HC4: Cancer etiology

Risk factors

There are multiple risk factors for cancer. The most important ones are:

• Age
  • The number of times a cell has divided
• Genetics/hereditary: syndromes that lead to cancer, mainly in DNA repair
  • Lynch syndrome: predisposes to colon and endometrial cancer
  • Li Fraumeni: TP53 mutation
  • BRCA1 and BRCA2 → breast cancer
  • Cowden: PTEN mutation → breast, thyroid, uterine, renal and colon cancer
• Environmental factors
  • Tobacco
  • Alcohol
  • Chronic inflammation
  • Diet
  • Hormones
  • Immunosuppression
  • Infection
  • Obesity
  • Radiation
  • Sunlight

Risk factors can be split into controllable and non-controllable risk factors. Most are non-controllable, such as age and gender.

Age

Age is the greatest risk factor for cancer development. The peak of incidence of cancer is around 70 years. This isn’t equal for all cancer types → during puberty, the incidence of bone cancer rises due to fast growth.

The more someone ages, the more times cells are divided and the more likely it is that mistakes are accumulated in DNA-strands. Because there are 3 billion base pairs, mistakes occur easily.

Odds:

Odds are generally against cancer:

• There is a minority of mutations in oncogenes and TSGs
  • Mutations are much more likely to occur outside these genes
• There are DNA repair mechanisms
  • Make sure that if mistakes happen during replication, they are repaired
• Several features need to be acquired by cells to go from a healthy cell to a malignant cell
  • The 10 hallmarks of cancer

Stem cells:

Nevertheless, if someone lives long enough, many cell divisions occur and the chance of developing mutations becomes more likely. Because stem cells have to supply a constant amount of new cells throughout life, they divide a lot. This can cause mutations to accumulate at different sites.

Hereditary cancers

Hereditary means segregating in the family → transmission of cancer material. There is a familial high chance of genetic problems in the family, but the cause is unknown. Prevalence of hereditary cancers depends on the cancer type:

• Hereditary: transmission of genetic material
  • The gene that causes it is known
• Familial: most likely due to more than 1 genetic alteration
  • Vague clues that there is something in the family, but with what or what gene is unknown

Environmental factors

Environmental factors most often directly affect DNA molecules. Geographical and societal differences hint that environmental factors play a part in the development of cancer:

• Prostate cancer is more common in developed countries → it is a disease of old age, and in developed countries people live longer
• Liver cancer has something to do with hepatitis B infections → in developed countries hepatitis B vaccination is common → liver cancer is less prevalent
• Cervical cancer is prevented in developed countries → cervical cancer is mainly caused by HPV

Other examples of environmental factors are:

• Alcohol → mouth, throat and esophagus cancer
• Estrogen → breast and endometrial cancer
• Obesity → breast and colon cancer
• Radon → lung cancer
• Sunlight → skin cancer
• Tobacco → almost every cancer type
  • Predisposes very strongly to lung cancer
• HPV → cervix uteri cancer

Some risk factors are moderate, some are high. If multiple moderate risk factors are combined, it can lead to a high risk of developing cancer.

Unproven associations:

It isn’t easy to establish association between a certain lifestyle factor and the development of cancer. There are several unproven associations:

• Artificial sweeteners
• Cell phones
• Power lines
• Aluminium perspirants

Tobacco:

Tobacco is the worst environmental risk factor → contains 7000 chemical structures that can bind directly to the DNA, disrupting the DNA strand. Of these chemicals, more than 60 are well-established carcinogens. This is extremely difficult or even impossible to repair. A chronic inflammation state is induced, which leads to cancer development.

Benzopyrene is metabolized and can bind to bases in double stranded DNA, causing gross structural alterations.

Mutations can be found with different cancers in the signature. The type of mutations are usually found in sequencing. C to A mutations are commonly found in smoking lung adenomas.

Other people smoking can also cause lung cancer in non-smoking individuals:

• Passive smoking
• Smoking in the environment
• A mother smoking during pregnancy

Alcohol:

It isn’t entirely clear how alcohol causes cancer. During metabolism of alcohol, oxygen radicals come free. Consumption of 80 grams alcohol per day increases the risk of developing cancer 5 times. Alcohol also is a major risk factor for the development of breast cancer.

Hormones:

Hormones such as estrogen can lead to an increased risk of cancer:

• Estrogen receptors are growth receptors → work as an oncogene → proliferation

These estrogen receptors are located in the breasts and endometrium and can cause cancer. They stimulate cell proliferation and division.

Sources of estrogen can be exogenous and endogenous:

• Exogenous source: hormonal therapy after the menopause
• Endogenous source: ovaria overproduction of progesterone and estrogen

Obesity:

Obesity is characterized by accumulation of adipose tissue, which produces estrogen. There is a chronic inflammation:

1. Adipose tissue dysfunction releases inflammatory cytokines
2. Chronic inflammation → related to cancer

Food and diet can transform the microbe in the gut. An unbalanced microbiome results in a higher risk of cancer. Because adipose tissue also is an important source of estrogen, obesity is related to breast and endometrial cancer.

UV:

People can be exposed to UV radiation via sun exposure or tanning machines. UV radiation can form covalent bonds between pyrimidine bases in DNA strands → 2 thymine or cytosine dimers bind, leading to a kink in the DNA. Thymine bonds are easier to repair than cytosine bonds. This cannot be repaired and can lead to several types of skin cancer:

• Melanoma
  • Not very common → less than 1% of skin cancers
  • Very deadly
• Squamous cell carcinoma
  • More common
  • Not as deadly
• Basal cell carcinoma
  • More common
  • Not very deadly

Infectious agents:

Most infectious agents causing cancer are DNA viruses:

• Human papillomavirus (HPB)
  • Associated with cervical, vulvar, penile and anal carcinomas
• Hepatitis B/C
  • Associated with liver cancer
• Epstein-Barr virus (EBV)
  • Associated with Burkitt and naso-pharyngeal cancer
• Human herpes virus 8
  • Associated with Kaposi-sarcomas

Important notes regarding viral carcinogenesis are:

• Host susceptibility factors are important determinants
  • E.g. the immune system
• Viruses are seldom carcinogenic on their own
  • Many people are exposed to HPV but don’t develop cancer
• Viral infections are far more common than viral cancers
• Viral strains may be different in their capacity to cause cancer
• Viruses can be subjected to control through preventive or therapeutic vaccination
• 1 virus species can be associated with multiple cancer types

The human papillomavirus integrates in the host cell and uses the translational machinery of host DNA to start producing proteins, such as:

• HPV E6: inhibition of p53 and increased telomerase expression → blocking of apoptosis and stimulation of cell survival
• HPV E7: inhibition of pRB and increased CDK4 expression → stimulation of proliferation

Normally, E6 and E7 are tumor suppressor genes.

The Epstein-Barr virus can cause:

• Burkitt lymphoma
  • An endemic in the equatorial region of Africa
  • Malaria causes immunosuppression → higher risk of getting a lymphoma
• Hodgkin lymphoma: naso-pharyngeal cancer

EBV mainly transforms B-cells → translation of proteins from the genome leads to apoptosis, cell cycle progression, proliferation and survival. Additional hits are needed for full transformation → translocation of MYC/IgH is necessary. This will cause B-cells to produce MYC instead of immunoglobulins.

Radioactivity:

Radon is a gas derived from uranium:

1. Uranium transforms into radium
2. Radium transforms into radon

It isn’t very common in the Netherlands. There also are other radiation sources, such as exposure to medical procedures → X-rays are a source of radiation.

Asbestos:

Asbestos is widely used in construction, insulation and manufacturing. It belongs to the family of fibrous silicates:

1. Silicon particles perforate the lungs and accumulate in the pleura
2. Chronic wounds lead to chronic inflammation
3. Chronic inflammation leads to mesotheliomia in pleural and peritoneal cavities
   • Mesotheliomia is very rare and has a latent period of more than 20 years

Chronic inflammation and cancer

Many chronic inflammations are associated with different kinds of tumors. Inflammation promotes cell proliferation because tissue needs to repair itself. Chronic inflammation causes cancer as follows:

1. A wound attracts inflammatory cells
2. Inflammatory cells cause:
   • Migration
   • Proliferation
   • Apoptosis
   • Angiogenesis
3. Tumor cells take advantage of the signals → cause a wound that never heals
4. Macrophages produce reactive oxygen species which can damage the DNA