Why cancers start?
Within each cell in the human body lies a structure called a nucleus, containing strips of material called DNA. To be precise 46 strips each containing millions of packages of information called genes. These genes are the codes and templates for all the functions of the entire human body. In particular they code for the development of organs and structures of an exact size telling cells when to grow and exactly when to stop and when to die after a precise number of cell cycles to make room for healthy new cells. That’s why our skin is a certain thickness, the hairs on our arms stop growing at a precise length but when we cut ourselves skin is able to grow at an alarming rate but stop when it is healed. These growth signalling and check point genes have evolved over the centuries through countless generations to produce the humans we know today. Over this time, however, our genes have picked up a considerable amount of genetic debris from non-fatal mutations generated through spontaneous damage or infections particularly viruses. Some of this debris includes strips of genes that interfere with growth mechanisms growth leading to cancer but are kept from doing harm by other genes, which lie next to them on the same strip of DNA. These good genes, called tumour suppressor genes, have an essential function of guarding the body from the bad cancer genes, called promotor oncogenes.
Various types of genetic damage can occur such as point mutations, deletions, inserions or even copies of strips of chromosoames. Ultimately, they alter the normal sequence of genes separating (translocating) the suppressor genes from the promotor genes or placing oncogenes next to genes causing amplification or over expression of their function, which are the first steps why cancers start. The first evidence of tranlocated DNA causing cancer discovered in Chace Fox Hospital, Philadelphia in 1959. Scientist showed that a type of leukaemia called Chronic Myeloid Leukaemia (CML) cells had a translocation of a strip of DNA between chromosome 9 and chromosome 22. Later they were able to successfully target their specific abnormal function caused by this damage with a drug called Glevec (imatinib). This and other subsequent drugs are now keeping people with CML alive and well for many years when it wass previously fatal.
Numerous other promoter oncogenes have been discovered so far which when activated, promote development, abnormal growth and spread of many cancers. Targeting the function of these oncogenes with antibodies or drugs such as tyrosine kinase inhibitors has resulted some successful anti-cancer biological therapies, for example:
- HER-2 (breast) – transuzumab (Herceptin)
- VEGF – colon, breast, kidney – bevacizumab (Avastin)
- B-RAF (melanoma) – vemurafenib (Zelboraf) and dabrafenib (Tafinlar)
- C-KIT (GIST tumours) – imatinib (Gleevec) and nilotinib (Tasigna),
- EGFR (Lung) – erotinib (
- EGFR (Colon) – cetuxinab (Erbitux)
Many other oncogenes such as a mutated form of RAS (pancreas, prostate) and Cyclin D1 (head and neck, oesophagus) have been shown to be important in the start of cancer and the race is on to develop drugs which target the abnormal metabolic processes causes by their over expression.
Essentially therefore we were born with the tendency to get cancer – it is part of us! DNA damage leading to amplification of our own genes or mutated versions of our own genes could result in 4 scenarios:
- Immediate death of the cell,
- Damage which the cell repairs and subsequent grow is normal
- Not repaired but the damage doesn’t effect growth regulation
- Not repaired and the cells continues to grow dysfunctionally
These genetically dysfunctions cells are the seeds of the cancer but many other pathways are required before they develop into full blow cancer. In particular in the early stages whether they are identified and killed by our immunity. It has been estimated that standing in strong sun for few hours will generate over three thousand genetic dysfunctional which could go on to form cancer but are dealt with efficiently by the immune killer cells. This importance on the immunity is discussed further below.
Considering that our cells divide millions of times a day, many sustaining spontaneous mutations in the process risking rearrangement of the thousands of potential cancers already programmed in our DNA it does not come as a surprise that one in two of us will get cancer at one stage in our lives. Perhaps instead of asking “why me?” when we develop cancer, we should be asking “why not me?” when we don’t.
Why does one person get cancer and another does not?
We have all come across people who have been diagnosis with cancer, who have lived a perfectly healthy lifestyle whilst some hardened smoking, junk food aficionados can live until their 90’s. This does not mean the majority of us should adopt a nihilistic approach to our health because, as all gamblers know it’s about improving our odds. As mentioned in the introduction, medical think tanks such as The World Cancer Research Fund and Cancer Research UK (CRUK) estimate that up to 50% of cancers are likely to be related to lifestyle as opposed to genetic susceptibility or just chance spontaneous formation. Furthermore, The World Health Organization estimated that the fraction of cancers attributable to carcinogen exposure is between 10-20%.
Some people are fortunate to be born with their cancer genes locked in tightly by very stable suppressor genes resulting in a very robust DNA profile. Others have DNA, which can be easily damaged or worse have been born with defective genes or repair mechanisms, which make cancer almost inevitable. Most people, however, are somewhere in between these two extremes but what ever risk group you are in, a healthy lifestyle can either reduce the odds of cancer forming, delay the age of diagnosis or result in less aggressive types developing which are more easily treated.
The situation of identical twins can exemplify the nurture over nature discussion. Due to the common genes that are shared by identical twins there is an increased likelihood that the twin of a person diagnosed with cancer will suffer from the same disease. Recent studies among Scandinavian twins have for breast cancer in women it was found that heritability accounted for 27% of the variation in susceptibility to this form of cancer. Environmental factors that were shared by both twins explained 6%, and environmental factors not common to the pair contributed 67%. This means that the most important contributor to the causation of breast cancer is non-genetic or environmental, even under circumstances where the genetic background is very similar. Other studies shave been published showing similar results for other cancer types.
Even if an individual has a defective genetic syndrome, often associated with grow defects, which carries an increased cancer risk, the severity of the syndrome could change from one person to another. This is called penetrance and is often affected by other genes, which effect similar biochemical pathways. Lifestyle choices, also have a considerable influence on how genes are expressed – a process called epigenetics, which will be explained further below. Other important factors include the level of immunity and exposure to carcinogens.
The lifestyle and nutritional factors which influence our genes and hence the risk of cancer and its progression are the highlighted in the various sections in the rest of this book. In the mean time, they be as a summarised into the following categories:
- The genes your were born with (Genetic susceptibility)
– Cancer suppressor genes
– Cancer promotor genes
– DNA repair genes
- Medical interventions
– Screening for early detection
– Targeted interventional investigational procedure
– Immune surveillance
– Chronic inflammation
– Immunotherapy agents
- Carcinogen exposure
– Chronic environmental and nutritional exposure
– Acquired genetic risk from a previous carcinogenic event
- The epigenetic expression of our genes by:
– Polyphenol and phytochemical intake
– Process sugar intake
– Body composition
– Mineral and vitamin status
– Healthy and unhealthy fat balance
– Psychological status
1. Genetic cancer susceptibility (genes you were born with)?
Some families have higher rates of cancer because they have similar unhealthy habits such as smoking, watching too much TV and eating junk food. Other families are unlucky because they have genetic defects in their genes that increase their risks of cancer. This does not mean people actually inherit cancer or even catch cancer from another member of their family, but their susceptible genes are passed through their children to future generations. They are either autosomal dominant or recessive. If autosomal dominant, only one of the pair of genes (either coming from the mother or father) needs to be defective to be a risk and express of the syndrome. If recessive both pairs of genes (from a mother and father) are required for the syndrome to be apparent. So if a man familial adenomatous polyposis (FAP) congress (an dominant gene) met a women without FAP there is a 50% risk that their child will have FAP. If a couple met at the xeroderma pigmentosa (XP) annual congress (a recessive gene) had sex, their offspring would have a 100% chance of the syndrome. On the other hand, if a woman with XP falls in love and mates with an unaffected man, none of their children will be affected but 50% will be carriers. If two persons unknowingly carrying the gene mated, 25% will develop XP, 50% would be carriers and 25% would not be carriers.
Testing for genetic syndromes.
The few inherited cancers that doctors can test for at the moment, include those linked with breast, ovarian, bowel and womb cancers. More research is happening all the time so if you have a strong family history of other cancers it is still worth going to the doctor because even if they don’t know much about your particular gene you could enter a study which may help scientists find out more about it for future generations. Consider testing if you have:
- Two or more first-degree relative (brother, sister, child or parent), with breast or ovarian cancer especially under 50 years
- A male close relative with breast cancer
- One first-degree relative with prostate cancer < 60 years
- Two or more second-degree relative, (grandfather, grandson, uncle and nephew diagnosed) with the same cancer
The first stage of genetic testing is to be referred to specialist genetic team. They will discuss your situation, draw up a family tree of your close relatives and their illnesses, listen to your concerns and advise you on your and your families risk of developing cancer. They may test your blood for genetic defects testing. They will discuss strategies to reduce your risk, which could include lifestyle advice, having regular screening tests such as mammograms and colonoscopies or even medical interventions such as drugs or removing organs at increased risk.
Types and mechanisms of genetic cancer susceptibility.
There are several classes of germline mutations in genes (genes you were born with) that may be involved in cancer development and promotion. Fortunately they are rare and even if present they can alter in their ability to cause cancer (Penetrance) by other surround genes and expression altered by epigenetic lifestyle factors. Only a minority of all cancers are caused by germline mutations, whereas the vast majority (90%) are linked to acquired mutations and environmental factors. The main categories of suscepyibility genes include:
- Tumour suppressor genes,
- Genes involved in DNA repair and cell cycle control
- Genes involved in stimulating the angiogenic pathways.
Tumour suppressor genes; The paradigm of inherited alterations in tumour suppressor genes (TSG) was first elucidated by Knudson and colleagues in the 1970’s after recognizing that a rare cancer of the eye (retinoblastoma) was seen in 50% of the offspring of sufferers – i.e. an autosomal dominant pattern. Now the list cancer susceptibility conditions linked to TSG that have been discovered now includes:
- Inherited retinoblastoma syndrome – eye
- Familial adenomatous polyposis (FAP) – polyps and bowel
- Gorlin Syndrome – Skin cancers
- Cowden syndromes – skin, mucsle, brain
- Neurofibromatosis types 1 and 2 – Skin, brain
These genes keep the bad genes in check, so their normal function is important. These genes can be damaged directly or damage to the DNA rearranges them away from the abnormal genes they are suppressing. Either way, this lack of control initiates the cancer sequence. FAP is a good example, caused by germline mutations (mutations a person has been born with) in the APC gene. Multiple adenomas begin to develop in the large bowel from the early teenage years, as the premalignant lesion. These usually develop into a cancer by the age of 40 years if the polyps are not removed. Currently, it is possible to detect mutations in the APC gene in up to 82% of families. Predictive genetic tests are available to the at-risk relatives of an affected individual once the mutation has been detected in an affected person in the family. Screening of at-risk relatives is usually by annual colonoscopy screening and if the polyps cannot be removed fast enough preventative removal of the whole Colon is often considered.
Oncogenes; Inherited mutations in oncogenes are rarer and syndromes are often associated with growth defects Noonan’s syndrome or multiple adenomas as in multiple endocrine neoplasia type 2. MEN2 is due to inherited mutations in the RET oncogene, and predisposes to medullary thyroid cancer with early onset, phaeochromocytomas and parathyroid hyperplasia. Management of mutation carriers includes prophylactic thyroidectomy in childhood, and annual screening for phaeochromocytoma. Numerous genes have be studied but ones which seems particularly important oncogenes are known as the RAS oncogenes which, when activated, promotes cancer growth (a promoter oncogens). There does not seem to be any syndromes which enhance RAS expression but it is overexpression in many cancers. A prospective trial involving men with low-risk prostate cancer, called the GEMINAL study, found the RAS oncogenes to be down-regulated after exercise and polyphenol rich foods. This is also important for the prostate caner (which is stimulated by the male hormone androgen) because the proteins produced as a result of RAS overexpression activate the androgen receptor. This explains why exercise (which inhibits RAS expression) slows cancer progression in men on active surveillance.
DNA repair genes; Some genes control pathways which help mend DNA mutations, so play a critical role in maintaining genetic stability so protecting us from cancer. DNA repair defects are a common cause of inherited cancer susceptibility, and many examples have now been recognized, including
- Ataxia telangectasia,
- Fanconi anaemia
- Xeroderma pigmentosum
- Hereditary non-polyposis colon cancer (Lynch syndrome)
- Breast cancer susceptibility – BRCA1 and BRCA2.
Li-Fraumeni syndrome is a rare disorder that greatly increases the risk of developing several types of cancer, particularly in children and young adults. As described in the previous section the role of the P53 to slow the cell cycle if it has sustain some partially genetic damage. This allows DNA repair to take place. If repair is not possible it does not allow the cell to divide with damaged DNA, which could eventually cause cancer. Instead it triggers pathways to tell the cell to commit suicide – this is called programmed cell death or apoptosis. The cancers most often associated with Li-Fraumeni syndrome include breast cancer, form of bone cancer called osteosarcoma, and cancers of soft tissues (such as muscle) called soft tissue sarcoma. Other cancers commonly seen in this syndrome include brain tumors, cancers of blood-forming tissues leukaemias and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney). Several other types of cancer also occur more frequently in people with Li-Fraumeni syndrome.
Hereditary non-polyposis colon cancer (HNPCC), also known as Lynch syndrome, is one of the commonest forms of inherited predisposition to colorectal cancer (CRC), accounting for about 5% of all CRC. Lynch syndrome is caused by an autosomal dominant germline mutations (born with) in one of the mismatch repair (MMR) genes. CRC in individuals with HNPCC differs from sporadic form as they present at an earlier age, are mainly on the right sided colon cancers and an increased propensity to synchronous (one after an another) or metachronous (more than one cancer presenting at the same time) cancers. Individuals with HNPCC have an 80% probability of developing CRC by the age of 65 years. In addition, affected individuals are at increased risk of a number of extra-colonic malignancies, such as uterus in women and a rare type of seat gland skin tumour. Several published studies have fairly consistently suggested that smoking, a high BMI and excess alcohol intake markedly increase the risk of CRC in persons with LS. Whilst physical activity, regular aspirin intake and a healthy diet reduce the risk.
Women with autosomal dominant germline mutations in tumor suppressor genes, BRCA1 or BRCA2 have a high risk of developing breast and ovarian cancer. Fortunately, these are still rare with such mutations account for about 5% of all breast cancers. Although the structures of BRCA 1&2 are different, they both have important caretaker functions in the DNA process. BRCA 1 senses damage to DNA and signals BRCA2 and other genes to initiate repair processes. Detecting and repairing double or single strand breaks maintains the stability of the human genome and prevent dangerous gene rearrangements that can lead to cell death or cancer.
A meta-analysis of 500 families with BRCA1 and BRCA2 mutations studies has estimated the risks of breast and ovarian cancer in BRCA1 carriers to be 65% and 40% by age of 70 years, respectively. For BRCA2 the risk was 45% for breast cancer and 11% for ovarian cancer, respectively. BRCA1 carriers also have a statistically significant increased relative risk of pancreatic cancer and a slight increased risk of uterine and prostate cancer diagnosed under the age of 65 BRCA2 mutation carriers also have a statistically significant increased relative risk of stomach, malignant melanoma, prostate, gallbladder and pancreas.
There is good evidence that removal of the ovaries and fallopian tumor (salpingo-oophorectomy) halves risk of breast cancer in women, both in the general population and in BRCA1/2 mutation carriers and is thus a prophylactic option for women who carry BRCA1/2 Prophylactic mastectomy decreases the risk of breast cancer in BRCA1 mutation carrier by 90%. The public awareness of this procedure was raise to prominence after the actor Angelena Jollie discovered she carried the defect. She chose double mastectomy in 2013 the oophorectomy in 2015.
Although this seems as a sensible approach, it is not the only option. Women can opt for regular MRI and/or ultrasound surveillance, which do not involve x-rays. Woman carriers with breast cancer’s which are sensitive to oestrogen may will often take drugs such a tamoxifen or aromatase inhibitors which is likely to reduce the risk of a new cancer forming. Likewise, although more research is needed, lifestyle factors clearly have a role in reducing risk. In one study, women carrying of BRCA mutations born before 1940, had a 24% the risk of developing breast cancer before 50 years but who were born after 1940, had a 67% This difference was though to be due to increases in obesity rates, smoking and alcohol intake over the century. This was corroborated in other studies which showed that physical activity and leanness delay disease onset of cancer in predisposed women Both laboratory experiments and studies involving women who were born with mutations of BRCA 1 or 2 have shown that exercise up regulates BRCA expression. Regular exercise also has positive effects directly on other repair mechanisms including those involving the cellular policeman p53. This strongly suggests that carriers of BRCA mutations would get an even greater benefit from exercise.
For women with established cancers the treatment is changing. New biological drugs which inhibit poly (ADP-ribose) polymerase (PARP) and adding carboplatin to regimens appear increasingly effective in treating cancers in women with BRCA1 and BRCA2 mutations because their tumours lack the ability to repair DNA damage. The future could be that specific drugs could be developed to help women with the mutation to prevent cancer development
Angiogenesis genes: Alterations in genes which are involved in the vascular endothelial growth factor (VEGF) pathway, can lead to abnormal stimulation of blood vessel growth (angiogenesis). Individuals with these mutations either have von Hippel Lindau disease or something similar and are at high risk of rare cancers such as:
- cerebellar haemangioblastomas,
- renal cell cancers
People with these mutations require careful monitoring at least annually but fortunately, treatment of these tumours with anti-angiogenic agents is looking encouraging.
2. Medical interventions to reduce cancer risks
These can both increase and decrease the risks of cancer. The section on carcinogens highlights the increased risk of bowel and bladder cancer after radiotherapy to the abdomen in young men with a testicular seminoma. Women with Hodgkin’s Lymphoma have an increased risk of breast cancer after mantle radiotherapy to their chest and all patients have a marginal increased risk of leukaemia years after a course of curative chemotherapy. Woman taking long-term contraceptive pill have a higher risk of breast cancer and patients prescribed immunosuppressive drugs after transplantation have a higher risk of multiple cancers.
On the other hand, several medical interventions can reduce the risk of cancer and the most notable examples include:
Screening for early or precancerous cancers – general public
- Breast mammography
- Faecal blood analysis
- PSA screen in some countries
Targeted exploratory procedures for at risk populations
- Breast MRI in BRCA carriers or those previously irradiated
- Regular colonoscopy – previous cancers, polyps, or genetic risks
- Regular cystoscopy – previous bladder polyps
- Double mastectomy – BRCA mutation carriers
- Removal of ovaries – BRCA mutation carriers
- Removal of large bowel – genetic risk or ulcerative colitis sufferers
- Vaccination of HPV to prevent cervical cancer
- Tamoxifen for women with a higher risk of breast cancer
- Aspirin for people with a history of bowel polyp
As the understanding of what genetic and biochemical factors cause cancer, it is very likely that more chemopreventative strategies will be available especially in the area of vaccinations against cancers.
The interaction between the immunity and cancer is complex and extremely important. An intact, functioning immunity is a vital to prevent cancer forming and killing thousand of early cancer cells which form every day. For established cancers, a healthy immunity ensures the effectiveness of biological therapies that recruit killer cells and other natural weapons to attach them. On the other hand, a chronic abnormally dysfunctional immune inflammatory response can increase the risk of cancer and enhance its progression. In view of the importance and complexity of the immunity a whole chapter has been dedicated to lifestyle manoeuvres with could enhance it whilst avoiding the problems of chronic over inflammation.
4. Carcinogens and acquired genetic susceptibility
Carcinogens, can directly damage DNA causing mutations and hence cancer. They also have numerous modes of actions which can indirectly increase cancer risk by interfering with other importance, defence and repair pathways including epigenetics expression of genes, causing chronic inflammation, lowering the immunity and abnormal stimulation of hormone receptors. In view of the importance and complexity of previous and on-going carcinogen exposure a whole chapter has been dedicated to this subject.
This term is being used more commonplace over the last few years, in fact it was not even mention in the last edition of this book. It described a series of processes with alter the expression of both the genes we were born with (germline genes) and those acquired by cancers (somatic mutations). Expression means the influence that gene has on the function or growth of the cell. Highly expressed mean they have a strong influence, which could lead to altered biochemical function and malignant cellular transformation. On the other hand, epigenetic mechanism could reduce expression or even “silence” genes preventing their down stream influences on the cell and body. In the normal function of the body Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals as they help turn genes on and off at appropriate times – eg in a normal circadian rhythm.
In terms of cancer, if epigenetic processes increase expression of a tumour suppressor gene and decrease expression of a tumour promotor gene this would lead to a reduced risk of cancer or slower cancer progression. On the other hand, if adverse factors such as chronic inflammation and continued carcinogen exposure influence the epigenetic processes to switch off suppressor genes and switch on promotor genes, cancer is more likely to develop and progress.
The mechanics of epigenetics: This is a complex process relates to how the gene is presented to the mRNA, which is what forms the proteins from the gene template that then signal growth or metabolism. The components of the epigenetic machinery include DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs the precise roles of which are beyond the scope of this book. Put simply they can alter the supportive components (chromatin) of DNA which are responsible for the winding and unraveling of the helix. If the gene is hidden from the RNA by tightly woven chromatin structures within the DNA it is difficult for the RNA to reach it. This relationship between the genes and the surrounding structures was first defined by the British Biologist Conrad Waddington in 1956 but it’s only in the last few years that its relationship with lifestyle is becoming appreciated.
The rest of this section will address the lifestyle factors which can influence the epigenetic expression of both the genes we were born with and those acquired in cancer cells. In summary they are: