Prostate Cancer: Causes

Pathogenesis (development of disease)

It is now believed that the development of prostate cancer is a multistep process in which the genome (genetic material) is randomly damaged multiple times. This damage is referred to as “hits” in the international literature. Statistical calculations based on the increasing incidence (frequency of new cases) of tumor diseases with age assume between 4 and 6 such “hits”. In each of these “hits”, one or more oncogenes (tumor genes, genes that under certain conditions transform healthy cells into tumor cells (cancer) or tumor suppressor genes are activated or inactivated, respectively. Tumor suppressor genes prevent the activation of oncogenes or have a regulatory effect on cell growth and differentiation. These are not specific events and the order of “hits” does not seem to be significant. Rather, it is the accumulation (accumulation) of these events that then lead to the tumor disease. A multifactorial genesis is suspected, in which primarily androgens and growth factors, but also genetic factors, local inflammatory processes and DNA tumor viruses play a role. Australian scientists concluded in a meta-analysis that a causal relationship between human papillomavirus (HPV) infection and prostate cancer is very likely. DNA tumor viruses can stably transfect the genome of a host cell with their own DNA, which is capable of triggering cell growth and proliferation (cell growth), and thus trigger cell growth and cell division in the host cell. These genes have been named oncogenes. Inactive forms of such oncogenes, called protooncogenes, are present per se in all mammalian cells. When activated to become oncogenes, these can also trigger cell growth and proliferation. In prostate carcinoma, there are a large number of potential oncogenes and tumor suppressor genes. It is expected that the identification of these genes and the proteins they encode will significantly influence the diagnosis and therapy of prostate cancer in the future. Furthermore, there are precursors of prostate carcinoma. These are proliferations of epithelial cells in the glandular ducts, which are also called “prostatic intraepithelial neoplasia” (PIN). However, not all neoplasms (new cell formations) develop into invasive carcinomas. Despite this, these regions are genetically unstable and typically occur multifocally (at multiple sites simultaneously). Studies show that prostate cancer prevalence (prostate cancer incidence; here: “incidental carcinoma”; incidental histologic/fine tissue finding), based on systematic histologic examination of autopsies of the prostate, increases with increasing age. In those younger than 30 years, the prevalence was still 5%; at ages 60 to 69, one in three was already affected, and in those aged 70 to 79 years and in even older men (> 79 years), the prevalence was as high as 46% and 59%, respectively.

Etiology (Causes)

Biographical Causes

  • Genetic burden
    • Increased risk in ancestral prostate cancer. A man whose father or brother have prostate cancer has a 1.7-fold higher risk than the rest of the male population; e.g., the high-risk germline mutation (G84E) for prostate cancer in the HOXB13 gene.
    • The risk for prostate cancer is also similarly increased for precursors in direct relatives. This is true for atypical microacinar proliferation or prostatic intraepithelial neoplasia.
      • Genetic risk dependent on gene polymorphisms:
        • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
          • Genes: DAB2IP, ESR2, FUNDC2P2, SOD2, VDR.
          • SNP: rs2107301 in gene VDR
            • Allele constellation: TT (2.5-fold)
          • SNP: rs4880 in the gene SOD2
            • Allele constellation: TT (2.3-fold for aggressive prostate cancer at high iron intake).
          • SNP: rs1447295 in the FUNDC2P2 gene.
            • Allele constellation: AC (1.4-fold).
            • Allele constellation: AA (1.7-fold)
          • SNP: rs6983267 in an intergenic region.
            • Allele constellation: GT (1.3-fold).
            • Allele constellation: GG (1.6-fold)
          • SNP: rs16901979 in an intergenic region.
            • Allele constellation: AC (1.5-fold).
            • Allele constellation: AA (1.5-fold)
          • SNP: rs1571801 in gene DAB2IP
            • Allele constellation: AC (1.36-fold)
            • Allele constellation: AA (1.36-fold)
          • SNP: rs2987983 in the ESR2 gene.
            • Allele constellation: CT (1.2-fold).
            • Allele constellation: CC (1.2-fold)
        • In one in 14 patients, a loss-of-function mutation can be detected in one of four DNA repair genes
  • Ethnicity – Significant differences in the incidence of prostate cancer exist between races. Blacks living in Atlanta have the highest incidence (frequency of new cases) worldwide for prostate cancer (91.2/100 000/year), while Chinese living in Shanghai have the lowest (1.3/100 000/year). Blacks in Africa have a lower incidence, although this may also be due to lower overall life expectancy and poorer diagnostic capabilities. Thus, there appears to be a race-specific genetic predisposition to prostate cancer.
  • Age – individual risk increases with age (50 years and older). Over 80 percent of all men diagnosed with prostate cancer are older than 60 years [the most important risk factor!]
  • Occupations – welders, battery manufacturers; occupational handling of rubber, heavy metals (e.g. cadmium).
  • Socioeconomic factors – high socioeconomic status.
  • Geographic factors – An increase in prostate cancer incidence has been observed with increasing distance from the equator. In addition, incidence is higher in northern Europe and northern states of the United States than in more southern areas. Therefore, sun exposure and vitamin D (1,25 dihydro-cholecalciferol) have been attributed protective properties with respect to prostate cancer.

Behavioral causes

  • Nutrition
    • High consumption of red meat, i.e., muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat; this is classified by the World Health Organization (WHO) as “probably carcinogenic to humans,” i.e., carcinogenicMeat and sausage products are classified as so-called “definite group 1 carcinogens” and are thus comparable (qualitatively but not quantitatively) to the carcinogenic (cancer-causing) effect of tobacco smoking. Meat products include products whose meat component has been preserved or improved in flavor by processing methods such as salting, curing, smoking, or fermenting: Sausages, sausage products, ham, corned beef, jerky, air-dried beef, canned meat.
    • Too little consumption of fruits and vegetables.
    • Fried frozen food (due toconnection between frying and carcinogenesis: formation of acrylamide (group 2A carcinogen), heterocyclic amines, aldehydes and acrolein), once a week.
    • High-fat diet
    • High proportion of refined carbohydrates (sugar, white flour, rice, pasta, foods sweetened with sugar).
    • Too little fiber intake
    • Eating dinner after 10 p.m. or just before bedtime (risk increase of 26%) versus eating dinner before 9 p.m. or eating the last meal at least 2 hours before bedtime
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Stimulants
    • Alcohol – per drink (12 g alcohol) per day increased prostate cancer risk by about10%; low consumption of up to three drinks per week lowest tumor rate; complete abstinence resulted in 27% increased disease rate
  • Psycho-social situation
    • Shift work/night work, especially the alternation of early, late and night shifts – according to the International Agency for Research on Cancer (IARC) assessment, shift work is considered “probably carcinogenic” (Group 2A carcinogen).
  • Gender behavior:
    • Earlier first sexual intercourse (OR: 1.68 if it was before age 17 instead of after age 22).
    • Promiscuity (sexual contacts with relatively frequently changing different partners): > 7 sex partners 2-fold risk (OR: 2.00).
  • Overweight (BMI ≥ 25; obesity); controversial: In a Canadian study of newly diagnosed prostate cancer with a random sample of healthy men of the same age, the following result was found:
    • BMI 25.0-29.9: lower risk of prostate cancer (odds ratio, OR = 0.87)-for both low-grade (Gleason score ≤ 6, OR = 0.83) and high-grade (OR = 0.89
    • BMI ≥ 30: lower risk of prostate cancer (odds ratio, OR = 0.72) – 0.71 (low-grade prostate cancer) and 0.73 (high-grade prostate cancer)
  • Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – there is a high waist circumference or an increased waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)) is present; waist circumference ≥ 102 cm is associated with an increased rate of prostate cancer (OR = 1.23), especially in advanced stages (OR = 1.47)When measuring waist circumference according to the International Diabetes Federation guideline (IDF, 2005), the following standard values apply:
    • Men <94 cm

    The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men.

Disease-related causes

  • Chronic prostatitis (inflammation of the prostate).
  • Gonorrhea (gonorrhea; sexually transmitted infection) – increased prostate cancer rate after sexually transmitted infection (STI) in general and 20% more prostate cancers after gonorrhea.
  • Second tumor risk is increased after chemotherapy wg :

Laboratory diagnoses – laboratory parameters considered independent risk factors.

Environmental pollution – intoxications (poisoning).

  • Arsenic
  • Occupational handling of rubber, heavy metals (e.g. cadmium).
  • There is evidence that 51Cr, 59Fe, 60Co and 65Zn exposure can also trigger prostate cancer
  • Polychlorinated biphenyls (PCB)Note: Polychlorinated biphenyls are among the endocrine disruptors (synonym: xenohormones) that, even in the smallest amounts, can damage health by altering the endocrine system.

Drugs

  • NSAID (non-steroidal anti-inflammatory drugs) – there is a positive correlation between the use of NSAIDs and the development of prostate cancer; however, for acetylsalicylic acid (ASA), there is an inverse correlation, i.e., reduction in the risk of prostate cancer
  • Second tumor risk is increased after chemotherapy due tochronic lymphocytic leukemia (CLL) – twice as high risk for prostate cancer.

Further

  • Alopecia androgenetica-occurrence at age 45 years is associated with an increased rate of aggressive prostate cancer (Gleason score 7 or higher, stage III or higher, and/or deaths); for the total number of prostate cancers, there is no association with alopecia androgenetica