American biotechnologist Dr Craig Venter highlighted the complexity of human biology after sequencing his own genome.
He emphasised that while genes provide useful information about disease risk, they have limited impact on life outcomes, compared to the intricate interplay of proteins, cells and environmental factors.
Studies indicate that migration to different countries influences chronic illness rates more than genetic predisposition. For example, identical twins show low concordance rates for diseases like breast cancer, suggesting that non-genetic factors play a dominant role.
Indeed, it is suggested that lifestyle and environmental factors, not genes, contribute 90-95% to the development of chronic diseases like cancer. Cancer arises from both internal (e.g. inherited mutations) and external factors (e.g. tobacco, diet), with lifestyle choices significantly impacting cancer development.
The modifiability of these external factors suggests that cancer is preventable, emphasising the importance of lifestyle modifications in reducing cancer risk. Let us take a look at the major external factors that can cause cancer:
Tobacco
Smoking was identified as the primary cause of lung cancer in a 1964 report by the US Surgeon General’s Advisory Commission, and efforts to reduce tobacco use have been ongoing ever since. Tobacco use increases the risk of developing at least 14 types of cancer and accounts for a significant portion of cancer-related deaths, particularly lung cancer.
The carcinogenic effects of both active and passive smoking are well-documented, with tobacco containing numerous carcinogens. While smoking has been declining in developed countries, it is increasing in developing countries where most of the world’s population resides.
The exact mechanisms by which smoking contributes to cancer are not fully understood, but it is known to alter cell-signalling pathways and induce inflammation, as evidenced by the activation of NF-kB, an inflammatory marker. Studies have shown that curcumin, which is derived from turmeric, and other natural phytochemicals can block NF-kB induced by cigarette smoke, potentially reducing the carcinogenic effects of tobacco.
This suggests that dietary agents with anti-inflammatory properties may have chemopreventive effects against smoking- related cancers.
Alcohol
Since 1910, studies have consistently linked chronic alcohol consumption to an increased risk of various cancers, including those of the upper aerodigestive tract (i.e. the oral cavity, pharynx, hypopharynx, larynx and oesophagus), liver, pancreas, mouth and breast.
Notably, heavy alcohol intake is a well-established risk factor for liver and colorectal cancers, with evidence of a synergistic effect with hepatitis C or B viruses (HCV or HBV) in promoting hepatocellular carcinoma. Alcohol-induced inflammation, mediated partly by the NF-kB pathway, is implicated in carcinogenesis (the formation of cancer).
Ethanol metabolism generates acetaldehyde and free radicals, which damage DNA (deoxyribonucleic acid) and proteins, contributing to cancer development.Other mechanisms include alterations in cell-cycle behaviour, nutritional deficiencies and immune system dysfunction.
Abstaining from alcohol and smoking can prevent up to 80% of upper aerodigestive tract tumours. Globally, 3.5% of cancer deaths are attributed to alcohol, with variations between countries.
Diet
A 1981 report in the Journal of the National Cancer Institute estimated that around 30-35% of cancer deaths in the United States were linked to diet, with the contribution varying by cancer type. For example, diet is associated with up to 70% of colorectal cancer cases.
The mechanisms by which diet influences cancer risk are not fully understood, but ingested carcinogens like nitrates, nitrosamines, pesticides and dioxins, along with cooking methods, play a role.
Heavy consumption of red meat is a risk factor for several cancers due to carcinogens produced during its cooking and processing. Food additives, plastic contaminants and arsenic ingestion also increase cancer risk.
Obesity
Obesity is associated with increased death from various cancers, including colon, breast (for postmenopausal women), endometrium, renal cell, oesophagus (i.e. adenocarcinoma), gastric cardia, pancreas, prostate, gallbladder and liver cancers.
In the US, excess weight or obesity contributes to 14% of cancer deaths in men and 20% in women. The rise of modernisation and a Westernised diet has led to an increased number of overweight individuals in many developing countries.
Common factors linking obesity and cancer include neurochemicals, hormones (e.g. IGF-1, insulin, leptin), sex steroids, adiposity, insulin resistance and inflammation. Signalling pathways like IGF/insulin/Akt and leptin/JAK/STAT, along with inflammatory cascades, are implicated in both obesity and cancer.
Hyperglycaemia (high blood sugar levels) activates NF-kB, potentially linking obesity with cancer. Cytokines produced by adipocytes (fat cells), such as leptin, TNF and IL-1, also activate NF-kB. The close relationship between energy balance and carcinogenesis underscores the need for research into inhibitors of these pathways to reduce obesity-related cancer risk, likely requiring multi-targeting agents.
Infectious agents
Worldwide, approximately 17.8% of tumours are associated with infections, with the percentage varying from less than 10% in high-income countries to 25% in African countries.
Viruses are the primary infectious agents linked to cancer, with human papillomavirus (HPV), Epstein-Barr virus, Kaposi’s sarcoma-associated herpes virus, human T-lymphotropic virus (HTLV) 1, HIV (human immunodeficiency virus), HBV and HCV posing risks for various cancers.
These include cervical, anogenital, skin, nasopharyngeal, Burkitt’s and Hodgkin’s lymphomas, Kaposi’s sarcoma, adult T-cell leukaemia, B-cell lymphoma, and liver cancer. In developed countries, HPV and HBV are the most common cancer-causing DNA viruses.
HPV induces mutation via its viral genes E6 and E7, while HBV (and HCV) generates reactive oxygen species through chronic inflammation, leading to indirect mutations. HTLV also directly causes mutations.
Other microorganisms such as certain parasites (Opisthorchis viverrini or Schistosoma haematobium) and bacteria (Helicobacter pylori) may also act as co-factors or carcinogens. The mechanisms by which infectious agents promote cancer are becoming increasingly understood, with infection-related inflammation being a major risk factor.
Most viruses linked to cancer activate NF-kB as do components of H. pylori. Agents that can block chronic inflammation hold promise for treating these conditions. It has also been suggested that the SARS-CoV-2 virus might influence the vulnerability of specific organs to cancer due to its ability to infect multiple organs directly or indirectly.
However, the long-term consequences of this virus on cancer development are still being investigated and require further observation over time.
Environmental pollution
Environmental pollution is associated with various cancers. It encompasses outdoor air pollution by carbon particles containing polycyclic aromatic hydrocarbons (PAHs); indoor air pollution from environmental tobacco smoke, formaldehyde, and volatile organic compounds (VOCs) like benzene and 1,3-butadiene; and food pollution from additives and carcinogenic contaminants such as nitrates, pesticides, dioxins and organochlorines.
Carcinogenic metals, pharmaceuticals and cosmetics also contribute to pollution-related cancer risks. Outdoor pollutants like PAHs, especially in fine carbon particles, increase lung cancer risk through inhalation, with long-term exposure in polluted cities associated with elevated lung cancer deaths.
Nitric oxide from pollution also raises lung cancer risk, while motor vehicle exhaust exposure is linked to childhood leukaemia. Indoor pollutants like VOCs and pesticides increase childhood leukaemia and lymphoma risk, along with the risk of brain tumours, Wilm’s tumours, Ewing’s sarcoma, and germ cell tumours in both children and adults.
Exposure to pollutants while in the womb raises testicular cancer risk, while chlorinated drinking water and nitrates transform to mutagenic compounds, increasing risks of lymphoma, leukaemia, colorectal and bladder cancers.
Radiation
Radiation – both ionising and non-ionising – contributes to up to 10% of total cancer cases. Ionising radiation sources include radioactive substances and medical X-rays, leading to cancers like leukaemia, lymphoma, thyroid cancer, skin cancer, sarcoma, lung cancer and breast carcinomas.
Notably, the 1986 Chernobyl incident in the then-Soviet Union underscored the increased cancer risk from radioactive fallout. Radon exposure, primarily in homes and workplaces, poses a significant risk for gastric cancer. Medical X-rays, especially during puberty, elevate breast cancer risk.
Patient age, synergistic interactions with carcinogens, and genetic susceptibility, influence radiation-induced cancers. Non-ionising radiation, notably UV (ultraviolet) rays from sunlight and sunbeds, contribute to skin cancers like basal cell carcinoma, squamous cell carcinoma and melanoma. Ozone layer depletion exacerbates UV exposure risks.
Low-frequency electromagnetic fields from power lines and electrical equipment increase the risk of childhood leukaemia, brain tumours and breast cancer. Prolonged mobile phone use is associated with an increased risk of brain tumours, as shown in recent meta-analyses.
By Datuk Dr Nor Ashikin Mokhtar
Published in Star Newspaper, 20 May 2024
