Genetic Cancers: Welcome back to “The Science Of Health”, ABP Live’s health column. Last time, in the health column, we discussed the difference between small cell lung cancers and non-small cell lung cancers, and explained why small cell lung cancers are less common than non-small cell lung cancers, despite the former spreading faster than the latter. This week, we delve deep into the role played by genetics in determining which people have a greater risk of cancer, the kinds of mutations and genetic changes that lead to cancer, and the scientific basis behind people developing hereditary cancers.
The human body contains millions of cells, and inside each cell lies genetic material in the form of DNA (deoxyribonucleic acid). Clumps of DNA together form genes, which code for proteins. DNA is a double-stranded molecule, and made of up chemical bases which are of four types: adenine, guanine, cytosine, and thymine.
These bases are arranged in a certain order in genes. When their arrangement is out of place, or a base is replaced by a different one, a mutation is said to occur. Certain mutations can lead to cancer, and the genes which contain these mutations are referred to as cancer genes. The presence of cancer genes in a person’s body increases their chance of suffering from cancer.
Check ABP Live’s stories explaining the science behind various health phenomena, and the articles appearing in the weekly health column here.
Role of genetics in determining which people have a greater risk of cancer
Only about five to 10 per cent of all cancers are hereditary, and in families with hereditary cancer, a genetic mutation has been identified as the reason behind the family members developing cancer.
Different cancers have different likelihoods of being hereditary. For instance, lung and skin cancers have a lower likelihood of being hereditary. Meanwhile, ovarian cancer has a 15 to 20 per cent chance of being hereditary.
Some of the signs which may be indicative of a cancer being genetic include being diagnosed with cancer at a young age, which is usually 50 years for breast or colon cancer, having multiple people in a family diagnosed with the same or related cancers, having cancer in both sides of a paired organ, such as both breasts or both kidneys, genetic testing identifying some type of genetic mutation in individuals or families, being diagnosed with a rare cancer at any age, having multiple primary cancer diagnoses in the same person, and being of certain ethnic backgrounds, among other scenarios, according to the Memorial Sloan Kettering Cancer Center, a Manhattan-based cancer research and treatment institution, and the world’s oldest and largest private cancer centre.
In order to understand more about the role played by genetics in determining which people have a greater risk of cancer, ABP Live spoke to Dr Amit Verma, Molecular Oncologist and Cancer Geneticist, Dr AV Cancer Institute of Personalized Cancer Therapy and Research, Gurugram; and Dr Kanury VS Rao, Co-Founder and Chief Scientific Officer, PredOmix, a Gurugram-based health-tech company.
The acquisition of faults or mutations in genes cause a normal cell to be transformed into a cancerous one. When faults in genes are acquired, the resulting cancer is called sporadic cancer, which means that it occurs due to chance or the environment. When mutations are inherited, the resulting cancer is called a hereditary cancer.
The body can repair these faulty genes through DNA repair mechanisms, preventing the development of cancer.
“The underlying mechanism of the transformation of a normal cell into a cancerous cell lies in the acquisition of faults in the genes. The faults in the genes can be acquired (multifactorial), resulting in sporadic cancer, or can be inherited. Such cancers are called hereditary cancers. The body has a mechanism to repair these faulty genes (DNA repair mechanism), which prevents the development of cancer. Exposure to various carcinogenic factors followed by failure to repair the abnormalities lead to the accumulation of the alterations in the genes (genetic mutations). During subsequent cell division cycles, the cells grow fast, leading to cancer,” said Dr Verma.
Involvement of genes in the development of cancer is not a novel concept. Genetic variations disrupt critical cellular processes, increasing the risk of cancer. Mutations can disrupt such mechanisms. Some examples of genetic mutations that increase the risk of cancers include BRCA1/2 mutations, that impair DNA repair, and raise the risk of breast and ovarian cancers; KRAS mutations, which increase the risk of colorectal, lung or pancreatic cancers by promoting uncontrolled cell growth; TP53 mutations, which increase the risk of breast, ovarian, colorectal and lung cancers by inactivating TP53, a tumour suppressor gene, leading to abnormal cell proliferation; and RET mutations, which lead to thyroid tumorigenesis, among others.
“Cancer, a global health challenge causing significant mortality and morbidity, is influenced by genetics, lifestyle, and environment. The concept of gene involvement in cancer is not new. Genetic variations impact cancer risk by disrupting critical cellular processes. Mutations in specific genes can disrupt normal cellular regulation, leading to an elevated predisposition to cancer. Certain genetic mutations, like those in BRCA1/2 mutations, impair DNA repair, raising breast and ovarian cancer risk. Mutated KRAS increases the risk of several cancers, including colorectal, lung, and pancreatic cancers, by promoting uncontrolled cell growth. Mutations in TP53 also elevate cancer risk, as this tumour suppressor gene’s inactivation allows abnormal cell proliferation, contributing to various cancers like breast, ovarian, colorectal, and lung cancers. Alterations in RET are frequent key events in thyroid tumorigenesis,” said Dr Rao.
While hereditary cancers account for only five to 10 per cent of all cancers, heritable BRCA1 and BRCA2 mutations are quite prevalent in India. The incidence of heritable BRCA1 and BRCA2 mutations in India is 30 per cent, which is thrice that in the West, according to Dr Rao. “Genetics, environment, and lifestyle collectively influence cancer risk. Genetic testing aids tailored prevention, detection, and risk management.”
Kinds of mutations and genetic changes that lead to cancer
Genetic and epigenetic alterations in cells can lead to cancer, and these modifications can be studied using certain technologies. The difference between genetic and epigenetic alterations is that in the case of genetic changes, a permanent damage to the DNA is caused, while in epigenetic changes, the DNA is not permanently damaged. Using special technologies, one can study genes at the DNA level, and also the effect of genetic alterations on the RNA (ribonucleic acid), and on proteins, said Dr Verma. “The common technologies used are Polymerase Chain Reaction, Sequencing, Fluorescence In Situ Hybridisation (FISH), Microarray, Karyotyping for the purpose of identification of four classes of genetic alterations i.e., Single Nucleotide Variations (SNV), insertions and deletions, Copy Number Variations (CNV), and translocations.”
FISH is a technique that helps locate specific DNA sequences, diagnose genetic diseases, map genes, and identify novel genetic aberrations.
In microarray technology, an array of thousands to millions of known nucleic acid fragments is bound to a solid surface, which is referred to as a chip, following which the chip is bathed with DNA or RNA isolated from a study sample, say cells or tissues. After this, complementary base pairing occurs between the sample and the fragments on the chip, and through fluorescence, light is produced. Any genetic aberrations can be detected using a specialised machine.
Karyotyping tests chromosomes, and a copy number variation is a situation in which the number of copies of a specific segment of DNA varies among the genomes of different individuals.
It is important to identify and understand genetic variations in order to figure out suitable therapies based on the alterations. If a particular individual carries abnormal genes, they may pass these genes on to the next generation. The offspring may have a risk of developing hereditary cancer, and hence, must be made to undergo cancer preventive techniques.
According to Dr Verma, a higher probability of cancer is observed in the cells which are either highly exposed to carcinogens, or multiply faster than other cells. Cells which are highly exposed to carcinogens include lung epithelium, which is exposed to tobacco. Colon epithelium cells multiply faster compared to other cells. Therefore, lung epithelium cells are at an increased risk of developing lung cancer, and colon epithelium cells are at a greater risk of having colon cancer.
DNA mutations can be described as typographical errors in the DNA sequence. Mutations may affect nucleotides, which are single letters in the DNA. Certain nucleotides may either be absent or replaced, resulting in point mutations, said Dr Rao. For instance, in five per cent of cancers, G-to-A point mutation occurs in the KRAS gene. This means that guanine is replaced by adenine. When this happens, abnormal KRAS proteins are produced. These abnormal KRAS proteins drive relentless cell growth, according to Dr Rao.
Chromosomal rearrangements can also lead to cancer. In chromosomal rearrangements, large-scale DNA segments rearrange, delete or duplicate, Dr Rao explained.
Gene fusion is also a form of mutation. The fusion of the BCR and ABL genes leads to the formation of BCR-ABL proteins, which trigger excessive cell growth, and lead to chronic myelogenous leukaemia (CML), a type of blood cancer, said Dr Rao.
Genes are not the only place where cancer-triggering alterations occur. These aberrations can occur in DNA segments serving as switches for nearby genes, Dr Rao explained. “Brain cancer cells might amplify these switches, supercharging growth-promoting genes.”
This means that if one suffers from brain cancer, the brain cancer cells may increase the number of DNA segments that serve as switches for nearby genes. If these DNA segments have cancer-triggering alterations, they may increase the number of growth-promoting genes, and raise the risk of cancer.
Epigenetic changes or shifts, also known as epimutations, do not directly modify the DNA code, but alter how DNA is organised in the cell nucleus. This influences the production of gene-related proteins, said Dr Rao. “Environmental substances, like tobacco smoke and viruses, can induce both genetic and epigenetic alterations, further underscoring their roles in cancer development.”
The scientific basis behind people developing hereditary cancers
Human bodies naturally have tumour-suppressor genes, which are meant to protect people from cancers. In each cell, there are two copies of tumour-suppressor genes, one of which is inherited from the mother, and the other is inherited from the father.
If a random genetic mutation occurs on one copy of the tumour-suppressing gene in one cell of the body, due to age or environmental exposure, it is as though the back brakes on a car stop working. If the other copy also undergoes a random genetic mutation later on in the person’s life, it is as though the front brakes on the car also stop working. After this, the person is likely to suffer from sporadic or non-hereditary cancer, because all the brakes on the car have failed.
However, in the case of hereditary cancer, each cell in the body of a person has one copy of a tumour suppressor gene that already has a genetic mutation, the situation being similar to that of a car without any back brakes. A random genetic mutation occurring in the other copy of the tumour-suppressor gene can cause cancer in the person.
When people are born with a faulty copy of the tumour-suppressing gene in each cell, the chances of the other copy developing a mutation is high, and hence, hereditary cancers tend to develop earlier in life.
Up to 50 per cent of sporadic cancers are preventable by avoiding exposure. However, the ability of multiplying cells to repair genetic alterations decreases with ageing, and hence, the chances of cancer also increase with age. Meanwhile, inherited genetic alterations passed on from one generation to the next put a person at a higher risk of developing cancer, and cannot be corrected, said Dr Verma. “Inheriting a cancer-related genetic change does not mean the person will definitely get cancer. The reason behind this is that every gene has two copies (one inherited from the mother and the other from the father). The normal gene decreases the cancer probability. But sometimes, the normal gene can become abnormal, and increase the risk of developing cancer.”
There are different ways in which genetic conditions are passed on from one generation to another. Some mutations are autosomal dominant, which means that if an offspring inherits one copy of a mutated gene, it is enough to increase the risk of cancer development in the person. The chance of inheriting an autosomal dominant mutation from the mother is equal to that from the father.
The five genes associated with Lynch syndrome, which increases the risk of developing cancers such as colorectal cancer at a young age, are examples of autosomal dominant cancer genes.
Autosomal recessive mutations are the ones in which a person is at risk of developing a cancer only if the mutations are inherited from both parents. Xeroderma pigmentosum, which causes extreme sensitivity to sunlight, leading to skin cancer, is an example of an autosomal recessive cancer syndrome.
Certain people inherit only one copy of an autosomal recessive mutation. Such people are called carriers. While being a carrier is not detrimental to their health, they are at an increased risk of developing certain types of cancers, especially if a mutation occurs in the other copy of the gene.
When both parents are autosomal recessive mutation carriers, the offspring has a 25 per cent of inheriting genetic mutations from both parents, and have the associated condition.
If a child inherits a mutated BRCA1 or BRCA2 gene, they are at an increased risk of breast cancer, said Dr Rao. He explained that certain mutations trigger multi-organ cancer within families. For instance, Li-Fraumeni syndrome increases one’s susceptibility to breast, bone and brain cancers.
In rare cases, a genetic alteration may occur during embryonic development. While the mutation is not inherited either of the parents, the person may pass the alteration on to the future generation.
Check out below Health Tools-
Calculate Your Body Mass Index ( BMI )