Lynch syndrome is a hereditary non-polyposis colon cancer. Hereditary non-polyposis colorectal cancer, or Lynch syndrome How to cope with Lynch syndrome

Cancer neoplasms that grow from the tissues of the large intestine cause dyspeptic disorders. But some of the malignant neoplasms quickly penetrate into neighboring tissues. Lynch syndrome is distinguished by such features.

Characteristic features of the syndrome

Non-polyposis colorectal cancer, or Lynch syndrome, is a malignant tumor that develops against the background of a genetic predisposition. The neoplasm affects the walls of the large intestine, localizing mainly on the right side.

Non-polyposis colorectal cancer is inherited in an autosomal dominant manner, in which the presence of one “defective” gene in either parent is sufficient for the development of a cancerous tumor in a child.

Lynch syndrome is diagnosed in people of both sexes under the age of 50. Moreover, the first signs of a malignant neoplasm begin to disturb 5-6 years before.

The development of Lynch syndrome is often accompanied by the formation of tumors in neighboring structures: small intestine, ovaries, biliary tract, stomach and other organs. Therefore, in case of detection of such neoplasms among relatives, persons older 25 years It is recommended to conduct a gastrointestinal examination twice a year to detect non-polyposis colorectal cancer.

There are two types oncological disease: Lynch-Ⅰ and Lynch-Ⅱ syndromes. The first neoplasm is localized within the large intestine. This type of syndrome is characterized by the early development of multiple tumors, which are not preceded by polypous growths.

Lynch-Ⅱ differs in that, in addition to cancer, the patient has colon adenocarcinoma and neoplasms in other parts of the body. More often, with this form of cancer, malignant cells penetrate into the genital organs (in women) or into the digestive tract.

In the first case, the risk of developing uterine cancer reaches 30-60%. In Lynch-Ⅱ syndrome, patients have a 10-15% chance of developing tumors in other parts of the body.

Causes

Lynch syndrome develops as a result of a mutation of the genes (PMS2, MSH6 and others) that are responsible for correcting such errors. Multiple transformation is not excluded, which increases the likelihood of a malignant tumor.

Each gene contains DNA, through which information is transmitted to the processes occurring in the body. During growth and division, cells receive this data from the "progenitors". However, sometimes errors occur during code transfer.

In a normal state, cells eliminate such anomalies at the expense of their own resources. But individuals with a genetic predisposition (with mutated genes) lack this ability. As a result, there is a "layering" of errors, which leads to the transformation of cells into malignant ones.

Symptoms

Lynch syndrome develops suddenly. The appearance of a tumor is not preceded by clinical signs indicating damage to the large intestine.

The presence of a neoplasm in the organ is indicated by pain in the lower abdomen, diarrhea, lack of appetite and general weakness. Because of these phenomena, the patient develops anemia.

Cancerous tumors of this type are located mainly in the upper intestines, so blood clots are not found in the feces.

The characteristics of pain vary from patient to patient. More often, the symptom is aching or pulling. less often pain syndrome occurs in the form of seizures characteristic of acute appendicitis and cholecystitis.

Non-polyposis colorectal cancer types 1 and 2 is palpable when it reaches a large size. The tumor is characterized by a nodular structure and a dense or soft consistency.

Over time, the neoplasm disintegrates, which is expressed in symptoms of acute intoxication of the body. If, as the tumor grows, it retains its own structure, then intestinal obstruction occurs.

During the period when the neoplasm gives metastases, general weakness is noted, fever body. During this period, the patient becomes emotionally unstable with pronounced tendencies to depression. In addition, malnutrition progresses due to insufficient nutritional intake and dysfunction of the large intestine.

In the case of the growth of a malignant tumor, symptoms of urination disorders occur. In women with lesions of the ovaries, there is a violation of the menstrual cycle.

Diagnostics

Diagnosis of Lynch syndrome is based on the collection of information about the early detection of this type of cancer among the next of kin. However, in order to prevent malignant neoplasms, general screening examinations are not carried out.

To diagnose the latter, enzyme immunoassay and the method by which microsatellite instability is determined are also used.

When the first signs of cancer appear, colonoscopy and irrioscopy are prescribed. Also, analyzes of stool masses for the detection of blood clots, ultrasound, CT and MRI of organs are carried out. abdominal cavity.

In the case of spread of metastases, other methods of examination are used to identify the area affected by malignant cells.

Treatment and prevention

When Lynch syndrome is detected, the optimal treatment is subtotal colectomy, in which the large intestine is removed. This method is more preferable to partial resection of the affected organ.

Surgical intervention is resorted to if the removal of the large intestine will have a positive effect on the patient's condition and improve the quality of life.

Chemotherapy methods in the treatment of non-polyposis colorectal cancer are used based on the characteristics of each case.

The basis of prevention is the dynamic monitoring of patients at risk. Patients with Lynch syndrome should be regularly examined by an oncologist and a gastroenterologist.

Colonoscopy is also performed every six months, starting at the age of 25. It is important that the patient does not miss the procedure. The maximum duration of the period between colonoscopy sessions should not exceed 1-2 years.

Women at risk, in addition to surgery for non-polyposis colorectal cancer, are often prescribed hysterectomy and bilateral oophorectomy.

The first method involves the removal of the uterus. As part of a bilateral oophorectomy, the doctor completely excised the tissues of the ovaries and fallopian tubes.

The use of both methods can reduce the risk of developing cancer of these organs. Moreover, all three surgical interventions are usually performed at the same time.

Methods for the prevention of Lynch syndrome in individuals with a genetic predisposition include regular intake of vitamin C. The optimal dosage is selected based on the results of complex treatment.

Possible Complications

The risk of complications in Lynch syndrome depends on the timeliness of treatment. The danger is represented by cases when the tumor process is accompanied by metastasis to the nearest or distant structures.

Lynch syndrome develops:

1. Cancer endometrium. Neoplasm is detected in 42-54% of women with Lynch syndrome. The 5-year survival rate for this combination is 82%.
2. colorectal cancer. It affects the left side of the intestine. The risk of developing this form of neoplasm in patients reaches 100%.
3. Cancer ovaries. The risk of developing a tumor in women with neoplasia in the large intestine reaches 12%. If the tumor is detected early, the 5-year survival rate is 58.1%.
4. Cancer stomach. It is diagnosed in 5% of cases of Lynch syndrome (the third most common complication).
5. Cancer urinary channels. Occurs with Lynch-Ⅱ syndrome. The latter 20 times increases the likelihood of developing a tumor of this type. The risk group includes men aged 50-70 years. The 5-year survival rate is 90%. With invasive forms of neoplasm, this figure decreases to 60-70%.
6. Tumor of the thin intestines. It occurs in patients with a genetic predisposition aged 39 years and older. The 5-year survival rate in this case reaches 30-35%.
7. Tumor prostate. A rare complication of Lynch syndrome. Some researchers note the lack of relationship between both forms of cancer.
8. head cancer brain. It is diagnosed in 0.3-0.6% of patients with genetic mutations. At the same time, a neoplasm in the brain is detected mainly in persons belonging to this category, aged 25-38 years.

Malignant breast tumors in women with genetic mutations are relatively rare. However, patients with a hereditary predisposition older than 45 are recommended to undergo mammography twice a year for the purpose of early diagnosis of neoplasms.

With Lynch syndrome, the development of neoplasia in the sebaceous glands is possible. In addition, the course of leukemia and other forms of the tumor process is not excluded.

Non-polyposis colorectal cancer is a dangerous neoplasm that affects the large intestine. The tumor is characterized by signs of dyspeptic disorders. Treatment of Lynch syndrome involves dynamic monitoring of patients or complete removal of the large intestine.

Which is accompanied mainly by the development of non-polyposis colon cancer (blind, colon and rectum). Also, with Lynch syndrome, cancer of the uterus (endometrial carcinoma), ovaries, kidneys, stomach, pancreas and brain can occur. As a rule, the disease manifests itself at the age of 40–45 years.

The disease is based on genetic mutations that lead to disruption of the DNA repair system. Therapy for Lynch syndrome involves treatment with surgical or endoscopic methods.

Historical reference

In 1913, Aldred Warthin first described hereditary non-polyposis in a family whose members had died of cancer for generations. In 1966, Henry Lynch described two more families with similar clinical and genetic features. Lynch originally coined the term "cancer familial syndrome" to refer to the syndrome. However, later (1985) the concept of "hereditary non-polyposis colorectal cancer" was introduced to separate the disease from the syndrome of familial adenomatous polyposis of the colon. However, the term does not fully reflect clinical picture disease and is currently considered to be the preferred name "Lynch syndrome".

In 1990–2000 molecular technologies have made it possible to establish that Lynch syndrome is caused by mutations in the genes of the DNA repair system.

Prevalence and mode of inheritance

Lynch syndrome causes up to 3% of all cases in the world. Carriers of pathogenic mutations associated with Lynch syndrome have up to a 75% risk of developing colon cancer. In second place in terms of frequency of occurrence is endometrial carcinoma - 21–60%.

According to Russian studies, in 2012, 34,000 cases of colon cancer and 26,000 cases of rectum, rectosigmoid, and anus were diagnosed in the country.

The prevalence of the disease is determined by the frequency of mutations. According to some estimates, about 1 million people in Europe may be carriers of pathogenic mutations, since the frequency of occurrence of these mutations is 1 case per 500-1000 people.

Lynch syndrome is a disease with an autosomal dominant type of inheritance, for its occurrence it is enough to receive one copy of the gene with a mutation from the parents. In most cases, the disease leads to carcinogenesis in the proximal intestine.

Diagnostics

Clinical manifestations with Lynch syndrome, as a rule, occur at the age of 40-45 years. The diagnosis is based on the Amsterdam criteria (1999) and the Bethesda criteria (2004). Key criteria:

• the presence in at least two generations of the family of at least three relatives with tumors of the colon, endometrium, small intestine, ureter, renal pelvis;
• early age (up to 50 years) of the development of the disease in at least one of the relatives;
• the presence of the disease in relatives of the 1st degree of kinship;
• absence of polyps in the gastrointestinal tract;
• the presence of microsatellite instability under the age of 60 years;
• the presence of colorectal cancer in a patient and his relatives in two or more generations, regardless of age.

To confirm the diagnosis, it is necessary to detect an inherited mutation in the genes of the DNA repair system in the patient. In the presence of a mutation, molecular genetic studies are usually assigned to all close relatives. This makes it possible to monitor all carriers of this pathological variant in the family, as well as to develop personal treatment in case of oncogenesis.

Specialized software has been developed for diagnosing the syndrome, which analyzes clinical data and family history. It calculates the probability of finding mutations in the genes associated with the syndrome.

With the development of colon cancer clinical treatment involves a choice between observation, endoscopic resection, and surgery. Often, in the case of endoscopic resection of non-polypoid formations, endoscopic dissection is required: a specialized operation used to remove compacted tumors in the submucosal layer of the intestine.

Chemotherapy may be given for Lynch syndrome. Chemotherapy often uses 5-fluorouracil, oxaliplatin, and irinotecan. One of the most promising drugs for the treatment of Lynch syndrome is considered to be pembrolizumab, which is a humanized monoclonal antibody that blocks surface interactions between the PD-1 receptor (T cells) and its PD-L1 and PD-L2 ligands (tumor cells and its microenvironment) .

At timely diagnosis and in the absence of microsatellite instability, the prognosis for Lynch syndrome is relatively good.

Molecular mechanisms

Genes are involved in the elimination of errors in the process of DNA repair MLH1, MSH2, MSH6, PMS1, PMS2, MSH3 And EXO1. In the vast majority of cases, Lynch syndrome has sequential changes in genes. MLH1, MSH2, MSH6. Currently, 126 types of gene mutations are registered in the international database MLH1 And MSH2, accounting for 90% of all known mutations responsible for Lynch syndrome.

As a result of the occurrence of mutations, the repair system is inactivated, the level of microsatellite instability increases, and repair processes are disrupted. This leads to an even greater accumulation of mutations and to the development of tumors characteristic of Lynch syndrome.

The MSH2 and MSH6 proteins are involved in mutation recognition during DNA replication. When mutations are detected, these proteins, together with the MLH1 and PMS2 proteins, form a complex that ensures the restoration of altered sections of the DNA molecule.

The gene is also involved in the molecular mechanisms of the development of Lynch syndrome EPCAM, which is located next to MSH2 and involved in cellular processes

Dr. Zajatz is a general practitioner, researcher and entrepreneur in the field of biotechnology. He received his PhD in Genetics from the University of Cambridge in 2014 and his MD from Baylor College of Medicine in 2015.

Number of sources used in this article: . You will find a list of them at the bottom of the page.

Lynch syndrome is also known as hereditary non-polyposis colorectal cancer (NPCC). This is an inherited condition that increases the chance of developing colon and other cancers. This disease also increases the risk of developing these types of cancer at a younger age (under 50). If you think you're at risk, learn how to diagnose Lynch syndrome.

Steps

Recognize the likelihood of developing Lynch syndrome

Establishing diagnosis

Make an appointment with a doctor. If you think you may be developing Lynch syndrome, see a doctor who will refer you to a specialist in genetics (medical genetics). They are experts in genetic testing, counseling and control of genetic diseases like Lynch syndrome.

• Seek immediate medical attention if you experience any of the physical symptoms mentioned above, or if anyone in your family has had colon cancer or another type of cancer.

1. Determine if you have a genetic predisposition. A doctor may suspect Lynch syndrome if someone in your family has had colon cancer, uterine cancer, or other types of cancer, especially if they had them at a young age. Diagnosis is made by genetic testing.

   • Your doctor may ask you about relatives with cancer of the stomach, small intestine, brain, kidney, liver, or ovaries, as a gene that mutates in Lynch syndrome increases the risk of developing a number of other cancers.
   • Your doctor may also ask you if anyone in your family has had cancer in past generations, especially if your family has had cancer for generations.

2. Get a tumor biopsy. If you or a family member has tumors, the doctor will be able to examine them and see if you have Lynch syndrome. He will be able to determine the presence of certain proteins in the tumor that indicate Lynch syndrome.

   • If the tumor biopsy is positive, you most likely do not have Lynch syndrome. Mutations can only develop in tumors and cancer cells. After a positive result, the doctor may conduct a genetic examination to make sure that Lynch syndrome is absent or present.
   • If someone in your family has had cancer in the last few years, there may be a tissue sample left in the hospital for the doctor to examine.

3. Get a genetic test. At the moment, there are a number of mutations that can occur in Lynch syndrome. This test looks for mutations in the MLH1, MSH2, MSH6, and EPCAM genes.

   • Ask your doctor to send your blood for testing. If you want, donate blood for analysis in several different laboratories.

Lynch syndrome and everything connected with it

1. Lynch syndrome is a hereditary disease. Lynch syndrome is a genetically determined disease. The genetic error that is present in patients with Lynch syndrome is a group of genes that assign the genetic code to proteins that promote gene repair.

   Find out what a positive result means for Lynch Syndrome. If a genetic test confirms the presence of Lynch syndrome, this means that you have a lifetime risk of cancer is 60-80%. This does not mean that you will definitely get colon cancer or endometrial cancer, only that you are more likely to develop these types of cancer.

How to diagnose Lynch syndrome?

How to deal with Lynch Syndrome

Lynch syndrome overview

Lynch syndrome is an (autosomal) inherited cancer syndrome that causes cancer of the uterus, intestines, stomach, and urinary tract. Patients with Lynch syndrome have a 27% to 70% risk of developing uterine cancer and a 5-12% risk of developing ovarian cancer. Unusual tumors associated with Lynch include cancer diseases kidneys, ureters, stomach, small intestine, bile duct, skin (sebaceous neoplasms) and brain (gliomas).

Often, Lynch syndrome survivors are diagnosed with cancer younger than expected, may develop additional cancer, and know other family members who have developed different types of cancer (stomach, bladder, bowel, uterus, ovary).

Patients who were diagnosed with uterine cancer at age 50 or less have an 18% chance of experiencing Lynch syndrome. These patients require regular screening (eg, colonoscopy) for other types of cancer.

Patients who have been diagnosed with Lynch-related bowel cancer have a 25% risk of developing subsequent uterine or ovarian cancer. In these patients, prophylactic, risky surgery to remove the uterus, tubes, and ovaries can save lives. These operations are performed laparoscopically (key hole) and virtually eliminate the risk of developing cancer of the uterus and ovaries.

Women with link-related endometrial cancer are 40 times more likely to develop colorectal cancer.

Women diagnosed with Lynch-related colon cancer are 28 times more likely to develop endometrial cancer.

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Why is it so important to diagnose Lynch?

Patients with Lynch syndrome should be screened for other cancers. Screening or preventive surgery can save a life.

First-degree relatives (descendants, siblings) of Lynch patients have a 50% risk of also experiencing Lynch. Once Lynch syndrome is confirmed, first-degree relatives also need genetic testing.

Family history is a poor predictor of Lynch syndrome, and 50% of patients with proven Lynch syndrome have no family history.

A missed diagnosis can cause cancer and treatment (surgery, chemotherapy, radiation therapy).

I routinely request testing for Lynch syndrome in all patients with endometrial cancer who are less than 60 years of age, who are not obese, or who exhibit histopathological features often associated with Lynch syndrome (eg, lower uterine or cervical involvement, presence of infiltrating tumor lymphocytes).

The first step to diagnose Lynch is an immunohistochemical test, which can be done from a surgical sample from an original uterine or bowel cancer sample. This test is not diagnostic. However, if the test is positive, confirmatory genetic testing must be prompted and requires a blood test. It is recommended to consult a familial cancer clinic or a clinical geneticist.

Clinical Management

1. Surveillance for ovarian cancer is unreliable and is not usually recommended. Surveillance for uterine cancer can be done by endometrial sampling (Pipelle) (for premenopausal women) or via ultrasound (in postmenopausal women), but is also unreliable. Colonoscopy (every 1-2 years) from age 25 (reduces morbidity and mortality from colon cancer by 60%) is really reliable and recommended. Annual urine cytology to detect early stages of cancer Bladder and ureter.
2. Prevention: oral birth control pill reduce the risk of developing ovarian cancer by 50%. There is no set medicinal product for the prevention of uterine cancer.
3. Preventive surgery (laparoscopic hysterectomy) is the most effective way eliminate the risk of developing cancer of the uterus and ovaries; It should be offered to all women who have completed childbearing or are postmenopausal. It virtually eliminates the risk of developing uterine or ovarian cancer and should be performed by an experienced laparoscopic surgeon. Patients must be with medical point vision are suitable for tolerance to surgery, should be aware of the most common risks and possible complications surgery and require some research (blood tests, medical imaging) before surgery.

For information about Lynch syndrome, which is a consumer group, gynecology.

How is Lynch syndrome diagnosed?

For doctors general practice it should be suspected that a person may have the gene for Lynch syndrome when there is a strong family history of cancer. This means that three or more family members were diagnosed with the cancers listed above, two consecutive generations or more were affected by these cancers, and one of these affected family members was diagnosed with cancer before the age of 50. It should also be suspected that the patient has little or no access to family health information and has already had one or more cancers before the age of 50.

If Lynch syndrome is not identified and the patient develops cancer, they usually need surgical intervention to remove the tumor. Current best practice for all colon and endometrial tumors in patients under the age of 50 or who have a strong history of heart cancer is for the treatment team to order a pathological test to check for abnormal genes that are functioning properly.

Unfortunately, studies show that less than half of these tumors are tested, and patient follow-up is unclear and inconsistent.

Any patient suspected of having Lynch syndrome should be referred to a family cancer clinic. There, a genetic counselor will conduct a thorough assessment and explain the gene testing process and its implications. With the consent of the patient, the clinic will arrange for testing of a tissue sample from a past tumor (both the patient and another family member) to look for a gene mutation to resolve the discrepancy.

If a gene mutation is found, risk reduction strategies are discussed. Diagnosis for other family members then involves a relatively simple blood test that looks for the same mutation.

How do you deal with Lynch Syndrome?

Management of Lynch syndrome includes a follow-up plan for regular testing to detect problems early. Polyps can then be removed before they become cancerous, or cancers can be removed early. The potential for risk-reducing surgery (to remove organs such as the ovaries, which are high risk but difficult to screen for) or supplements such as aspirin (which longitudinal studies believe can significantly reduce the incidence of Lynch syndrome) may also be considered. ).

Recommendations Annual colonoscopies (starting at age 25 or 30, depending on the gene mutation, or five years younger than the younger relative diagnosed with bowel cancer) and prophylactic removal of the uterus, fallopian tubes, ovaries, and cervix should be considered after childbearing is completed or at age 40 years.

Frequent colonoscopies are important because the median time from polyp to bowel cancer is reduced from ten years in the general population to 35 months in patients with Lynch syndrome. The same way, average age development of uterine cancer is reduced from 64 years to 42-46 years.

An individual's surveillance plan can be further tailored to their specific cancer risks based on family history or factors. environment. For example, a family history of stomach or skin cancer may warrant including yearly endoscopies or dermatological reviews.

Effective diagnosis and treatment of people with Lynch syndrome can save lives. Unfortunately, this is not the experience for thousands of Russian families. It is important to raise awareness of this condition among healthcare professionals, healthcare organizations and the general public.

Non-polyposis colorectal cancer is a genetically determined malignant tumor of the large intestine. It's Lynch Syndrome. It is inherited in an autosomal dominant manner. If one of the parents is a carrier of a “broken” gene, then the child is at risk for developing a tumor.

When and how do symptoms appear?

This type takes from 3 to 5% of the total number of cases of colorectal cancer.

It is found in people of both sexes up to 50 years. The first signals of a growing tumor appear 5-6 years before it. The median age at diagnosis of initial symptoms is 44 years.

There are no obvious manifestations until a malignant tumor appears. After that, the patient has:

• anemia;
• weakness;
• increasing exhaustion;
• emotional lability;
• elevated temperature;
• depressive states;
• loss of appetite;
• stool disorder;
• intoxication;
• pain.

Pain can manifest itself in different ways. These are aching and pulling pains of very weak or moderate intensity. Rarely, there is a brief attack of pain, similar in nature to an attack in appendicitis or acute cholecystitis.

Visual determination of blood in the feces usually does not take place due to the fact that the neoplasm is high.

What distinguishes Lynch syndrome from other types of colorectal cancer:

• early start;
• the most common lesion of the right side of the intestine;
• abundance of primary tumors.

In patients with a proven gene mutation, the risk of developing cancer can reach 30 to 80%.

Causes of development and types of syndrome

The disease progresses against the background of gene mutation. The more mutations involved in the process, the higher the risk of malignant neoplasia formations.

In the case of Lynch syndrome form I, abundant tumors are located within the large intestine. There is an early development of a large number of tumors without preliminary polypous growths.

Form II is characterized by malignant neoplasia in different parts of the body and colonic adenocarcinoma. More often, female genital organs suffer from tumors, less often - overlying departments. digestive system.

Factors that affect the risk of developing cancer in Lynch syndrome include:

• smoking, alcohol;
• excess body weight;
• consumption of food low in fiber and enriched with solid animal fats;
• prolonged use of antibiotics.

Diagnostics

The main sources of diagnosis before the appearance of a malignant tumor are genetic studies and family history. In the case of detection of confirmed carcinomas in three or more relatives, genetic analyzes are performed. The mutation must have manifested itself in two or more generations.

If the mutation is detected by genetic testing, then the patient is additionally enzyme immunoassays and a microsatellite instability test.

Colonoscopy and barium enema are prescribed when clinical signs syndrome. Conduct fecal examinations for the presence of hidden blood, as well as magnetic resonance or computed tomography abdomen and ultrasound.

• both sexes every two to three years - gastroscopy and tests for Helicobacter pylori infection;
• women annually - examination by a gynecologist, ultrasound and blood for tumor markers;
• men annually - urinalysis.

Prevention

The diagnosis of Lynch syndrome involves dispensary observation of the patient throughout his life. It consists of examinations by an oncologist and a gastroenterologist.

In addition, they are prescribed once every one to two years:

• colonoscopy after 25 years;
• fibrogastroduodenoscopy - after 30 years;
• ultrasonography abdominal cavity - after 30 years.
• gynecological examination - for women.

Instrumental examinations are prescribed every one to two years after 30 years.

Regardless of the presence of confirmed tests, any person who is at risk needs to take control of their own health. Simple Rules healthy lifestyle life will significantly reduce the chances of developing pathology:

• Getting rid of bad habits. Alcohol and smoking increase the risk of several types of cancer.
• Maintaining normal weight. Proper nutrition and feasible exercise stress help you keep your mass under control.
• healthy eating. Depending on the lifestyle, it is necessary to provide yourself with all the necessary nutrients - proteins, fats, carbohydrates, vitamins, micro and macro elements, fiber.

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