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Familial Prostate Cancer

Malignant Prostate Neoplasm

Familial prostate cancer (FPC) refers to malignancies of the prostate developing due to a genetic predisposition to this type of cancer. Although several loci related to familial clustering of prostate cancer have been identified, few mutations can directly be linked to an increased risk for the disease. They tend to interact multiplicatively, rendering the evaluation of genetic studies a tedious task. To date, FPC is generally diagnosed based on data obtained during familial anamnesis, and these same data may allow for the early identification of family members at risk. According to clinical practice guidelines, these men should start screening for prostate cancer about 5-10 years earlier than those at average risk.


Presentation

The clinical presentation of FPC doesn't differ from that of non-hereditary prostate cancer, except for the fact that FPC patients tend to be diagnosed at younger ages. The share of familial cases among patients aged <65 years is significantly higher than among older men [1]. Be that as it may, most malignancies of the prostate go unnoticed for prolonged periods of time. Although patients with symptomatic disease may claim frequent urination, dysuria, or hematuria, most cases are identified during preventive screenings. Additional complaints, including constitutional symptoms like fever, night sweats, chills, loss of appetite and weight, may not be present until advanced stages of the disease [2].

Hunting
  • Cannon L, Bishop DT, Skolnick M, Hunt S, Lyon JL, Smart CR: Genetic epidemiology of prostate cancer in the Utah Mormon Genealogy. Cancer Surveys 1:47–69, 1982 Google Scholar 12.[link.springer.com]
  • Cannon L, Bishop DT, Skolnick M, Hunt S, Lyon JL, et al. (1982) Genetic epidemiology of prostate cancer in the Utah Mormon genealogy. Cancer Surveys 1: 47–69. View Article Google Scholar 47.[journals.plos.org]
  • ., Hunt S., Lyon J. L., Smart C. R. Genetic epidemiology of prostate cancer in the Utah Morman genealogy. Cancer Surv., 1 : 47 -69, 1982. Meikle A. W., Smith J. A., West D. W.[cebp.aacrjournals.org]
  • Jones CU, Hunt D, McGowan DG, Amin MB et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. N Engl J Med . 2011 Jul 14. 365(2):107-18. [Medline] . Mulcahy N. Major Prostate Cancer Trial: Short HT Best in Middle Risk.[emedicine.medscape.com]
Constitutional Symptom
  • Additional complaints, including constitutional symptoms like fever, night sweats, chills, loss of appetite and weight, may not be present until advanced stages of the disease.[symptoma.com]
Large Breast
  • Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12–13. Am. J. Hum. Genet. , 61 : 120 -128, 1997 . Langston A. A., Stanford J. L., Wicklund K. G., Thompson J. D., Blazej R. G., Ostrander E. A.[cancerres.aacrjournals.org]
Anger
  • Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01221168 Layout table for location information Department of Urology, CHU Angers Angers, France, 49100 Principal Investigator: Abdel-Rahmene Azzouzi, MD, PhD Department of[clinicaltrials.gov]

Workup

The distinction of FPC from sporadic prostate cancer is primarily based on data obtained during familial anamnesis and, less frequently, on the results of molecular biological studies. This is due to the genetic heterogeneity of FPC and the disease' association with several genes of low penetrance, which largely complicate the evaluation of genetic tests. Accordingly, patients with an extensive family history of prostate cancer should be considered at risk, regardless of the results of screenings for mutations of determined genes. What's more, inquiries regarding the patient's family history should not be limited to cases of prostate cancer but should be extended to other types of malignancies: Certain conditions predisposing to FPC are known to trigger other diseases, too [3]. The rather common mutations of BRCA1 and BRCA2, for instance, may cause breast and ovarian cancer in female relatives [2]. More recent studies additionally suggest an association between FPC, myeloma, kidney cancer, and nervous system tumors [4].

Beyond the genetic workup to be carried out to identify the mutations underlying FPC, the actual diagnosis of the disease follows the general guidelines for the diagnosis of prostate cancer [5]:

  • Prostate-specific antigen levels alone are little conclusive. Single elevated values should be verified in a second test.
  • Digital rectal examinations are the second pillar of preventive screenings for prostate cancer.
  • Elevated prostate-specific antigen levels and/or suspicious findings in the digital rectal examination should be interpreted in the light of age, ethnicity, medical and family history, and may prompt the performance of a biopsy. Transrectal ultrasound-guided prostate biopsy is the method of choice to obtain a minimum of 10-12 specimens.
  • Histological findings may be complemented by magnetic resonance imaging of the prostate. In the case of positive results, magnetic resonance imaging may also be employed for tumor staging. Computed tomography and positron emission tomography/computed tomography may similarly be used to this end.

Treatment

There are different treatment options for localized prostate cancer. Curative treatment regimens for low-risk prostate cancer include radical prostatectomy, external beam radiotherapy, and brachytherapy. Intermediate and high-risk patients may additionally receive neoadjuvant or adjuvant androgen deprivation therapy, and the surgical intervention may include pelvic lymphadenectomy. Treatment recommendations for relapsing or metastatic disease depend on the development of prostate-specific antigen levels and symptoms, and may include salvage radiotherapy, androgen deprivation therapy, and docetaxel. In the post-docetaxel setting, abiraterone, enzalutamide, cabazitaxel, and radium-223 may constitute further alternatives [5]. Palliative chemotherapy with docetaxel or mitoxantrone and prednisone is recommended in case of metastatic prostate cancer and irresponsiveness to any of the aforementioned treatment regimens [2].

The patient should be informed that any combination of these therapies may have serious side effects and may cause sexual dysfunction, infertility, urethral strictures, urinary incontinence, or rectal complications. Accordingly, post-treatment monitoring should include assessments of sexual, urinary, and bowel functions, as well as regular measurements of prostate-specific antigen levels.

Personalized treatment has long since been introduced in cancer therapy. The genetic complexity of FPC, however, hinders the development of personalized treatment regimens, with no breakthroughs to be expected in the absence of a better understanding of the molecular background of this type of tumor [6].

Prognosis

It has not yet been finally clarified whether mutations predisposing to the development of prostate cancer do or don't affect the aggressiveness of the tumor [7]. Case studies evaluating the impact of a family history of prostate cancer on outcomes and survival times yielded inconsistent results: On the one hand, FPC patients were reported to be more likely to be diagnosed with low-risk, organ-confined disease, which possibly contributed to higher cancer-specific and overall survival times. On the other hand, FPC has been stated to be linked with higher risks of relapse after prostatectomy [3].

Etiology

Genome-wide association studies have identified about 100 common loci related to prostate cancer, and they may account for about one-third of those cases affecting patients of European ancestry [6] [8]. These loci are of low penetrance, though, and neither one alone is able to trigger cancerogenesis; they act together with a broad range of additional genetic, lifestyle, and dietary factors. What's more, at least ten times as many single-nucleotide polymorphisms are estimated to contribute to the development of FPC, and they are yet to be described [8].

On the other hand, FPC has been linked to a number of mutations with high penetrance. This applies to mutations in genes BRCA1 and BRCA2, well known for the respective hereditary breast and ovarian cancer syndromes in women, and anomalies of the HOXB13 gene [9] [10]. While BRCA1 and BRCA2 are required for the conservative repair of double-strand DNA breaks, HOXB13 encodes for a prostate-specific transcription factor that plays an important role in urogenital development and maintains high expression levels in the prostate of adult men. Its function in adulthood remains unclear. Additionally, dysfunctional DNA mismatch repair proteins (encoded by genes like MLH1 and MSH2) are the cause of Lynch syndrome, which may not only predispose to familial colorectal cancer but also to FPC. It is generally assumed, though, that the aforementioned, highly penetrant germline mutations do not account for a significant portion of prostate cancer cases [11].

Epidemiology

Among males worldwide, prostate cancer is the most common malignancy. More than 1.5 million men are diagnosed each year with this disease. Many more are presumed to develop prostate cancer, but deficiencies in medical care and diagnostics hinder the workup in developing countries. Industrialized nations, by contrast, have experienced an apparent increase in the incidence of prostate cancer during the last decades, which is mostly explained by the implementation of population screenings and improvements in diagnostics. These same factors account for more men being diagnosed at increasingly younger ages and earlier stages of the disease [12].

Even though epidemiological studies on prostate cancer generally highlight the geographical variation in incidence rates, the patients' age at diagnosis, and other statistical values, the contribution of hereditary factors to these differences is less clear [12]. In this context, meta-analyses support the notion that the genetic component of prostate cancer is usually underestimated [6] [13]:

  • The risk of developing prostate cancer increases 2.5-fold in men with one first-degree relative who has been diagnosed with this type of cancer.
  • Two first-degree relatives found to have prostate cancer indicate the patient's risk to be enhanced by 4.4 times.
  • More than half of prostate cancer cases among men with some type of family history are attributable to familial clustering.
  • Susceptibility loci associated with prostate cancer risk are rather common but of low penetrance. They interact multiplicatively, which complicates the mere analysis of pedigrees and points out the need for genetic studies.
  • The family history of prostate cancer is most important to identify at-risk patients aged <65 years.

In sum, up to 30% of prostate cancers diagnosed in patients aged <65 years may be classified as FPC. The share of familial cases decreases as the patients' age at diagnosis increases [1].

Sex distribution
Age distribution

Pathophysiology

The development of prostate cancer is influenced by both genetic and environmental factors [7]. Via as-of-yet unknown mechanisms, these factors result in the accumulation of mutations in tumor suppressor genes, oncogenes, and mismatch repair genes. In FPC patients, the presence of germline mutations in some of these genes results in a lower threshold for cancerogenesis. Conversely, this means that environmental factors and lifestyle decisions do modulate the individual risk of developing prostate cancer despite the genetic predisposition.

Prevention

Genetic counseling and testing play important roles in the early identification of men at risk.

  • The strongest predictors of prostate cancer are mutations in highly penetrant genes, e.g., BRCA2 and HOXB13. If a family is known to harbor such mutations, the identification of the respective carriers is not a problem. Technical limitations on screening large panels of alleles, however, reduce the possibilities for common genetic variants to be linked to an increased risk of prostate cancer.
  • Patients with a positive family history are recommended to start with preventive check-ups at an earlier age than the general population. In this context, both prostate-specific antigen blood tests and digital rectal examinations should be offered annually from the age of 45, or even earlier if there are multiple relatives with the disease and/or highly penetrant genes predisposing to prostate cancer have been identified [1] [13].

Summary

Prostate cancer is one of the most common cancers among males worldwide. Besides advanced age and African descent, a family history of the disease is a major risk factor for this type of malignancy [3] [12]. In the case of FPC, germline mutations in genes involved in the regulation of cell growth, division, differentiation, and death confer a certain predisposition to tumor growth. Genetic factors don't, however, trigger cancerogenesis independent of environmental conditions and lifestyle decisions. For a better understanding of the interplay between these factors, further research is required. Additionally, major shares of the underlying mutations have not yet been determined, and it may thus not always be feasible to clearly distinguish sporadic from hereditary cases.

Knowledge gaps regarding the etiology of FPC are also the reason why there is no consistent definition of FPC. To date, either one of the following definitions may be used in the workup of FPC [3]:

  • Patients with either two first-degree relatives diagnosed with prostate cancer at any age or with one first-degree relative and two or more second-degree relatives diagnosed at any age
  • Patients with at least three first-degree relatives diagnosed with prostate cancer at any age, or with two first-degree relatives diagnosed with prostate cancer at <55 years, or patients from families with prostate cancer diagnosed in three successive generations of the same lineage (paternal or maternal)

Patient Information

Prostate cancer is one of the most common cancers among males worldwide. The causes of prostate cancer development are incompletely understood, but genetic factors are known to play a major role. Indeed, men with an extensive family history of prostate cancer are at an increased risk of the disease. Two or more first-degree relatives diagnosed with prostate cancer, or one first-degree relative and two or more second-degree relatives found to suffer from this disease are sufficient grounds to seek genetic counseling and to start with preventive check-ups at an earlier age. This is particularly true if those relatives have been diagnosed at <55 years, since familial prostate cancer tends to develop earlier than sporadic tumors.

Familial prostate cancer is a genetically heterogeneous disease, so the identification of men at risk by means of molecular biological studies poses a major challenge. Few genes have directly been linked to familial clustering of prostate cancer, such as BRCA1 and BRCA2, better known as triggers of breast and ovarian cancer in females. Most genes related to prostate cancer interact multiplicatively, rendering the evaluation of genetic studies a tedious task. Accordingly, preventive screenings largely rely on prostate-specific antigen blood tests and digital rectal examinations - as do screenings carried out in average-risk men. But they should be realized from the age of 40-45 years.

References

Article

  1. Hemminki K. Familial risk and familial survival in prostate cancer. World J Urol. 2012; 30(2):143-148.
  2. Taherian N, Hamel N, Bégin LR, et al. Familial prostate cancer: the damage done and lessons learnt. Nat Rev Urol. 2013; 10(2):116-122.
  3. Giri VN, Beebe-Dimmer JL. Familial prostate cancer. Semin Oncol. 2016; 43(5):560-565.
  4. Frank C, Sundquist J, Hemminki A, Hemminki K. Familial Associations Between Prostate Cancer and Other Cancers. Eur Urol. 2017; 71(2):162-165.
  5. Parker C, Gillessen S, Heidenreich A, Horwich A. Cancer of the prostate: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v69-77.
  6. Eeles R, Goh C, Castro E, et al. The genetic epidemiology of prostate cancer and its clinical implications. Nat Rev Urol. 2014; 11(1):18-31.
  7. Isaacs WB. Inherited susceptibility for aggressive prostate cancer. Asian J Androl. 2012; 14(3):415-418.
  8. Al Olama AA, Kote-Jarai Z, Berndt SI, et al. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet. 2014; 46(10):1103-1109.
  9. Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004; 23(38):6445-6470.
  10. Pilie PG, Giri VN, Cooney KA. HOXB13 and other high penetrant genes for prostate cancer. Asian J Androl. 2016; 18(4):530-532.
  11. Haraldsdottir S, Hampel H, Wei L, et al. Prostate cancer incidence in males with Lynch syndrome. Genet Med. 2014; 16(7):553-557.
  12. Pernar CH, Ebot EM, Wilson KM, Mucci LA. The Epidemiology of Prostate Cancer. Cold Spring Harb Perspect Med. 2018.
  13. Kiciński M, Vangronsveld J, Nawrot TS. An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One. 2011; 6(10):e27130.

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Last updated: 2019-07-11 20:36