Colorectal Cancer (Colon Carcinoma): Causes

Pathogenesis (disease development)

Colorectal carcinoma (CRC) can be divided pathogenetically into three categories:

  • 70% occur sporadically (“adenoma-carcinoma sequence”).
  • 20-30 % due to polymorphisms and gene loci with a low penetrance in combination with various environmental factors. This leads to the development of familial (polygenic) CRC.
  • Approximately 5% of all CRC are of hereditary origin.

Precursor lesions are adenomas (IEN) of the gastrointestinal tract (gastrointestinal tract), which can develop into adenocarcinomas after different time intervals (several months to years). Adenomas are classified according to the WHO into low-grade (LGIEN = low-grade intraepithelial neoplasia) and high-grade (HGIEN = high-grade intraepithelial neoplasia) forms. Histologically, adenomas are subdivided according to the following growth pattern:

  • Tubular adenomas with >80% tubular tree pattern (70-80% of all adenomas and approximately 90% of adenomas <1 cm).
  • Villous adenomas (> 80 % villous structures) or tubulo-villous adenomas (20-80 % villous portions) adenomas (in total, about 20 % of all adenomas).

In addition to the adenoma-carcinoma sequence, other pathways of sporadic carcinogenesis exist:

  • Serrated carcinogenesis (precursor lesion: “sessile serrated adenoma (SSA)” [typically > 5 mm, flat raised and located in the right-sided colon]Note: SSAs are relatively difficult to detect endoscopically; therefore, may be a major cause of so-called interval carcinomas.
  • Mixed type combining molecular genetic characteristics of the other two carcinogenic pathways [precursor lesions: “traditional serrated adenoma (TSA)” or villous adenoma].

Most colorectal carcinomas arise over years from adenomas – so-called adenoma-carcinoma sequence. An accumulation of mutations (changes in genetic material) are responsible. The adenoma peak occurs approximately 10 years before the onset of carcinoma. As the size of the adenoma increases, so does the risk of developing invasive carcinoma. The causes of the gene alterations that are ultimately responsible for the transition of a normal intestinal mucosal cell into a cancerous cell cannot usually be precisely identified. It is a multifactorial event. Familial adenomatous polyposis (FAP) is characterized by the presence of innumerable polyps in the intestine. These degenerate in FAP to 100% (= obligate precancerosis), usually already from the 15th year of life! 1 in 10,000 people are affected by this disease. Start of colorectal cancer screening including colonoscopy already from the age of 10.MUTYH-associated polyposis (MAP) is the most important differential diagnosis of FAP. The phenotype is usually the same as AFAP; MAP also has a very high lifetime risk of CRC. However, due to autosomal recessive inheritance, there is only a low risk of disease in children of a patient and heterozygous carriers. Diagnosis is usually possible only by molecular genetic testing. In people with an undiagnosed predisposition to HNPCC (hereditary non-polyposis colorectal cancer, also known as “Lynch syndrome“; see below), the risk of developing colorectal cancer is over 80 percent. However, this risk cannot be detected by the increased occurrence of adenomas – the colon carcinomas in HNPCC do not develop at the base of adenomas or polyps. Due to this fact, an intensified screening program is required. In most cases, this predisposition is only suspected when relatives at a younger age also have or have had colon carcinoma. Note: Familial clustering does not always equate to genetic risk. In a case-control study of CRC risk, family history and a genetic risk test complement each other in prediction. To general initial surprise, there was little overlap between patients with a positive family history and those with a high genetic risk score. Patients who had both an elevated genetic risk score and also had other family members with colorectal cancer had a 6-fold increased risk of CRC. Microbiome and colon cancer

A companion metagenome analysis shows that some intestinal bacteria (including Fusobacterium nucleatum) produce increased amounts of molecules that may be responsible for carcinogenesis.A “genetic signature” can be demonstrated, with which the intestinal flora of cancer patients and healthy persons could be well distinguished: The limit optimization curve (AUROC), which combines sensitivity and specificity, reached a value of 0.80 (0.5 is chance, 1.0 certainty.The authors also concluded from their results that the fact of increased production of secondary bile acids from CRC metagenomes suggests a metabolic link between cancer-associated gut microbes and a high-fat, high-meat diet. The intestinal bacterium Streptococcus gallolyticus ssp. gallolyticus (SGG) could potentially represent an important etiologic component in CRC development. Antibodies to SGG proteins were found more frequently in participants in one study who later developed colorectal cancer than in those who remained cancer-free. HPV infection and anal carcinoma

In anal carcinoma (anal cancer), infection with human papillomavirus (HPV) is causative in 80% to 85% of cases.

Etiology (Causes)

Biographic causes

  • Genetic burden
    • In a German case-control study DACHS with nearly 4,450 patients and 3,480 healthy controls, it was found that the 100 single nucleotide polymorphisms (SNP) known to influence colorectal cancer risk explained only 10-23% of the colorectal cancer risk, depending on the calculation method; this indicates that the large residual risk may be due to the account of a family learned lifestyle.
    • First-degree relatives of colorectal cancer patients: 1.7-2.0 times colorectal cancer risk than population average
      • Lifetime risk for siblings is 7%, 1.7 times that of people without a positive family history; similar for half-siblings (lifetime risk of 6%)
    • Second-degree relatives of colorectal cancer patients: 1.3-fold increased
    • Relatives of patients who developed the disease when younger than 40 years: highest risk (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79)
    • Genetic risk dependent on gene polymorphisms:
      • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
        • Genes: AURKA, GATA3, SMAD7, TCF7L2.
        • SNP: rs4779584 in an intergenic region.
          • Allele constellation: CT (1.23-fold).
          • Allele constellation: TT (1.70-fold)
        • SNP: rs6983267 in an intergenic region.
          • Allele constellation: GT (1.39-fold).
          • Allele constellation: GG (1.68-fold)
        • SNP: rs2273535 in the gene AURKA.
          • Allele constellation: TT (1.5-fold).
        • SNP: rs4143094 in the gene GATA3
          • Allele constellation: TT (1.39-fold risk due to red meat consumption).
          • Allele constellation: GT (1.17-fold risk due to consumption of red meat).
          • Allele constellation: GG (low risk of colon cancer from red meat consumption).
        • SNP: rs7903146 in the TCF7L2 gene.
          • Allele constellation: CT (1.12-fold).
          • Allele constellation: TT (1.25-fold)
        • SNP: rs4939827 in the SMAD7 gene.
          • Allele constellation: CT (0.86-fold).
          • Allele constellation: CC (0.73-fold)
    • Genetic diseases
      • Familial adenomatous polyposis (FAP); mutation of the adenomatosis polyposis coli (APC) gene; autosomal dominant; especially if affected individuals were younger than 50 years of age at onset! as well as if close relatives had other cancers, for example, breast carcinoma (breast cancer), ovarian carcinoma (ovarian cancer), or endometrial carcinoma (uterine cancer)Polyps: Adenomas, > 100 to > 1,000 polyps; adenomas from 10 and CRC from 20 years of age; obligatory precancerous (risk of degeneration relatively high).
      • HNPCC (English “Hereditary Non Polyposis Colorectal Cancer”; hereditary non-polyposis colorectal carcinoma; Lynch syndrome; about every 500th person carries a pathogenic mutation)autosomal dominant (germline mutation of DNA repair enzymes; one of the four genes MLH1, MSH2, MSH6 and PMS2 shows a mutation); polyps: Adenomas, single to > 30 polyps; median age at CRC diagnosis 40 yearsIn addition to the increased risk of early colorectal cancer, mutation carriers develop a higher incidence of endometrial and ovarian cancer.Dermatologic tumors such as sebaceous adenomas may also be associated with HNPCC. Note: The median risk of developing endometrial cancer in such cases is approximately 45 years.
      • Other polyposis syndromes:
        • Autosomal dominant inheritance: Gardner syndrome, Peutz-Jeghers syndrome, familial juvenile polyposis (FJP), Cowden syndrome, Turcot syndrome with polyposis.
        • Unclear heredity: hyperplastic polyposis[hereditary gastrointestinal polyposis syndromes are responsible for approximately 1% of all cases of colon cancer]
  • Medical history:
    • Any adenoma detected histologically (by fine tissue) represents an increased risk for colorectal cancer. This is particularly true for:
      • Multiple (≥ 3) adenomas
      • Large (> 1 cm) adenomas
    • Condition after mammary carcinoma (breast cancer).

Behavioral causes

  • Nutrition
    • High consumption of red meat, i.e., muscle meat of pork, beef, lamb, veal, mutton, horse, sheep, goat
      • Red meat is classified by the World Health Organization (WHO) as “probably carcinogenic to humans”, that is, carcinogenic.Meat and sausage products are classified as so-called “definite group 1 carcinogen” 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, cold cuts, ham, corned beef, jerky, air-dried beef, canned meat. Daily consumption of 50 g of processed meats (equivalent to two slices of sausage) increases the risk of colon cancer by 18%, and daily consumption of 100 g of red meat by 17%.
      • Other studies suggest that iron ingested with meat may contribute to the increase in risk, as iron can promote the formation of harmful nitroso compounds in the body. Red meat or processed meats have a higher average iron content than poultry, so its consumption may not have affected colorectal cancer risk in this study.
      • A meta-analysis of several prospective cohort studies demonstrated an increased risk of colorectal cancer with very high meat consumption of beef and lamb. Pork was not associated with increased cancer risk.
      • Studies in rats with chemically-induced colon carcinoma (chemically-induced colon cancer) uniformly showed that dietary hemoglobin (red blood pigment) and red meat promote lesions (tissue damage) in the intestine as a precursor to carcinoma (tumor). The mechanism is still unknown, but heme iron has a catalytic (accelerating) effect on the endogenous (endogenous) formation of carcinogenic (cancer-promoting) nitroso compounds and on the formation of cytotoxic (cell-damaging) and genotoxic (genetic-damaging) aldehydes by means of lipid peroxidation (conversion of fatty acids, creating free radicals).
      • Hämeisen, but not inorganic iron, promotes ROS production (reactive oxygen species, ROS) and oxidative DNA damage in HCEC and CRC cells (HCEC = human colon epithelial cells / human colon cells; CRC = colorectal carcinoma / colon and rectal cancer).
      • Other studies describe animal protein as an independent risk factor. With high-protein diets, increased proteins, peptides and urea pass into the colon. As an end product of bacterial metabolism ammonium ions are formed, which have a cytotoxic effect.
    • Too little fish consumption; inverse correlation between fish consumption and risk of disease.
    • Too little fruit and vegetable consumption
    • Heterocyclic aromatic amines (HAA) – these are formed exclusively when food (especially meat and fish) is heated (> 150 °C) and are considered carcinogenic. HAA develop mainly in the crust. The more browned the meat, the more HAA are formed. Individuals who have a high intake of HAAs have a 50 percent higher risk of developing polyps (adenomas) of the colon (large intestine), which are often precancerous lesions (precursors) for colon carcinoma (colon cancer).
    • Diet too rich in fats (high intake of saturated fatty acids of animal origin and of the polyunsaturated fatty acid linoleic acid (omega-6 fatty acid), contained in safflower, sunflower and corn oil) and low in complex carbohydrates and fiber.
    • Micronutrient deficiency (vital substances) – including insufficient supply of vitamins C and D, calcium (calcium binds promoters such as bile acids) and selenium; see Prevention with micronutrients.
  • Consumption of stimulants
    • Alcohol (female: > 20 g/day; male: > 30 g/day); ≥ 50 g/day alcohol significant increase in colorectal cancer mortality (death rate).
    • Tobacco (smoking)
  • Physical activity
    • Physical inactivity
      • >14 hours of TV consumption per week as a measure of physical inactivity increases the likelihood of colorectal cancer by nearly 70% even at ages younger than 50
      • High cardiorespiratory fitness (average 13.0 MET ≈ 13 times basal metabolic rate) in middle age resulted in 44% reduced colorectal cancer mortality (colorectal cancer mortality rate)
    • “Frequent” (24% higher risk).
  • Psycho-social situation
    • High work stress: + 36% colorectal cancer (carcinomas of the colon (large intestine) and rectum (rectum)).
    • Night work – according to the assessment of the International Agency for Research on Cancer (IARC), shift work is considered “probably carcinogenic” (group 2A carcinogen).
  • Overweight (BMI ≥ 25; obesity):
    • For every 5 kg of weight gain, 5% increase in risk of colon cancer.
    • Overweight or obese teenagers in their teens (17 years):
      • 50 percent increased risk of later colon cancer for overweight or obese teens
      • 70 percent increased risk of rectal cancer for obese males; obese females about 100 percent increased
      • Obesity was not significantly associated with rectal cancer (cancer of the rectum)
    • Severe weight gain in young adulthood was associated with increased risk of colorectal cancer.
    • Increase in waist circumference and leptin receptor and high HbA1c levels.
  • Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – there is a high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)); increased abdominal fat has a strong atherogenic effect and promotes inflammatory processes (“inflammatory processes”)When measuring waist circumference according to the guideline of the International Diabetes Federation (IDF, 2005), the following standard values apply:
    • Men < 94 cm
    • Women < 80 cm

    The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men and < 88 cm for women.

Disease-related causes

  • Inflammatory bowel disease (IBD)-occurrence of ulcerative colitis, primary sclerosing cholangitis, and post-inflammatory polyps in patients with IBD increases the risk of colorectal cancer
  • Ulcerative colitis
  • Diabetes mellitus type 2
    • Diabetics without relatives with colon carcinoma (colorectal cancer) have a similarly high risk of colorectal cancer as in familial non-diabetics.
    • Diabetics whose first-degree relatives were diagnosed with colon cancer had about a 7-fold increased risk of developing colorectal cancer themselves under the age of 50 compared with the general population.
  • Cancers, such as mammary carcinoma (breast cancer), ovarian carcinoma (ovarian cancer) or endometrial carcinoma (uterine cancer).
  • Crohn’s disease – chronic inflammatory bowel disease; it usually progresses in relapses and can affect the entire digestive tract; characteristic is the segmental affection of the intestinal mucosa (intestinal mucosa), that is, several intestinal sections may be affected, which are separated from each other by healthy sections
  • Celiac disease (gluten-induced enteropathy) – chronic disease of the mucosa of the small intestine (small intestinal mucosa), which is based on hypersensitivity to the cereal protein gluten.

Laboratory diagnoses – laboratory parameters that are considered independent risk factors.

  • Hypercholesterolemia (elevated total cholesterol).
  • Hypertriglyceridemia
  • Matrix metalloproteinase-7 (MMP-7) elevated in serum – in patients with colon cancer (in Caucasians and Asians).

Medications

  • Patients who received antibiotics for two months or longer between the ages of 20 and 39 were 36% more likely to have colonic polyps (intestinal polyps) at screening colonoscopy when they were older

Surgeries

  • Ovarectomy (unilateral or bilateral) – ovariectomy: significant standardized incidence ratio (SIR) of 1.30 ( 95 percent confidence interval of 1.26 to 1.35):
    • Age 15 to 29 years: SIR 1.10; 0.97-1.23
    • Age 40-49 years: SIR 1.26-1.19-1.33)

    Highest risk: first 4 years after ovariectomy (SIR 1.66; 1.51-1.81); ovariectomy bilateral: twice as likely to develop rectal cancer (rectal cancer) than in women in whom only one ovary was removed (SIR 2.28; 1.33-3.91)

Environmental exposure – intoxications (poisonings).

  • Nitrate in drinking water (nitrate is converted in the body to nitrite and N-nitroso compounds); group of individuals exposed to the highest level of exposure at ≥ 16.75 mg/l had nearly 20% higher risk of colorectal cancer compared with individuals who had the lowest intake of nitrate in drinking water at < 0.69 mg/l (HR 1.16, 95% CI 1.08-1.25). CONCLUSION: The maximum limit of 50 mg nitrate per liter of drinking water under the EU Drinking Water Directive should be reconsidered.