Genetic causes of different types of cancer

The role of genetic factors in the development of specific types of cancer

Scientists today know that the process of cancer growth begins when one or more genes in a cell undergo a mutation process. This means that the gene either begins to code for a changed, abnormal protein, or changes so much that it no longer codes for the protein at all. As a result, the normal processes of cell growth and division are disrupted, which can lead to the formation of a malignant tumor.

Genetic mutations can occur during different periods of human life: if they occur before a person is born, then all cells in the body will contain this mutated gene (germ mutation), and it will be inherited, or the mutation can occur in a single cell of the body in throughout life, and the altered gene will be contained only in the descendant cells of the single cell in which the mutation occurred (somatic mutations). Most malignant diseases develop as a consequence of a random mutation in a single cell, the further division of which produces tumor progeny. However, about 10% of cases of malignant neoplasms are hereditary, that is, a mutation that predisposes to cancer is passed on from generation to generation.

What is the probability that the altered gene will be inherited?

Any cell in the body contains two copies of the same gene, one of these copies is inherited from the mother, the other from the father. When a mutation is transmitted from parents to a child, it is present in every cell of the child’s body, including the cells of the reproductive system – sperm or eggs, and can be passed on from generation to generation. Germ cell mutations are responsible for the development of less than 15% of malignant tumors. Such cases of cancer are called “familial” (that is, passed on in families) forms of cancer. However, inheriting one copy of the altered gene does not mean that the tendency to develop a certain type of tumor is also inherited. The fact is that hereditary diseases can have different types of inheritance: dominant, when one inherited copy of the gene is enough to develop the disease, and recessive, when the disease develops if the altered gene is received from both parents. In this case, parents who have only one altered gene in their hereditary apparatus are carriers and do not themselves get sick.

Genetics of breast cancer

Most cases of breast cancer (BC)—about 85%—are sporadic, meaning gene damage occurs after a person is born. Congenital forms of breast cancer (about 15%) develop when a mutant form of the gene is inherited by the patient, passed on from generation to generation. There are several types of genes that are involved in the development of breast cancer, including mutations that cause loss of tumor suppressor genes.

In accordance with their name, “tumor suppressor genes” prevent the occurrence of tumor processes. When their activity is disrupted, the tumor is able to grow uncontrolled.

Normally, each cell in the body carries two copies of each gene, one from the father and one from the mother. Breast cancer is usually inherited in an autosomal dominant manner. With an autosomal dominant mode of inheritance, it is sufficient for the mutation to occur in only one copy of the gene. This means that the parent who carries a mutant copy of the gene in its genome can pass on both it and a normal copy to its offspring. Thus, the probability of transmitting the disease to a child is 50%. The presence of a cancer mutation in the genome increases the risk of developing tumors that are specific to this mutation.

What is the average risk of developing breast cancer?

The average woman has a lifetime risk of developing breast cancer of about 12%. According to other data, every 8th woman will develop breast cancer during her lifetime.

How common is breast cancer?

Breast cancer is the most common tumor in women (excluding skin cancer, which is very common in old age) and the second most common cause of death from tumors after lung cancer. Breast cancer also occurs in men, but its frequency is approximately 100 times lower than in women.

In order to identify individuals at risk for developing breast cancer, it is recommended to conduct genetic testing among patients with a family history of breast cancer. Most experts insist on conducting a preliminary consultation with a geneticist before deciding to undergo genetic testing. The specialist must discuss with the patient all the pros and cons of genetic testing, so it is necessary to make an appointment with a geneticist.

What should a woman know about the likelihood of breast cancer transmission in her family?

If close relatives (mother, daughters, sisters) have breast cancer, or if other family members (grandmothers, aunts, nieces) have had this disease several times, this may indicate the hereditary nature of the disease. This is especially likely if the diagnosis of breast cancer was made to one of the relatives who has not reached the age of 50 years.

If first-degree relatives (mother, sister or daughter) develop breast cancer, then the risk of developing the disease increases by 2 times compared to the average. If two of your close relatives become ill, then the risk of developing breast cancer during your lifetime is 5 times higher than the statistical average. At the same time, it is unclear how many times the risk of getting the disease increases for a woman whose family has had a male relative with breast cancer.

What hereditary mutations increase the risk of developing breast cancer?

There are several genes associated with an increased risk of breast cancer. The most common syndromes associated with an increased risk of developing breast cancer are described below.

• Hereditary breast-ovarian cancer (HBOC) syndrome. The BRCA1 and BRCA2 genes (BRCA = BReast CAncer) are tumor suppressor genes that are damaged in familial breast cancer syndrome. Those women who are carriers of a mutant form of the BRCA gene have a 50-85% chance of developing breast cancer during their lifetime. However, their risk of developing ovarian cancer is about 40%. Men who carry mutant forms of the BRCA1 or BRCA2 genes in their genome may also have an increased risk of developing breast or prostate cancer. Both men and women who have a BRCA2 gene mutation may be at increased risk of developing breast cancer or other cancers. The mutant form of the gene has a certain accumulation in some ethnic groups, for example, approximately one in 50 Ashkenazi Jewish women carries a congenital mutation in the BRCA1 or BRCA2 gene, which increases the risk of developing breast cancer during life to 85% and the risk of developing ovarian cancer to 40 %. It is currently known that about 80% of all hereditary breast cancer are caused by mutant forms of the BRCA1 and BRCA2 genes.
• Ataxia-telangiectasia (A-T). A hereditary syndrome called ataxia-telangiectasia is caused by a mutation in a gene located on chromosome 11, the so-called ATM gene. With this syndrome, the risk of developing breast cancer also increases.
• Lee-Fromeny syndrome. Members of families with Leigh Fromen syndrome (LFS) have a 90% chance of developing cancer during their lifetime. The most common tumors that develop in SLF are: osteogenic sarcoma, soft tissue sarcoma, leukemia, lung cancer, breast cancer, brain tumors and adrenal cortex tumors. This rather rare syndrome accounts for less than 1% of all breast cancers. The gene with which SLF is associated is called “p53”. This gene is a tumor suppressor gene. Testing for the presence of the p53 gene is recommended for family members who meet diagnostic criteria for FFS. Many studies are being conducted to achieve a better understanding of the mechanism of development of LFS. Another gene that has been studied, CHEK2, may lead to the development of a syndrome resembling FFS in some families. In carriers of a mutant form of this gene, the risk of developing breast cancer is increased by 2-5 times among women and 10 times among men. Testing for mutations in the CHEK2 gene region is currently available as part of research.
• Cowden syndrome. Women with Cowden syndrome have an increased lifetime risk of developing breast cancer, ranging from 25% to 50%, and a 65% risk of benign breast tumors. Also, with this disease, there is an increased risk of developing uterine cancer, which ranges from 5% to 10% and much more – the likelihood of developing benign processes in the uterus. With Cowden syndrome, the likelihood of developing cancer and benign tumors of the thyroid gland is increased. Other signs of Cowden syndrome include macrocephaly—large head size—and skin changes such as trichilemmomas and papilomatous papulosis. The gene associated with Cowden’s syndrome is called. PTEN. It is also believed to be a tumor suppressor gene, and specific tests have been developed to identify it.
• Peutz-Jeghers syndrome (SPJ). In women with PCY, the lifetime risk of developing breast cancer is increased to 50%. However, the main symptom of SPY is the presence of multiple hamartomatous polyps in the digestive tract. The presence of these polyps significantly increases the risk of developing colon and rectal cancer. People with PI syndrome also have increased pigmentation (dark spots on the skin) of the face and hands. Hyperpigmentation often begins in childhood and lasts throughout life. This syndrome also implies an increased risk of developing cancer of the ovaries, uterine body and lungs. The gene associated with SPY is called STK11. The STK11 gene is a tumor suppressor gene and can be identified through genetic testing.
• Other genes. Currently, much remains unknown regarding the role of individual genes in increasing the risk of developing breast cancer. It is possible that there are other genes, not yet identified, that influence the hereditary predisposition to the development of breast cancer.

What determines your personal risk level?

In addition to family history, there are additional environmental and lifestyle risk factors that may also increase the risk of developing breast cancer. To better understand your own risk for developing cancer, you should discuss your family medical history and personal risk factors with your doctor. Those people who are at increased risk of developing breast cancer can undergo special genetic testing and follow their individual early diagnosis plan. In addition, they need to rule out those additional risk factors that can be excluded. Regarding the risk of developing breast cancer, such controllable risk factors are: unbalanced diet, excess weight, physical inactivity, alcohol abuse, smoking and uncontrolled use of female sex hormones.

Genetics of ovarian cancer

For any woman without a family history of increased incidence of ovarian cancer and no other risk factors, the lifetime risk of developing ovarian cancer is less than 2%.

Ovarian cancer accounts for about 3% of all malignant tumors that develop in women.

It ranks 8th among all female cancer diseases and 5th among the causes of death for women from cancer, which an oncologist can confirm to you.

How do you know if a hereditary form of ovarian cancer runs in your family?

If close relatives (mother, sisters, daughters) have had cases of ovarian cancer, or several cases of the disease occurred in one family (grandmother, aunt, niece, granddaughters), then it is possible that in this family ovarian cancer is hereditary. .

If a first-degree relative has been diagnosed with ovarian cancer, then the individual risk of a woman from this family is on average 3 times higher than the average statistical risk of developing ovarian cancer. The risk increases even more if the tumor has been diagnosed in several close relatives.

What inherited genetic mutations increase the risk of developing ovarian cancer?

To date, scientists know several genes, mutations in which lead to an increased risk of developing ovarian cancer.

The most common inherited syndromes associated with the risk of developing ovarian cancer are described below.

• Hereditary breast-ovarian cancer (HBOC) syndrome. Damage to the BRCA1 and BRCA2 genes is the most common situation in cases of familial breast and ovarian cancer. It was calculated that mutations in the BRCA1 gene occur in 75% of cases of hereditary forms of ovarian cancer, and the BRCA15 gene is to blame for the remaining 2%. At the same time, the risk of ovarian cancer ranges from 15% to 40% throughout life, and breast cancer – up to 85%. Men who carry mutant forms of the BRCA1 or BRCA2 genes in their genome may also have an increased risk of developing breast or prostate cancer. Carrying mutations in the BRCA2 gene is also associated with an increased risk of developing other types of cancer: melanoma and pancreatic cancer. The BRCA1 and BRCA2 genes belong to the so-called “tumor suppressor genes.” This means that based on these genes, a protein is synthesized that is involved in the cell cycle and limits the number of cell divisions. This limits the likelihood of tumor formation. If a mutation occurs in tumor suppressor genes, the protein is either not synthesized at all or has a defective structure and is not able to prevent the formation of tumor cells.

  The mutant form of the gene has a certain accumulation in some ethnic groups: there are three most common mutations: 2 in the BRCA1 gene and one in the BRCA2 gene, in the Ashkenazi Jewish population. Among this population, the risk of carrying one of the three forms of mutant genes is 2,5%.

  Women who carry mutations in the BRCA1 or BRCA2 genes should undergo careful screening for early detection of ovarian and breast cancer. Screening for early detection of ovarian cancer should include: examination by a gynecologist, ultrasound examination of the pelvic organs, and a blood test for the CA-125 oncogene. Screening for early detection of breast cancer should include: breast self-examination, examination by a mammologist, mammography once a year, breast ultrasound and MRI.

• Hereditary Nonpolyposis Colon Cancer (HNPTC) (Lynch syndrome) accounts for about 7% of the incidence of hereditary ovarian cancer. Women with this syndrome have a 10% risk of developing ovarian cancer. The risk of developing uterine cancer is up to 50%. NNPTC is most often associated with a risk of developing colon cancer, which ranges from 70 to 90%, many times higher than the risk in the general population. Patients with NNPTC also have an increased risk of developing cancers of the stomach, small intestine, and kidneys. There is also an increased incidence of breast cancer in these families.

  Scientists have found several genes, breakdowns in which lead to the development of NPTK. The most common causes of the syndrome are mutations in the MLH1, MSH2 and MSH6 genes. Although mutations are most often found in several genes at once, families have been described in which changes are found in only one gene.

  The genes in which mutations cause the development of HNPTC syndrome are representatives of a group of genes belonging to the so-called “mismatch repair genes”. The genes of this group synthesize proteins that restore errors in the DNA structure that occur during cell division. If one of these genes is modified, a protein is formed that is unable to eliminate errors in the DNA structure; the defective DNA structure increases from one cell division to another, which can lead to the development of cancer.

  Women from families in which NNPTC is diagnosed should undergo mandatory additional screening for the early detection of uterine and ovarian cancer, in addition to tests aimed at the early detection of colon cancer.

• Peutz-Jeghers syndrome (SPJ). Women with PCY have an increased risk of developing ovarian cancer. Although the main symptom of SPY is the presence of multiple hamartomatous polyps in the digestive tract. The presence of these polyps significantly increases the risk of developing colon and rectal cancer. People with PI syndrome also have increased pigmentation (dark spots on the skin) of the face and hands. Hyperpigmentation often appears in childhood and may fade over time. In women from families with PCY, the risk of developing ovarian cancer is about 20%. This syndrome also implies an increased risk of developing cancers of the uterus, breast and lungs. The gene associated with SPY is called STK11. The STK11 gene is a tumor suppressor gene and can be identified through genetic testing.
• Nevusoid cell carcinoma syndrome (NBCC) Also known as Gorlin syndrome, it is characterized by the development of multiple basal cell carcinomas, cysts of the jaw bones, and small pockmarks on the skin of the palms and soles of the feet. In women with Gorlin syndrome, benign ovarian fibroids develop in 20% of cases. There is a definite, although minor, risk that these fibromas may develop into malignant fibrosarcomas. An additional complication of the syndrome is the development of brain tumors – medulloblastomas in childhood. External features of patients with Gorlin syndrome include macrocephaly (large head size), unusual facial structure, and skeletal abnormalities affecting the structure of the ribs and spine. Despite the fact that SNBCC is inherited in an autosomal dominant manner, about 20-30% of patients do not have a family history of the disease. It is known that the PTCH gene is associated with the disease, the structure of which can be determined in special tests.

Are there other inherited conditions that lead to an increased risk of developing ovarian cancer?

Other congenital conditions that increase the risk of developing ovarian cancer include:

• Lee-Fromeny syndrome. Members of families with Leigh Fromen syndrome (LFS) have a 90% chance of developing cancer during their lifetime. The most common tumors that develop in SLF are: osteogenic sarcoma, soft tissue sarcoma, leukemia, lung cancer, breast cancer, brain tumors and adrenal cortex tumors. This syndrome is quite rare and is caused by a mutation in a gene called “p53”, which is a tumor suppressor gene. Testing for the presence of the p53 gene is recommended for family members who meet diagnostic criteria for FFS. Many studies are being conducted to better understand the mechanism of development of LFS. Another known gene, CHEK2, can lead to the development of a syndrome resembling LFS in some families.
• Ataxia-telangiectasia (A-T) a rare inherited autosomal recessive disorder characterized by progressive gait disturbances that usually develop in childhood. Soon after acquiring walking skills, children begin to stumble, their gait becomes unsteady, and most patients with A-T are forced to use a wheelchair. Over time, speech impairments and difficulty writing and performing precise movements develop. When examining patients, spider veins called telangiectasia, which are dilated capillaries, are noticeable on the skin, mucous membranes and sclera of the eyes. Patients with this syndrome also have a weakened immune system and are susceptible to infections. The risk of developing tumors is 40%, of which malignant lymphomas are the most common. The risk of developing breast, ovarian, stomach and melanoma cancers also increases.

  A-T is inherited in an autosomal recessive manner, that is, for the development of the disease it is necessary to inherit 2 mutant copies of a gene called the ATM gene and located on chromosome 11. This means that both parents of an affected child must be carriers of the altered gene, and their children have a 25% chance of inheriting the disease. Carriers of the altered ATM gene have an increased risk of developing certain forms of malignant diseases. First of all, breast cancer.

• KARNEY complex is a rare inherited condition characterized by patchy skin pigmentation, most commonly affecting the face and lips, that appears during puberty. In addition to skin spots, patients with this syndrome are prone to developing numerous benign tumors, the most common of which are myxomas, which are skin nodules of varying colors from white to bright pink, located on the eyelids, ear and nipples. About 75% of patients with CARNEY complex develop thyroid tumors, but most of them are benign. At all. The risk of developing malignant tumors in patients with CC is considered to be low. CARNEY complex is a congenital condition with an autosomal dominant pattern of inheritance. Despite this, approximately 30% of patients have no family history of the disease. One of the genes responsible for the development of this condition is called PRKAR1A. A second gene, thought to be located on chromosome 2, is under investigation and scientists believe it may also be associated with the development of the disease.

What determines your personal risk level?

In addition to a strong family history, there are additional risk factors associated with behavioral habits and the environment. These factors may influence your risk of developing ovarian cancer. Women at increased risk of developing the disease can undergo genetic testing to determine the need for screening tests aimed at early diagnosis of ovarian cancer. In particularly dangerous situations, a prophylactic orophorectomy (removal of healthy ovaries to reduce the risk of breast and ovarian cancer) may be recommended.

Carrying certain genetic mutations that increase the risk of developing ovarian cancer does not mean a 100% chance of developing this type of tumor. In addition, controllable risk factors play a significant role, including such well-known ones as excess weight, smoking, alcohol consumption and a sedentary lifestyle.

The role of genetic factors in the development of kidney cancer

Kidney cancer most often develops as a random event, that is, about 95% of cases do not have hereditary causes that would be known to today’s science. Only 5% of kidney cancers develop due to a hereditary predisposition. Thus, the average risk of developing kidney cancer is less than 1% throughout a person’s lifetime, and men are affected twice as often as women.

How can you tell if there is a family history of developing kidney cancer?

If immediate family members (parents, siblings, or children) have developed a kidney tumor, or have had multiple cases of kidney cancer among all family members (including grandparents, uncles, aunts, nephews, cousins, and grandchildren) , that is, there is a possibility that this is a hereditary form of the disease. This is especially likely if the tumor developed before age 50, or if there is bilateral disease and/or multiple tumors in one kidney.

What is the individual risk of developing kidney cancer if there is a family history?

If first-degree relatives (parents, siblings, children) had kidney cancer before the age of 50, this means that the risk of developing the disease may be increased. To determine an individual’s risk level, it is necessary to identify the inherited condition that may have led to the development of cancer.

Which congenital genetic mutations increase the risk of kidney cancer?

There are several genes that are known to be associated with the development of kidney cancer, and new genes affecting this process are being described every year. Some of the most common genetic conditions that increase your risk of developing kidney cancer are outlined below. Most of these conditions lead to the development of some type of tumor. Understanding the specific genetic syndrome in a family can help the patient and his or her physician develop an individual plan for prevention and early diagnosis and, in certain cases, determine the optimal treatment strategy. Some of the hereditary conditions are also associated, in addition to the risk of developing tumors, with an increased likelihood of developing certain non-tumor diseases, and this knowledge can also be useful.

• Von Hippel-Lindau syndrome (VHL). People with hereditary FHL syndrome are at risk for developing several types of tumors. Most of these tumors are benign (noncancerous), but in about 40% of cases there is a risk of developing kidney cancer. And of a certain specific type, called “clear cell kidney cancer.” Other organs. Tumors susceptible to the development of patients with FHL syndrome are the eyes (retinal angiomas), the brain and spinal cord (hemangioblastomas), the adrenal glands (pheochromocytoma) and the inner ear (endolymphatic sac tumors). The development of a tumor of the hearing organ can cause complete or partial hearing loss. Patients with FHL may also develop cysts in the kidneys or pancreas. The syndrome manifests itself clinically at the age of 20-30 years, but symptoms may also appear in childhood. About 20% of patients with FHL syndrome have no family history of the disease. The gene that determines the development of FHL syndrome is also called the VHL gene (VHL) and belongs to the group of tumor suppressor genes. Tumor suppressor genes are usually responsible for the synthesis of a specific protein that limits cell growth and prevents the emergence of tumor cells. Mutations in suppressor genes cause the body to lose its ability to limit cell growth and, as a result, tumors can develop. Genetic testing to determine mutations in the FHL gene is recommended for individuals with a family history of diseases associated with FHL syndrome. Screening for symptoms of FHL syndrome should be carried out in families whose members are at increased risk of developing this syndrome, and begin at an early age. This screening includes:
  • Eye examination and blood pressure monitoring from age 5 years;
  • Ultrasound of the abdominal organs from early childhood, MRI or CT scan of the retroperitoneal organs after 10 years;
  • Test for the level of catecholamines in 24-hour urine;
• Familial cases of clear cell renal cell carcinoma not associated with FHL syndrome. Most cases of clear cell kidney cancer are sporadic, meaning they develop at random. However, there is a very low percentage of familial cases of clear cell renal cell carcinoma in the absence of other features of FHL syndrome. Some of these patients inherit specific gene rearrangements on chromosome 3. Genetic diagnostic techniques can identify such rearranged chromosomes. In some patients, the genetic causes of kidney cancer are not yet known. For family members with these rare syndromes, it is recommended that screening for kidney tumors begin at age 20 using ultrasound, MRI, or retroperitoneal CT.
• Congenital papillary renal cell carcinoma (CPRCC). PPCC may be suspected when two or more close relatives are diagnosed with the same type of kidney tumor, namely papillary renal cell carcinoma type 1. Typically, this type of tumor in familial cases is diagnosed at the age of 40 years or later. Patients with SPPCC may have multiple tumors in one or both kidneys. Individuals belonging to families with a hereditary history of SPPCC should undergo screening diagnostic tests, including ultrasound, MRI or CT, from the age of about 30 years. The gene responsible for the development of VPPCC is called c-MET. The c-MET gene is a proto-oncogene. Proto-oncogenes are responsible for the synthesis of proteins that trigger cell growth in a normal cell. Mutations in proto-oncogenes cause too much of this protein to be produced and the cell receives too much of a signal to grow and divide, which can lead to tumor formation. At present, special methods have already been developed to detect mutations in the c-MET gene.
• Bert-Hogg-Dube syndrome (BHD). HDD syndrome is a rare syndrome and is associated with the development of fibrofollicles (benign tumors of the hair follicle), cysts in the lungs and an increased risk of kidney cancer. In patients with HDD syndrome, the risk of developing kidney cancer is 15-30%. Most kidney tumors that develop in this syndrome are classified as chromophobe tumors or oncocytomas, but in rare cases clear cell or papillary kidney cancer may develop. Due to the increased risk of developing malignant kidney tumors, members of families with HDD syndrome are advised to start early regular diagnostic tests to exclude this pathology (ultrasound, MRI or CT scan starting at the age of 25 years). The gene responsible for the development of HDD syndrome is called BHD, and can be determined through genetic testing.
• Congenital leiomyomatosis and renal cell carcinoma (CCRCC). Patients with this syndrome have skin nodules called leiomyomas. Most often, such nodes form on the limbs, chest and back. Women are often diagnosed with uterine fibroids, or, much less commonly, leiomyosarcoma. Patients with VLPPC have an increased risk of developing kidney cancer, which is about 20%. The most common type is papillary renal cell carcinoma. Screening for early detection of kidney cancer should be carried out among family members with VLPKD. The gene responsible for the development of this syndrome is called the FH gene (fumarette hydratase) and can be determined through genetic testing.

Are there other congenital conditions associated with increased rates of kidney cancer?

Clinical observations show that there are other cases of familial predisposition to the development of kidney tumors, and this topic is receiving increased attention from geneticists. A less significant increase in the risk of developing kidney cancer is observed in patients with tuberous sclerosis, Cowden’s syndrome, and congenital nonpolyposis colon cancer. For all these diseases, consultation with a geneticist is indicated.

Genetics of prostate cancer

Most cases of prostate cancer (about 75%) occur as a result of somatic mutations and are not transmitted randomly or hereditarily. Hereditary prostate cancer