic information could further aid in optimizing treatment selection, allowing for more tailored interventions based on an individual’s unique genetic profile and predicted disease course. For example, patients with certain genetic predispositions might respond differently to active surveillance versus radical treatment, or to specific chemotherapy regimens. Leveraging these genetic markers could lead to more effective long-term management strategies, ultimately improving patient outcomes and minimizing treatment-related morbidities.

Refining Monitoring Strategies and Understanding Disease Associations

The identification of genetic susceptibility loci for prostate carcinoma has significant implications for refining long-term monitoring strategies for affected individuals and those at high risk. For patients diagnosed with prostate carcinoma, understanding their genetic profile could enable more targeted surveillance protocols, allowing for closer follow-up in those with variants associated with more aggressive disease or higher recurrence risk. This approach ensures resources are allocated effectively and interventions are timely, impacting long-term implications for patient care.

Furthermore, research identifying genetic variations in genes such as the prostate stem cell antigen (PSCA) gene, which confers susceptibility to urinary bladder cancer, highlights the potential for overlapping genetic factors influencing different urological malignancies^[13]. While the direct role of PSCA variants in prostate cancer risk is a distinct area of study, such findings suggest a broader genetic landscape where specific variants might contribute to a predisposition for multiple related conditions. This understanding encourages a holistic view of patient risk and disease associations, potentially guiding comprehensive monitoring for individuals with genetic predispositions to multiple genitourinary cancers.

Frequently Asked Questions About Prostate Carcinoma

These questions address the most important and specific aspects of prostate carcinoma based on current genetic research.

1. My dad had prostate cancer; does that mean I’ll definitely get it too?

Not definitely, but a family history does mean you have an increased genetic predisposition. Research has identified several genetic variants associated with higher prostate cancer risk, and these can be passed down. However, many factors influence the disease, and genetics only explain a portion of the overall risk.

2. Is a DNA test truly helpful for understanding my personal prostate cancer risk?

Genetic discoveries are crucial for understanding the inherited component of prostate cancer risk. However, current identified genetic markers collectively explain only a small fraction of the total genetic risk, and the functional impact of many variants isn’t fully understood. So, while a test can offer some insight, it won’t give a complete picture of your individual risk.

3. Can I really overcome my family’s prostate cancer history by being very healthy?

Your lifestyle and environmental exposures do play a role alongside your genetic predisposition. Prostate carcinoma is influenced by a combination of genetic factors, hormonal factors, and environmental exposures. While a family history increases your risk due to shared genetics, these other factors also contribute to the complex development of the disease.

4. My brother has prostate cancer, but I don’t. Why would our risks be different?

Even with shared family genetics, individual risk varies significantly. While some genetic variants increase susceptibility, environmental factors and other undiscovered genetic influences or complex interactions play a role. Not everyone with a genetic predisposition develops the disease, highlighting the personalized nature of risk.

5. Is it true that scientists still don’t understand most of prostate cancer’s genetic causes?

Yes, that’s largely true. Despite identifying many genetic markers, they collectively explain only a small fraction of the total genetic risk. There’s a significant “missing heritability,” meaning many other genetic factors, including rarer variants or complex interactions, are still undiscovered and their precise functional roles are largely unknown.

6. Are the genetic factors for prostate cancer mostly a mystery, even if we know some?

Yes, that’s a fair assessment. While specific risk variants at locations like 22q13, 2p15, and Xp11.22 have been identified, many are in regions whose functions are not yet clear. This means that while we know some genetic pieces, the full puzzle of how they contribute to prostate cancer development is still an ongoing area of research.

7. Will my children definitely get prostate cancer if I have a strong genetic risk?

Not definitely. While you can pass on genetic predispositions, inheritance patterns are complex. Your children would inherit a mix of your genes and their mother’s, and the specific risk variants may or may not be passed down. The overall risk is also influenced by other genetic and environmental factors they encounter throughout their lives.

8. If I know my genetic risk, can doctors use that to pick better treatments for me?

Understanding your genetic predisposition is crucial for comprehending overall risk and the molecular pathways involved in prostate cancer development. However, the immediate utility of currently identified risk variants for enhanced prediction or more targeted treatment is limited because their precise functional mechanisms are often unknown. This is an active area of research for future therapies.

9. Why do some prostate cancers grow so slowly, and others spread fast? Is it genetic?

Prostate cancer does indeed show a wide spectrum, from very slow-growing, indolent tumors to aggressive, fast-spreading disease. While genetics are known to influence your overall risk of developing the disease, the specific genetic factors that determinewhy one tumor is aggressive and another is indolent are complex and an ongoing area of research.

10. Does my daily diet or exercise really matter if my family has a history of prostate cancer?

Yes, your daily habits and environmental exposures do matter. Prostate carcinoma is influenced by a combination of genetic predisposition, hormonal factors, and environmental exposures. While genetics are a significant component, these other factors also contribute to the complex process of disease development, making a healthy lifestyle important.

This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[6] Severi, G, et al. “ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer.”J Natl Cancer Inst. 2003;95:818–824.

[7] Kote-Jarai, Z, et al. “Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium.”Cancer Epidemiol Biomarkers Prev. 2008;17:2052–2061.

[8] Johanneson, B, et al. “Fine mapping of familial prostate cancer families narrows the interval for a susceptibility locus on chromosome 22q12.3 to 1.36 Mb.”Hum Genet. 2008;123:65–75.

[9] Murabito, Joanne M., et al. “A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics.”American Journal of Human Genetics, 2005.

[10] Kammerer, S., et al. “Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus.”Cancer Research, 2004.

[11] Bate-Shen C, Shen MM, Gelmann E. “Integrating differentiation and cancer: the Nkx3.1 homeobox gene in prostate organogenesis and carcinogenesis.”Differentiation, 2008.

[12] Li Y, et al. “Common regulatory variation impacts gene expression in a cell type-dependent manner.” Science, 2009.

[13] Wu X, et al. “Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer.”Nat Genet, 2009.

[14] Gudmundsson J et al. “Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.”Nat Genet, vol. 41, no. 11, 2009, pp. 1122-1126.