Lynch syndrome - causes, diagnosis and treatment. Hereditary nonpolyposis colorectal cancer, or Lynch syndrome Lynch syndrome symptoms

annotation scientific article on clinical medicine, author of the scientific work - Alla Petrovna Chudina

201 families were selected from the Moscow Oncogenetic Registry, where there were cases of colon cancer in first-degree relatives; the families were monitored for at least 5 years. The group is divided into 3 subgroups: 6 families with Lynch syndrome (hereditary non-polyposis colon cancer), 36 cancer families without Lynch syndrome and 159 non-cancer families. A comparative analysis showed that families with Lynch syndrome differ significantly from families of the other two subgroups in the following ways: 1) cancer burden - more than 60% of relatives over 20 years old are sick; 2) high frequency of multiple tumors in women (57.1%); 3) colon (affected by cancer more often than the rectum; 4) in women, cancer of the uterine body is the second location after colorectal cancer; 5) the first malignant neoplasms appear 10-20 years earlier, and patients live with the tumor 5-7 years longer than in the other two groups; 6) over 5 years of observation, new cases of cancer arose in 50% of families among relatives of the first degree of kinship and in 83% of families among relatives of the 1st-3rd degree of kinship. Cancer families differed from non-cancer families only in the overall burden of cancer (PC - 35.6%, Non-Cancer - 12.5%) and in the frequency of new cases in relatives of the 1st-3rd degree (PC - 33.3%, Non-Cancer - 10.7 %).

Text of scientific work on the topic “Lynch syndrome and sporadic colorectal cancer: clinical and genealogical features”

LITERATURE

1. Pikin O.V. // Ros. oncol. magazine - 2004. - No. 1. - P. 49-52.

2. Rashkin L. A., Bokan Yu. I., Novikov Yu. Yu. // Medicine for the quality of life. - 2006. - No. 2. - P. 29-34.

3. Sukhovskaya O. A., Ilkovich M. M., Ignatiev V. A. // Pulmonology. - 2003. - No. 1. - P. 96-100.

4. Tarasov V. A., Vinogradova M. V., Sharov Yu. K. et al. // III Congress of Oncologists of the CIS Countries. - Minsk, 2004. - P. 88.

UDC 616.345/.35-006.6-092:612.6.05]-07

A. P. Chudina

5. Cella D. F., Bonomi A. E., Lloyd A. R. et al. // Lung Cancer. - 1995. - Vol. 12. - P. 199-220.

6. Kogal R., Yamamoto J., Saiura A. et al. // Jpn. J. Clin. Oncol. - 2006. - Vol. 36, N 10. - P. 643-648.

7. Lencion R. // Lancet Oncol. - 2008. - Vol. 9. - P. 621-628.

8. Limmer S., Oevermann E., Kollaitis C. et al. // Langenbeck's Arch. Surg. - 2010. - Vol. 395, N 8. - P. 1129-1138.

9. Tristan D., Yan T., King J. et al. //Ann. Surg. Oncol. - 2007. - Vol. 14, N 5. - P. 1718-1726.

Received 05/11/11

LYNCH SYNDROME AND SPORADICH COLORECTAL CANCER: CLINICAL AND GENEALOGICAL FEATURES

Russian Oncology Research Center named after. N. N. Blokhina (director - RAS academician M. I. Davydov) RAMS, Moscow

Key words: Lynch syndrome, hereditary nonpolyposis colorectal cancer, cancer families

LYNCH SYNDROME AND SPORADIC COLORECTAL CANCER: CLINICAL AND GENEALOGICAL FEATURES

P. A. Herzen Moscow Oncology Research Institute, Ministry of Health and Social Development of the Russian Federation, Moscow

Two hundred and one families that had cases of colorectal cancer among first-degree relatives and had been followed up for at least 5 years were selected from the Moscow Familial Cancer Registry and divided into 3 groups: 1) 6 families with Lynch syndrome (hereditary nonpolyposis colorectal cancer); 2) 36 cancer families without Lynch syndrome; 3) 159 noncancer families. Comparative analysis has shown that the families with Lynch syndrome differ significantly from those of two other subgroups in the following respects: 1) hereditary cancer loading (cancer cases in more than 60% of relatives over 20 years of age); 2) high incidence rates for multiple cancers in women; 3) more common cancer involvement of the colon than the rectus; 4) cancer of the corpus uteri is a second malignancy after colorectal cancer among women; 5) primary malignancies occur 10-20 years earlier with the tumor-specific survival being 5-7 years longer than in the two other groups; 6) during a 5-year follow-up, new cancer cases occurred among first-degree and first-to-third-degree relatives in 50 and 83% of the families, respectively. The cancer families differed from noncancer ones only in general hereditary cancer loading (35.6 versus 12.5%) and in the rate of new cases in first-to-third relatives (33.3% versus 10.7%).

Key words: Lynch syndrome, hereditary nonpolyposis colorectal cancer, cancer families

The accumulation of cases of colon cancer (colorectal cancer - CRC) in families may be due to the inheritance of one of the mutant genes. These are primarily genes associated with the syndrome of hereditary nonpolyposis colon cancer (HNPCC) - Lynch syndrome (genes MSH2, MLH1, PMS1, PMS2, MSH6, etc.), as well as genes of hereditary polyposis of the gastrointestinal tract, mainly familial adenomatosis of the colon (APC gene). The risk of cancer in Lynch syndrome and familial adenomatosis is about 90%.

For correspondence: Alla Petrovna Chudina - Ph.D. honey. Sciences, Ved. scientific co-workers dept. chemical carcinogenesis; 115478, Moscow, Kashirskoe highway, 24; [email protected].

Accurate identification of the carrier of a mutant gene using molecular genetic methods cannot currently be widely used for screening hereditarily predisposed people due to the complexity and high cost of the methods. Clinical and genealogical analysis of pedigrees not only helps to narrow down the search area for high-risk individuals for possible further molecular genetic identification, but in many cases it still remains the only available method for identifying hereditary predisposition. Therefore, improving this method and clarifying its criteria is still relevant today.

The purpose of this work was to study the relationship between family accumulation of colorectal cancer as the main symptom of syn-

Lynch roma (sLynch) with other known criteria, such as a younger age of tumor onset, longer life expectancy after diagnosis, primary multiplicity of tumors. An objective assessment of the significance of the listed criteria in our study was the frequency of new cases of malignant neoplasms that arose during the 5-year follow-up.

The work was carried out using materials from the Moscow Oncological Genetic Registry (MOGR), which has been operating since 1990 at the Russian Oncological Research Center named after. N. N. Blokhin and on the basis of Oncology Dispensary No. 4 in Moscow. The MOGR includes data on the pedigrees of more than 6 thousand cancer patients. The information was obtained as a result of postal, less often telephone or personal survey of patients. Oncological diagnoses of all probands and some relatives were verified using extracts from hospitals, outpatient records and according to the Moscow Cancer Registry. Since 1995, information about families included in the register 5 years ago or more has been monitored. Information about probands and some relatives is first clarified using outpatient cards and the cancer registry database. Families who can be contacted through probands or relatives are offered a repeat survey.

Of the 1185 re-interviewed families, 201 were selected where there were patients with colorectal cancer among first-degree relatives (including the proband). The sample is divided into 3 groups. The 1st group included 6 families from Lynch. These are 5 families where mutations of the IMBI2 (4 families) and LMI1 (1 family) genes were previously identified, and 1 family that has not been studied molecular genetically, but with a typical clinical and genealogical picture of Lynch. The 2nd group included 36 families in which there were 3 or more cases of malignant neoplasms (MN) of different locations in relatives who were in the first degree of relationship to one of the patients, and the lesion affected two generations or more. Neither primary multiplicity nor age of disease onset were taken into account. The group is designated as cancer families (FC). The 3rd group consisted of 159 families conventionally designated as non-cancerous (Non-cancer), although 72 of them had cancer in 1-2 first-degree relatives, not counting probands.

The groups were compared according to the frequency of patients with cancer among first-degree relatives, the frequency of primary multiple lesions, the relative frequency of cancer in certain localizations, the age of onset of cancer, the life expectancy of the patient after diagnosis.

tumor staging and the frequency of families with new cases of cancer. Since families are observed for different periods of time, but not less than 5 years, the work used information relating only to this period of observation.

To analyze and evaluate the results obtained, standard biometric methods, the Excel 5.0 software package, as well as some methods of oncological epidemiology were used.

In the compared groups, the number of relatives was approximately the same. On average, there were 5-6 relatives per family, including probands. In all groups, there were more women than men due to the larger number of women among the probands. In the Lynch group, only women were probands. The families of the MS group were the most numerous, the families of the Lynch group were the least numerous, but these differences are statistically insignificant.

Family history of cancer was assessed by the overall frequency of patients with any cancer among first-degree relatives. It was greatest in the Lynch group: by the 1st registration, the frequency of patients among all relatives over 20 years of age was 61.5%. This is significantly higher than the similar frequency of MN in relatives in two other groups: 35.6% in the MS group and 10.5% in the Non-MS group (p< 0,01). Во всех группах частота больных среди женщин была несколько выше, чем среди мужчин. Наибольшая частота онкологических больных была среди женщин из группы сЛинча (66,7%).

One of the signs of hereditary forms of cancer is a high frequency of multiple lesions. According to various authors, the frequency of primary multiple malignant neoplasms (PMMN) among cancer patients ranges from 0.04 to 11% (usually 3-6%). In table Figure 1 shows the frequency of PMMN in probands and first-degree relatives in the groups we studied.

In the NeRS group, the frequency of patients with PMMN approximately corresponded to the literature data (ranged from 2.6 to 9.3%). In total, out of 243 patients in this group, 14 had PMMN (5.8%). In the MS group, the frequency of probands with PMMN was slightly higher compared to probands in the HeMS group, but it turned out to be unexpectedly low in relatives - only 1 case in 68 patients. In total, out of 103 patients, 6 (5.8%) people had PMMN, i.e., the MS group as a whole did not differ from the HeMS group.

In the Lynch group, the frequency of patients with PMMN was high in women, both probands and relatives (50.0 and 62.5%, respectively). The difference with HePC and RS is statistically significant (p< 0,01). Из 8 больных муж-

Frequency of patients with PMMN according to the 1st family registration (probands and first-degree relatives)

Table 1

Group (number of families) Patients Frequency of patients with PMMN*

probands first degree relatives

with Lynch (6) Total 6 0 8 8

WITH PMZN 3 5 1

(% + m) (50.0 + 22.4)** (62.5 + 17.1)*** (12.5 + 11.7)

RS (36) Total 294* 6 38 30

WITH PMZN 4 1 1 0

(% + m) (13.8 + 6.4) (16.7 + 15.2) (2.6 + 2.6)

NeRS (159) Total 116 43 46 38

With PMZN 6 4 3 1

(% + m) (5.2 + 2.1) (9.3 + 4.4) (6.5 + 3.6) (2.6 + 2.6)

Note. * - the frequency of patients with PMMN is calculated for the total number of patients; ** - the difference with the HePC group is significant (p< 0,01); *** - различие с группами РС и НеРС достоверно (р < 0,01); 4* - у 1 пробанда-женщины было доброкачественное новообразование.

In this group, only 1 had PMMN (3 CRC). The obtained result may indicate that a high incidence of PMMN is typical only for female patients with sLynch. However, it cannot be excluded that with a larger number of observations and in men with the syndrome, the frequency of PMMN will be increased. In total, out of 22 patients, 9 (40.9%) had PMMN.

During 5 years of observation, repeated cases of MN occurred in patients from all three groups. This, however, did not significantly affect the results: as with the first registration, the highest incidence of PMMN was in women from the sLynch group and there were no significant differences between the MS and NonMS groups.

An analysis of the relative frequency of malignancies in certain localizations in women and men is presented in Table. 2 and 3.

The analysis included malignancies that arose before the 1st registration of the family, as well as during 5 years of observation. In case of primary multiplicity, each tumor was counted separately. Since all 3 groups were selected based on the presence of patients with colon and/or rectal cancer, these tumors constituted the majority. Some localizations are represented by 1-2 cases; in the tables they are included only in the total amount of neoplasms.

In non-cancer families, colorectal cancer occurred with equal frequency: 32% in women and 33% in men. In the MS group, men also had the same incidence of colorectal cancer, 27.5% each, while women were slightly more likely to have colorectal cancer than rectal cancer (24.7 and 16.9%). According to statistical data on the structure of cancer incidence in Russia and the CIS countries for 2003, in men, colorectal cancer has approximately the same frequency (5.4 and 5.0%), and in women, colon cancer occupies a slightly larger place ( 6.8 and 5%) .

In the Lynch group, both women and men had colon cancer significantly more often than rectal cancer, respectively, in women 31.3 and 12.5%, and in men 66.7 and 25%. Apparently, this is due to more frequent involvement of the proximal colon in hereditary forms of colorectal cancer. Of the other cancer sites in Lynch's group, there was only 1 case in men - a brain tumor. In women from the Lynch group, uterine cancer takes 2nd place - 18.8%, which is significantly higher than the frequency of this form of cancer in the HePC group - 3.4% (p< 0,05). В группе РС большое

Relative frequency of malignancies in some localizations in women

The place is occupied by breast cancer - 16.9%, and ovarian cancer - 9.1%. In this group, some families may have hereditary breast and ovarian cancer syndrome (BrCa1).

A young age at onset of cancer and a long life expectancy with a tumor are also considered signs of hereditary cancer. Data on the average age of onset of cancer and life expectancy with a tumor are presented in Table. 4.

The summary includes those who were already sick by the 1st registration of the family. For primary multiplicity, the age of onset of the first tumor was taken into account.

On average, the first malignancies in family members from the sLynch group occurred 10-20 years earlier than in relatives from the other two groups: the average age in the sLynch group was 44-48 years, in the MS group 54-66 years, in the HeRS group 54-64 of the year. The differences are significant (p< 0,01). В то же время в группах НеРС и РС встречались и очень молодые (22, 23 года), и очень старые (87, 93 года) больные. В группе сЛинча возрастной разброс был меньше: минимальный возраст 30 лет, максимальный - 69 лет. В группе сЛинча большинство больных заболели до 50 лет: 71,4% женщин и 87,5% мужчин. При этом 21,4% женщин и 25% мужчин заболели в возрасте до 40 лет. В двух других группах картина прямо противоположна: 70-80% больных заболели после 50 лет и из них большинство заболели после 60 лет. В этих группах частота тех, кто заболел до 40 лет, не превышала 10%.

Life expectancy with a tumor is an indicator that depends on many reasons, and primarily on the level of medical care in the place and during the patient’s stay. But since the analyzed families were taken from the same source, it was considered possible to analyze this indicator as well. We used data on those who fell ill before the 1st registration of the family. The indicator is calculated from diagnosis until the death of the patient, and for those who are alive, including a 5-year period after the first registration of the family (see Table 4).

The longest average life expectancy with a tumor was in female probands from the sLin-cha group - 14.8 years. Ill relatives from this group also lived longer compared to relatives from the other two groups (p< 0,05). Обращает на себя внимание то, что во всех группах продолжительность жизни пробандов была больше, чем родственников. В качестве

table 2

Group ROK RPK RTM RYa RMJ Total*

with Lynch 10 31.3 ± 8.2 4 12.5 ± 5.9** 6 18.8 ± 6.9*** 3 9.4 ± 5.2 2 6.3 ± 4.3 32

RS 19 24.7 ± 7.9 13 16.9 ± 4.3** 5 6.5 ± 2.8 7 9.1 ± 3.3 13 16.9 ± 4.3 77

NeRS 57 32.0 ± 3.5 57 32.0 ± 3.5 6 3.4 ± 1.4 6 3.4 ± 1.4 16 9.0 ± 2.1 178

Note. ROC - colon cancer, RCC - rectal cancer, RTM - uterine cancer, OC - ovarian cancer, BC - breast cancer; * - including other localizations; ** - the difference with the HePC group is significant (p< 0,01); *** - различие с группой НеРС достоверно (р < 0,05).

Table 3

Relative frequency of malignancies in some localizations in men

Group ROK RPK RZh RPZh RBrL Total*

abs. % abs. % abs. % abs. % abs. %

with Lynch 8 66.7 ± 13.6** 3 25.0 ± 12.5 0 0 0 12

RS 11 27.5 ± 7.1 11 27.5 ± 7.1 3 7.5 ± 4.2 4 10.0 ± 4.7 2 5.0 ± 3.5 40

NeRS 31 33.0 ± 4.9 31 33.0 ± 4.9 13 13.8 ± 3.6 2 2.1 ± 1.5 6 6.4 ± 2.5 94

Note. ROC - colon cancer, RCC - rectal cancer, GC - stomach cancer, PC - pancreatic cancer,

RBrL - cancer of the bronchi and lung;

Including other localizations;

the difference with the HeRS and MS groups is significant (p< 0,05).

Table 4

Age of onset of MN and life expectancy of patients (M ± m)

Group Probands First degree relatives

women men women men

number of patients number of years number of patients number of years number of patients number of years number of patients number of years

age* 6 43.5 ± 2.6*** 0 0 8 47.8 ± 4.4*** 8 43.5 ± 2.6***

life expectancy** 14.8 ± 4.74* 10.2 ± 2.84* 9.3 ± 4.24*

age* 29 53.8 ± 1.8 6 58.7 ± 3.9 38 60.8 ± 2.4 30 65.7 ± 2.8

life expectancy** 9.3 ± 1.2 9.3 ± 2.6 4.3 ± 1.1 1.9 ± 0.4

age* 116 54.0 ± 1.1 43 57.0 ± 1.4 46 64.3 ± 2.2 38 62.8 ± 2.0

life expectancy** 9.6 ± 0.6 8.1 ± 0.7 2.9 ± 1.0 2.4 ± 0.7

Note. * - average age of onset of any malignancy. In PMZN, the age of the first tumor is taken; ** - life expectancy from the first cancer diagnosis to death, and for the living - including the 5-year period after the 1st registration of the family; *** - the difference with the HePC and MS groups is significant ^< 0,01); 4* - различие с группами НеРС и РС достоверно ^ < 0,05).

Table 5

Frequency of families with new cases of MN in blood relatives and probands over a 5-year observation period

Frequency of families with new cases of MN

Group of families Total families of relatives of the 1st degree of kinship and probands of relatives of the 1st-3rd degree of kinship and probands

abs. % abs. %

with Lynch 6 3 50.0 ± 20.4* 5 83.3 ± 15.2**

RS 36 5 13.8 ± 5.8 12 33.3 ± 7.9*

NeRS 159 13 8.2 ± 2.2 17 10.7 ± 2.5

Note.

the difference with the HePC group is significant (p< 0,05); ** - различие с группами НеРС и РС достоверно (p < 0,01).

explanations, it can be assumed that patients with a favorable course of the disease respond more readily to the survey. It is also possible that probands are not always accurately aware of the timing of the onset of the disease in relatives.

New malignancies arose in families of all three groups. In table Table 5 presents data on the frequency of families in which new malignancies were diagnosed in probands and blood relatives of the 1st-3rd degree of kinship over 5 years.

If we take into account only probands and first-degree relatives, then new cases of MN arose in 50% of families in the Lynch group, in 13.8% of families in the MS group, and in 8.2% of families in the Non-MS group. The differences are significant only between Lynch and HePC (p< 0,05). В группе сЛинча новые ЗН возникли лишь у тех, кто был ранее болен (вторые-третьи опухоли). В двух других группах были как повторные, так и первичные случаи ЗН. Можно предполагать, что в семьях с сЛинча практически не осталось носителей генетически обусловленной предрасположенности к раку (некому болеть).

If we take into account more distant relatives (up to the third degree of relationship) reported by probands, then new MNs arose in 83% of families in the sLynch group, in 33% of families in the MS group, and in 13% of families in the HeRS group. The differences are significant between all groups (p< 0,01).

Conclusion

The study showed that with sLin-cha, the frequency of patients with MN among first-degree relatives reaches 60% or more. In more than half of sick women and 12.5% of men, the lesions are multiple. A feature of the spectrum of neoplasms in patients with Lynch is the more frequent

lesions of the colon compared with the rectum and an increased incidence of uterine cancer. Neoplasms in members of families with Lynch syndrome appear 10-20 years earlier than in relatives from families without syndromic pathology. In this group, 71-88% of patients were under 50 years of age, and 21-25% were under 40 years of age. In the other two groups, the picture is exactly the opposite: 70-80% of patients fell ill after 50 years, and most of them after 60 years. In these groups, the frequency of those who became ill before the age of 40 did not exceed 10%. The average life expectancy of patients with a tumor from the Lynch group is 5-7 years longer compared to patients from the other two groups. Finally, new malignancies in families with Lynch within 5 years arise significantly more often than in families of the other two groups. In the MS group, new cases of MN arose somewhat more often than in Non-MS, but the difference became significant only if relatives up to the third degree of kinship were taken into account. In general, the group is apparently quite heterogeneous and mostly consists of families in which the accumulation of 3 cases of cancer or more is due to the action of several genes (polygenic inheritance), as well as the influence of environmental factors. It is obvious that only when monogenic heritability is established, all the declared signs of hereditary cancer manifest themselves in full.

LITERATURE

1. Malignant neoplasms in Russia and the CIS countries in 2003 - M., 2005.

2. Chudina A.P. // Vopr. oncol. - 2004. - T. 50, No. 5. - P. 540-543.

3. Yurin A. G. // Vopr. oncol. - 2003. - T. 49, No. 3. - P. 376-382.

How to diagnose Lynch syndrome?

How to cope with Lynch syndrome

Lynch syndrome review

Lynch syndrome is an (autosomal) inherited cancer syndrome causing cancer of the uterus, bowel, stomach and urinary tract. Patients with Lynch syndrome have a 27% to 70% risk of developing uterine cancer and a 5% to 12% risk of developing ovarian cancer. Uncommon tumors associated with Lynch include cancers of the kidney, ureter, 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 cancers, and may 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 younger have an 18% chance of developing 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. For these patients, preventative, high-risk surgery to remove the uterus, tubes and ovaries can be life-saving. These operations are performed laparoscopically (key hole) and virtually eliminate the risk of developing uterine and ovarian cancer.

Women with linkage-related endometrial cancer have a 40-fold higher risk of developing colorectal cancer.

Women diagnosed with Lynch-related colon cancer have a 28 times higher risk of developing endometrial cancer.

Moscow, make an appointment by phone 24/7!

Why is it so important to diagnose Lynch?

Patients with Lynch syndrome should be screened for other types of cancer. Screening or preventative surgery can save lives.

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

Family history is a poor indicator 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 histopathologic features often associated with Lynch syndrome (eg, involvement of the lower segment of the uterus or cervix, presence of tumor infiltrating lymphocytes).

The first step to diagnose Lynch is an immunohistochemical test, which can be done from a surgical specimen from the original uterine or bowel cancer specimen. 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 that you see a family cancer clinic or a clinical geneticist.

Clinical management

Surveillance for ovarian cancer is unreliable and is not generally recommended. Surveillance for uterine cancer can be done through endometrial sampling (Pipelle) (for premenopausal women) or through ultrasound (for postmenopausal women), but is also unreliable. Colonoscopy (every 1-2 years) from age 25 (reduces incidence and mortality from colon cancer by 60%) is really reliable and recommended. Annual urine cytology will detect early stages of bladder and ureteral cancer.
Prevention: The oral contraceptive pill will reduce the risk of developing ovarian cancer by 50%. There is no established medicine to prevent uterine cancer.
Preventative surgery (laparoscopic hysterectomy) is the most effective way to eliminate the risk of developing uterine and ovarian cancer; This 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 should be medically fit to tolerate surgery, should be aware of the most common risks and possible complications of surgery, and require some testing (blood tests, medical imaging) before surgery.

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

How is Lynch syndrome diagnosed?

General practitioners should suspect that a person may have the Lynch syndrome gene when there is a strong family history of cancer. This means that three or more family members have been diagnosed with the cancers listed above, two successive generations or more are affected by these cancers, and one of those affected family members was diagnosed with cancer before age 50. One should also suspect that the patient has little to no access to information about his family's health and has already had one or more types of cancer before age 50.

If Lynch syndrome is not identified and the patient develops cancer, they usually require surgery to remove the tumor. Current best practice for all colon and endometrial tumors in patients under 50 years of age or who have a strong history of heart cancer is for the treating team to order a pathology test to check for abnormal genes 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 patient's consent, the clinic will arrange for a tissue sample from a past tumor (either the patient or another family member) to be tested to look for a gene mutation to eliminate the mismatch.

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

How to cope with Lynch syndrome?

Management of Lynch syndrome includes a plan to monitor regular tests to identify problems early. Polyps can then be removed before they become cancerous or cancers can be removed at an early stage. 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 suggest may significantly reduce the incidence of Lynch syndrome) may also be considered ).

Recommendations of annual colonoscopies (starting at age 25 or 30, depending on the gene mutation, or five years younger than a 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 average time from polyp to bowel cancer is reduced from ten years in the general population to 35 months in patients with Lynch syndrome. Likewise, the average age for developing uterine cancer is falling 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 environmental factors. For example, a family history of stomach or skin cancer may justify including annual endoscopies or dermatological reviews.

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

– a hereditary disease accompanied by the development of malignant neoplasms in the large intestine. Clinical manifestations are similar to other types of colorectal cancer. Distinctive features are early onset, high incidence of primary multiple tumors and predominant involvement of the right parts of the large intestine. In Lynch syndrome II, colorectal cancer is combined with extraintestinal malignant neoplasia. The diagnosis is made taking into account family history, immunohistochemical tests, colonoscopy, irrigoscopy, biopsy and other studies. Treatment – surgery, chemotherapy.

General information

Lynch syndrome (hereditary nonpolyposis colorectal cancer) is a genetically determined disease in which the development of malignant tumors of the large intestine is observed. It is transmitted in an autosomal dominant manner. Accounts for about 3% of the total number of colorectal cancer cases. In 30% of cases with Lynch syndrome, the occurrence of synchronous or metachronous neoplasia is noted. In some cases, neoplasms of the colon are combined with oncological lesions of the ovaries, uterus, bladder, renal pelvis, ureter, stomach, bile ducts and small intestine.

The risk of developing cancer in patients with Lynch syndrome with a confirmed genetic mutation ranges from 30 to 80%. A distinctive feature is the early onset of the disease. Malignant tumors in Lynch syndrome are usually diagnosed before the age of 50, 10-15 years earlier than the population average. The average age of onset of symptoms is 44 years. About 70% of neoplasias are localized in the right half of the large intestine. Treatment is carried out by specialists in the field of oncology, abdominal surgery and gastroenterology.

Causes of development and classification of Lynch syndrome

The development is caused by mutations in genes responsible for DNA repair errors: PMS2, MSH6, MSH2 and MLH1. A combination of several mutations is possible with a corresponding increase in the risk of malignant neoplasms. An autosomal dominant pattern of inheritance is revealed. Typically, patients with Lynch syndrome are diagnosed with mucinous adenocarcinomas or signet ring cell carcinoma. Tumors are characterized by a low level of cell differentiation with rare metastasis, a good response to therapy and a relatively favorable prognosis.

There are two types of the disease: Lynch syndrome-I and Lynch syndrome-II. The first option occurs without extraintestinal manifestations; the only sign of the disease is the early development of multiple neoplasias of the large intestine in the absence of previous polyposis. In Lynch syndrome-II, a combination of adenocarcinomas of the colon and malignant tumors of other localizations is observed. Usually the internal female genital organs are affected, and the overlying parts of the digestive tract may also be affected. The probability of developing endometrial cancer in Lynch syndrome-II ranges from 30 to 60%, the risk of tumors in other localizations is 10-15%.

Symptoms of Lynch syndrome

There are no symptoms until the appearance of malignant tumors of the large intestine. With the development of neoplasia, the clinical manifestations correspond to non-hereditary colorectal cancer. Pain, appetite disturbances, stool disorders, weakness and anemia are observed. Due to the high location of the tumors, blood in the stool in Lynch syndrome is usually not visually detected. The severity and nature of the pain syndrome varies significantly. Typically, patients complain of aching or nagging pain of mild or moderate intensity. Less commonly, patients with Lynch syndrome experience short-term paroxysmal pain, reminiscent of pain in acute cholecystitis or acute appendicitis.

Upon palpation of sufficiently large tumors, inactive nodes with a dense or soft elastic consistency are determined. With the progression of a malignant neoplasm in patients with Lynch syndrome, symptoms of intoxication arising from the disintegration of neoplasia and intestinal obstruction caused by an obstruction in the passage of feces through the intestines are revealed. With distant metastasis, dysfunction of the relevant organs is observed. Severe weakness, emotional lability, a tendency to depression, fever and progressive exhaustion are noted.

Symptoms of tumors of other locations in Lynch syndrome also correspond to non-hereditary forms of cancer lesions of certain organs. Endometrial cancer and ovarian cancer in the initial stages can be asymptomatic. Subsequently, with endometrial cancer, pain, bloody, serous or serous-serous discharge are observed. When the tumor spreads to neighboring organs, defecation and urination disorders occur. Ovarian cancer is characterized by a feeling of discomfort, abdominal enlargement, menstrual irregularities, etc.

Diagnosis of Lynch syndrome

Before the appearance of malignant neoplasms, Lynch syndrome is diagnosed based on family history and genetic testing. Due to the low prevalence in the population, universal screening examinations are considered inappropriate; genetic tests are performed only if a relevant family history is identified. Anamnestic criteria for Lynch syndrome are the presence of histologically confirmed colon carcinomas in three or more close relatives representing two or more generations, as well as one or more cases of onset of the disease before the age of 50 years.

To detect genetic mutations characteristic of Lynch syndrome, enzyme immunoassays and a microsatellite instability test are used. When clinical signs of the disease appear, patients with Lynch syndrome are referred for irrigoscopy and colonoscopy. A stool test for occult blood is performed. An ultrasound, CT or MRI of the abdominal cavity is performed. The examination plan for patients with Lynch syndrome with suspected malignant tumors of the female genital organs and upper gastrointestinal tract is drawn up taking into account the established standards for neoplasia of the corresponding localizations. The list of studies for suspected distant metastasis is determined taking into account the estimated location of secondary foci.

Treatment and prevention for Lynch syndrome

All patients with a confirmed hereditary mutation are considered to be at risk. Patients with Lynch syndrome require lifelong follow-up, which includes regular examinations by an oncologist and gastroenterologist, colonoscopy once every 1-2 years, starting from the age of 25, fibrogastroduodenoscopy and ultrasound of the abdominal cavity - once every 1-2 years, starting from the age of 30 years. Women with Lynch syndrome undergo regular gynecological examinations. Instrumental examinations are prescribed once every 1-2 years, starting at age 30.

If a malignant tumor of the colon occurs, the preferred option for patients with Lynch syndrome is subtotal colectomy. This surgery increases life expectancy and provides a better prognosis than partial colon resection. Considering the impact of removing a significant part of the large intestine on the quality of life of patients, the decision to perform such an operation is made after a detailed explanation of the consequences of the intervention. The question of the advisability of chemotherapy for Lynch syndrome remains debatable, although some researchers point to the fairly high effectiveness of irinotecan.

Lynch syndrome is a genetic disorder of autosomal dominant inheritance.

Causes

One of the most important reasons is a mutation of the gene, which is responsible for repair processes in unpaired bases of the DNA molecule. There can be several types of mutations and each leads to the formation of cancer in different parts of the colon.

Microsatellite instability is formed, which leads to disruption of repair in the DNA molecule. Such processes undoubtedly increase genetic debris, which quickly accumulates in the cell's genome. The rate of its accumulation is several times higher than that of a healthy person.

Signs of microsatellite tumors in Lynch syndrome

Proximal location;
Mucinous variant;
Low degree of differentiation;
Primary multiple nature of tumor spread;

Epidemiology

Non-polyposis colorectal cancer occurs in 1 case in 500 patients with various types of colorectal cancer. Thus, its occurrence is determined to be within 2-3% of all episodes of colorectal cancer.

Differences from familial adenomatous polyposis (FAP)

Lynch syndrome, in contrast to FAP, manifests itself as single colorectal adenomas, which are in no way different from suddenly and accidentally occurring tumors.

Clinical criteria for Lynch syndrome

There are three or more relatives in the family with histologically confirmed colorectal cancer. Also if there is or has been cancer of the endometrium, ureter, small intestine, renal pelvis. One of the three relatives must be first degree related to the other two;
Manifestation of pathology in two generations;
At least one tumor must be identified and diagnosed by age fifty.

These criteria are quite strict. Almost half of the families that meet these criteria do not have any defects in their genes. This type of disease is called familial colorectal cancer type X.

In these families, the formation of microsatellite stable tumors occurs, in the presence of which the risk of developing colon cancer is quite low.

No one today can justify the appearance of this cancer on the basis of heredity and genetics.
Diagnostic criteria for Lynch syndrome according to the Bethesda manual

The following criteria are used to establish a diagnosis:

Cancer diagnosis occurred before age 50;
Presence of diseases that are usually associated with Lynch syndrome. This is a metachronous cancer;
A patient with colorectal cancer has symptoms of high-risk microsatellite instability;
The presence of a first-degree relative under 50 years of age in a patient with colorectal cancer;

Symptoms of Lynch syndrome

Colorectal cancer develops in Lynch syndrome before age 50. Then, within 10 years, such patients develop another neoplasm, which is characteristic of this syndrome. Family members also have similar tumors.

If the patient meets most of the criteria described above, testing for microsatellite instability is mandatory. In addition, it would not be superfluous to conduct an immunohistochemical analysis of the tumor.

To facilitate diagnosis in everyday work, a simple and fairly convenient questionnaire has been developed.

Questionnaire to determine the risk of developing familial colorectal cancer

Evaluating responses to survey questions

For all “no” answers, there is no increased risk of colorectal cancer.

If you answer “yes” to only 1 question, there is an increased risk of familial colorectal cancer and you should undergo standard screening testing.

If you answer “yes” to one or more questions numbered 2 to 6, there is a high probability of developing a hereditary form of cancer. In this case, it is necessary to undergo a complete genetic examination.

Difficulties in diagnosis

People do not always know the illnesses of their relatives, and very often families nowadays are small, so it is not possible to reliably determine the risk of disease.

Diagnosis of Lynch syndrome

In order to correctly diagnose Lynch syndrome, two steps are necessary:

A microsatellite instability test is performed if cancer is suspected in a given patient. The polymerase chain reaction technique is used;
After finding signs of instability, it is necessary to perform a complete genetic analysis for the presence of mutations in the genes. Lynch syndrome is only identified through interaction with a geneticist.

Screening diagnostic methods

Screening diagnostic methods have been developed to prevent the development of colorectal cancer and the formation of metastases. Screening is carried out not only for the patient, but also for his family members.

For example, in Germany, screening is used, which includes:

medical checkup;
colonoscopy;
Ultrasound of the abdominal cavity;
Gastroscopy;
Gynecological examination for women, which includes an endometrial biopsy and transvaginal ultrasound of the uterus.

Therapeutic measures

Non-polyposis colorectal cancer treated with surgery according to international standards. The feasibility of radical surgery has not yet been confirmed by randomized studies, since they have not been conducted.

Dr. Zajac is a physician, researcher, and biotechnology entrepreneur. He received his PhD in genetics from the University of Cambridge in 2014 and his medical degree 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 nonpolyposis colorectal cancer (HNPCC). This is an inherited disease 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 years of age). If you think you are at risk, learn how to diagnose Lynch syndrome.

Steps

Recognize your likelihood of developing Lynch syndrome

Establishing diagnosis

Make an appointment with your doctor. If you think you may have Lynch syndrome, see your doctor, who can refer you to a genetics specialist (medical geneticist). They are experts in genetic testing, counseling and management of genetic diseases such as Lynch syndrome.

See your doctor right away if you experience the above physical symptoms or if you have a family history of colon cancer or another type of cancer.

Determine if you have a genetic predisposition. Your doctor may suspect Lynch syndrome if someone in your family has had colon cancer, endometrial cancer, or other types of cancer, especially if they developed it at a young age. Diagnosis is carried out through genetic testing.
- Your doctor may ask you about family members with stomach, small bowel, brain, kidney, liver, or ovarian cancer, since the gene that mutates to Lynch syndrome increases your risk of developing a number of other cancers.
- The doctor may also ask you if anyone in your family has had cancer in past generations, especially if cancer runs in your family through generations.
Get a biopsy of the tumor. If you or a family member has tumors, your doctor will be able to examine them to see if you have Lynch syndrome. He will be able to detect 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 test to make sure that Lynch syndrome is absent or present.
- If someone in your family has had cancer in the past few years, the hospital may have leftover a tissue sample for a doctor to examine.
Get genetic testing. There are currently 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 wish, have your blood tested at several different laboratories.

Lynch syndrome and everything connected with it

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 genetic testing confirms Lynch syndrome, your lifetime risk of developing 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.

Lynch syndrome - causes, diagnosis and treatment. Hereditary nonpolyposis colorectal cancer, or Lynch syndrome Lynch syndrome symptoms

annotation scientific article on clinical medicine, author of the scientific work - Alla Petrovna Chudina

Related topics scientific works on clinical medicine, author of the scientific work - Alla Petrovna Chudina

Text of scientific work on the topic “Lynch syndrome and sporadic colorectal cancer: clinical and genealogical features”

How to diagnose Lynch syndrome?

How to cope with Lynch syndrome

Lynch syndrome review

Why is it so important to diagnose Lynch?

Clinical management

How is Lynch syndrome diagnosed?

How to cope with Lynch syndrome?

General information

Causes of development and classification of Lynch syndrome

Symptoms of Lynch syndrome

Diagnosis of Lynch syndrome

Treatment and prevention for Lynch syndrome

Causes

Signs of microsatellite tumors in Lynch syndrome

Epidemiology

Differences from familial adenomatous polyposis (FAP)

Clinical criteria for Lynch syndrome

Symptoms of Lynch syndrome

Questionnaire to determine the risk of developing familial colorectal cancer

Evaluating responses to survey questions

Difficulties in diagnosis

Diagnosis of Lynch syndrome

Screening diagnostic methods

Therapeutic measures

Steps

Recognize your likelihood of developing Lynch syndrome

Establishing diagnosis

Lynch syndrome and everything connected with it