Bladder Cancer: Causes

Pathogenesis (development of disease)

Urinary bladder cancer results from altered cells in the bladder wall area that proliferate in an expansion-like manner. These changes are caused by mutations (permanent genetic changes). In tumor biopsies (tissue cylinders from a tumor), one or more mutations associated with DNA mismatch repair or hereditary (inherited) tumor disease are found in approximately 20% of cases. New model of urinary bladder cancer: inactivation of epigenetic regulatory proteins (protein that regulates a molecular biochemical process, i.e., either activates or slows it down) such as UTX leads to expansion (extension) of stem cells with altered epigenetic state in the urinary bladder. This expansion of altered stem cells would also explain why tumors often appear at other sites after surgical removal. Invasive urothelial carcinoma usually develops from severe urothelial dysplasia or in situ carcinoma.

Etiology (causes)

Biographic causes

  • Genetic burden – unlikely to be a familial inherited condition
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: CASC11
        • SNP: rs9642880 in gene CASC11
          • Allele constellation: GT (1.2-fold).
          • Allele constellation: TT (1.49-fold)
        • SNP: rs710521 in an intergenic region.
          • Allele constellation: AA (1.4-fold).
          • Allele constellation: GG (0.83-fold)
        • SNP: rs1495741 in an intergenic region.
          • Allele constellation: AG (0.87-fold).
          • Allele constellation: GG (0.76-fold)
        • Combination of SNPs in the following genes with allele constellation increase urinary bladder cancer risk 2.59-fold overall:
          • SNP rs1014971 in the gene APOBEC3 with allele constellation AA.
          • SNP rs1058396 in gene SLC14A1 with allelic constellation AG or GG.
          • SNP rs11892031 between the genes UGT1A8 and UGT1A10 with the allelic constellation AA.
          • SNP rs8102137 in the gene CCNE1 with the allelic constellation CT or CC.

          Carrying any of the four risk variants increases the risk of urinary bladder cancer between 1.11-fold to 1.3-fold.25% of bladder cancer cases (never smoking cases) carry the combination of the four risk alleles as well as 11% of the control group (never smoking controls).

      • Genetic diseases
        • Special genetic syndromes: e.g., HNPCC (hereditary non-polyposis colorectal cancer; hereditary colorectal cancer without polyposis, also known as “Lynch syndrome“) – genetic disease with autosomal dominant inheritance; associated with early-onset colorectal carcinoma (cancer of the colon or rectum) and possibly other tumor diseases.
  • Occupations – occupational groups with increased risk, in descending order: workers who come into contact with or occupational groups:
    • Firefighters (RR 4.30; 0.78-23.80).
    • Brewery workers (RR 2.09; 0.34-12.88)
    • Chemical process workers (RR 1.87; 95 percent confidence interval 1.50-2.34)
    • Rubber (RR 1.82; 1.40-2.38)
    • Textile workers (RR 1.74; 1.45-2.08)
    • Dyes (RR 1.80; 1.07-3.04)
    • Glass workers (RR 1.66; 1.21-2.27)
    • Electrician (RR 1.60 (1.09-2.36)
    • Blast furnace worker (RR 1.55; 1.07-2.25)
    • Service personnel (RR 1.49; 1.05-2.12)
    • Waiters (RR 1.30; 1.01-1.65)
    • Health care worker (RR 1.16; 1.07-1.26)

Behavioral causes

  • Nutrition
    • Nitrosamine exposure Smoked and cured foods and foods high in nitrates and nitrites Nitrate is a potentially toxic compound: Nitrate is reduced to nitrite in the body by bacteria (saliva/stomach). Nitrite is a reactive oxidant that reacts preferentially with the blood pigment hemoglobin, converting it to methemoglobin. Furthermore, nitrites (also contained in cured sausage and meat products and ripened cheese) form nitrosamines with secondary amines (contained in meat and sausage products, cheese and fish), which have genotoxic and mutagenic effects.The daily intake of nitrate is usually about 70% from the consumption of vegetables (lettuce and lettuce, green, white and Chinese cabbage, kohlrabi, spinach, radish, radish, beet), 20% from drinking water (nitrogen fertilizer) and 10% from meat and meat products and fish.
    • Micronutrient deficiency (vital substances) – see prevention with micronutrients.
  • Consumption of stimulants
    • Tobacco (smoking) – among other things, because of aromatic amines in tobacco smoke such as 2-naphthylamine; 50-65% of patients have a positive smoking history

Disease-related causes

  • Analgesic nephropathy – renal changes that occur due to chronic use of analgesic combinations such as acetaminophen and acetylsalicylic acid (ASA): the combined use causes toxic damage to capillary endothelia and epithelial cells of the loop of Henle. The main lesion is in the renal medulla and proximal urinary tract, as substance concentrations are highest here. Paracetamol or acetylsalicylic acid taken alone, on the other hand, do not lead to analgesic anphropathy; in 75% of cases, middle-aged women are affected
  • Benign prostatic hyperplasia (BPH) – 4.9-fold risk; risk-adjusted, taking into account tobacco use and place of residence, there was a 4.1-fold increased incidence of bladder cancer in the group with BPH. Note: The men with BPH were more likely to have diabetes mellitus (18 versus 13%), a history of urinary tract infections (26 versus 5%), hydronephrosis (1.7 versus 0.3%), and renal insufficiency (13 versus 7%).Limitation: retrospective cohort study.
  • Schistosomiasis – worm disease (tropical infectious disease) caused by trematodes (sucking worms) of the genus Schistosoma (couple flukes) (infection of the urinary bladder with Schistosoma haematobium, a parasite).
  • Bladder papillomatosis – occurrence of numerous benign tumors in the area of the urinary bladder.
  • Chronic cystitis
    • Chronic cystitis (cystitis; inflammation of the urinary bladder) with leukoplakia (white efflorescences of the mucosa that cannot be wiped off).
    • Urinary tract infections that did not respond to treatment or recurred (recurred) were significantly and independently associated with a 2.3-fold risk of bladder cancer; the authors suggest that carcinogenesis (tumor development) may be triggered via chronic inflammation via NF-kappa B family transcription factors, the bacteria in the urine may have contributed to the production of nitrites and thus nitrosamines, and the absorption of carcinogens may have increased.
  • Paraplegia (paraplegia) – latency period (time between accident or onset of paralysis and diagnosis) ≥ 10 years; patients are significantly younger; muscle-invasive urinary bladder carcinoma occurred in 79% of cases Paraplegics

Medications

  • Aristolochic acids, a group of structurally similar aromatic nitro compounds from Aristolochia species (this genus includes about 400-500 species).
  • Chlornaphazine – drug, which is no longer available in Germany since the 1960s; was previously used against polycythemia (rare myeloproliferative disorder in which all cells in the blood multiply excessively).
  • Cyclophosphamide – drug used primarily for therapy in carcinoma (cytostatic drug).
  • Phenacetin (analgesic; antipyretic) – this drug is no longer on the market since 1986.
  • Rosiglitazone (antidiabetic drug from the group of insulin sensitizers) (+ 60%).
  • Second tumor risk is increased after chemotherapy due tochronic lymphocytic leukemia (CLL) – 3.5 times higher risk of bladder cancer.

Surgeries

  • Ureteral intestinal implantation – lead to adenocarcinoma in 43% of cases.
  • Kidney transplantation – 3.18-fold increased SIR (standardized incidence ratio; 95% confidence interval (CI): 1.34 – 7.53, P = 0.008), compared with general population

X-rays

  • External high-voltage irradiation in the small pelvis.
  • Radiotherapy (external radiatio or radioactive implants) of localized prostate carcinoma.

Environmental exposure – intoxications (poisonings).

  • Arsenic
    • Men: mortality risk (risk of death)/relative risk (RR) 4.79 (95 percent confidence interval 4.20-5.46).
    • Women: Mortality risk/relative risk 6.43 (95-percent confidence interval 5.49-7.54).
  • Intake of nitrosamines
  • Occupational contact with carcinogens such as aromatic amines (such as aniline, benzidine, toluidine, 2-naphthylamine, naphthylamine, etc., and their derivatives; starting material for pharmaceuticals, plastics, pesticides, or dyes)In terms of an occupational disease BK 1301, mainly aromatic amines of category 1 and, with restrictions, of category 2 are of importance: e. g. For example, exposure of the hazardous substance contained in gasoline and motor oil o-toluidine (chemical compound from the group of aromatic, single methylated anilines).
  • Dry cleaning (4-chloro-o-toluidine).
  • Diesel exhaust (due topolycyclic hydrocarbons, PAHs; excretion of PAH metabolites via kidneys).
  • Massive exposure to combustion products
  • Handling hair dyes (β-naphthylamine).