Lynch Syndrome by A.Griguolo

Generality

Lynch syndrome is a genetic, purely hereditary condition, which predisposes to the development of various malignant tumors, primarily colorectal cancer.

Also known as hereditary non-polypose colorectal cancer, Lynch's syndrome is due to the mutation of genes responsible for correcting errors in the DNA duplication system, during cell division processes.

An example of an autosomal dominant disease, Lynch syndrome maintains an asymptomatic condition until it induces the formation of some malignant tumor.

The analysis of family history and a genetic test on a blood sample are essential to reach the diagnosis of Lynch syndrome.

Lynch syndrome is an incurable condition, as there is no treatment capable of nullifying the genetic mutation that supports it.

Treatment for a tumor related to Lynch syndrome is equivalent to that for the same tumor developed in the absence of the aforementioned hereditary condition.

What is Lynch Syndrome?

Lynch syndrome is a genetic, purely hereditary condition that causes a predisposition to several malignant tumors (or cancers ), first of all colorectal cancer (or colorectal cancer ).

Lynch syndrome is a very particular condition, which does not produce any symptoms by itself, except when it causes the formation of some tumor.

Lynch syndrome is a member of the disease family that includes the so-called hereditary diseases / syndromes of predisposition to cancer .

Did you know that ...

A condition similar to Lynch syndrome is familial adenomatous polyposis (or FAP ).

What other Malignant Tumors is Lynch Syndrome Associated with?

In addition to colorectal cancer, the presence of Lynch syndrome induces a predisposition for:

• Ovarian cancer (or ovarian cancer);
• Endometrial cancer (or endometrial cancer);
• Stomach cancer (or stomach cancer);

• Small bowel cancer (or small bowel cancer);
• Biliary tract cancer (or biliary tract cancer);
• Liver cancer (or liver cancer);
• Pancreatic cancer (or pancreatic cancer);
• Prostate cancer (or prostate cancer);
• Kidney cancer (or kidney cancer);
• Urinary tract cancer (or urinary tract cancer);
• Brain cancer (or brain cancer);
• Skin cancer (or skin cancer).

Other names of Lynch Syndrome

Precisely because of its association with colorectal cancer, Lynch syndrome is also known as hereditary non-polyposis colorectal cancer (in English it is hereditary non-polyposis colorectal cancer or HNPCC ).

Causes

Lynch syndrome is associated with the mutation of one of the human genes known as MLH1, MSH2, MSH6, PMS2 and EPCAM .

In other words, an individual carries the Lynch syndrome, when one of the MLH1, MSH2, MSH6, PMS2 and EPCAM genes presents an alteration in the usual DNA sequence.

A genetic mutation is an alteration in the normal DNA sequence that makes up a certain gene.

The genetic mutations responsible for Lynch's syndrome are always the result of parental transmission (ie: the patient receives it from one of the parents); this peculiarity makes Lynch syndrome a purely hereditary (or familial ) condition.

What are the consequences of the Mutation of MLH1, MSH2, MSH6, PMS2 and EPCAM?

Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.

In the absence of mutations against them, the MLH1, MSH2, MSH6, PMS2 and EPCAM genes produce special proteins, whose task is to correct, during cell division, the mismatch errors that the DNA duplication process could commit.

To understand…

The phenomenon of cell division is always accompanied by a process of DNA duplication, which guarantees the two resulting cells to have the same genetic material as the starting cell.

DNA duplication is a process that involves numerous proteins, including those that replicate the genetic material and those that correct any replication errors (ie any mistakes in the first class of proteins just described).

MLH1, MSH2, MSH6, PMS2 and EPCAM are, as previously stated, some of the genes that produce proteins used to remedy any errors in the DNA duplication system.

In the presence instead of the mutations associated with Lynch syndrome, the MLH1, MSH2, MSH6, PMS2 and EPCAM genes lose their faculties and this deprives the DNA duplication system of fundamental elements for the correction of possible replication errors of the genetic material.

To understand…

When one of the genes MLH1, MSH2, MSH6, PMS2 and EPCAM is mutated, a fundamental protein is missing to correct the errors that the DNA duplication process can commit.

SOME IMPORTANT NOTES

• In most cases, mutations associated with Lynch syndrome involve MLH1, MSH2 and MSH6; more rarely, they affect PMS2 and EPCAM.
• EPCAM does not express a protein involved in the correction of possible errors deriving from the DNA duplication process; however, it is still responsible for Lynch's syndrome, because, due to its proximity to the human genome to the MSH2 gene, it is capable of altering its function, when it is obviously the bearer of a critical mutation.
• Not all carriers of genetic mutations associated with Lynch syndrome develop a malignant tumor among those indicated at the beginning of the article.

  The reason why the appearance of malignant tumors spares some patients with Lynch syndrome is completely unknown.

Why does Lynch Syndrome predisposes to the onset of tumors?

In general, tumors - such as colorectal cancer, pancreatic cancer, ovarian cancer, endometrial cancer, etc. - they are the result of a slow accumulation by DNA of alterations in some critical genes . This is the main reason why tumors are more frequent in older humans: in these subjects, in fact, DNA has had time to accumulate the right number of genetic alterations capable of triggering the tumor process.

Lynch syndrome predisposes to the appearance of tumors, because, by compromising the production of proteins that repair DNA during its duplication, it makes the accumulation, by genetic material, of one of those genetic alterations more probable (and accelerates). responsible for cancer processes.

In a healthy individual, the repair system responsible for correcting DNA duplication errors is efficient and this reduces the risk of developing genetic alterations related to tumors.

In people with Lynch syndrome, the same repair system is not very effective and this has the effect of making the accumulation of those genetic alterations responsible for tumors more likely.

Lynch Syndrome is an Autosomal Dominant Disease

To understand...

Each human gene is present in two copies, called alleles, one of maternal origin and one of paternal origin.

Lynch syndrome has all the characteristics of an autosomal dominant disease .

A genetic disease is autosomal dominant when the mutation of only one copy of the gene that causes it is sufficient to manifest itself.

Epidemiology: some interesting facts about Lynch syndrome

• Lynch syndrome is the most important and widespread condition among the so-called inherited cancer predisposition diseases.
• According to the most reliable estimates, one in 300 people would be born with an alteration in one of those genes associated with Lynch syndrome.
• It appears that Lynch syndrome is linked every year to 2-7% of all new colorectal cancer diagnoses.
• The age at which Lynch syndrome usually causes tumors (in particular colorectal cancer) is between 40 and 50 years.
• In people with Lynch syndrome, the average age of appearance of a possible colorectal cancer is 44 years; comparing this data to what happens in people without the syndrome in question, for the average age of appearance of a possible colorectal tumor is 64 years.

Symptoms and Complications

Lynch syndrome is symptom-free until it induces the formation of some malignant tumor; in this moment, in fact, it reveals itself with the typical manifestations of the tumor to which it gave rise.

In general, Lynch syndrome causes malignancy in adulthood, to be precise from the age of 30 to 40 years .

Typical symptoms of colorectal cancer

Given the particular relationship between Lynch syndrome and colorectal cancer, it is worth remembering the typical symptoms and signs of this neoplasm:

• Change in bowel habits;
• Rectal bleeding;
• Blood in the stool;
• Abdominal pain;
• Abdominal cramps;
• Abdominal swelling;
• Sensation of incomplete bowel emptying after defecation;
• Anemia;
• Weakness and ease of fatigue;
• Weight loss for no apparent reason.

Complications

The complications of Lynch syndrome correspond to the complications of the malignant tumors that can derive from it.

When should I go to the doctor?

People with Lynch syndrome should undergo periodic screening tests to identify malignant tumors associated with their inherited condition.

This is the best way to identify potential neoplastic transformations associated with mutations in one of the MLH1, MSH2, MSH6, PMS2 and EPCAM genes.

Diagnosis

For the diagnosis of Lynch syndrome a genetic test on a presumed patient's blood sample is required.

A genetic test is a DNA analysis aimed at identifying mutations against critical genes.

For a particular condition such as Lynch syndrome (which is asymptomatic until it gives rise to a tumor), DNA analysis is the only test that allows it to be identified .

When to suspect Lynch Syndrome: importance of Family History

For an inherited condition such as Lynch syndrome (which causes symptoms only when it develops into tumors), family history is the only investigation that allows us to suspect its presence and, in a certain sense, allow its early diagnosis.

Fundamental point of the so-called anamnesis, the family history is, in fact, an investigation concerning the pathologies suffered by the patient's closest relatives.

If from family history it emerges that some of the patient's relatives were or are carriers of the Lynch syndrome, the diagnostic doctor has the duty to consider the hypothesis that the same patient may suffer from the same hereditary condition.

What else is suspect?

A doctor is expected to suspect Lynch syndrome, when more than one relative of the patient has developed prematurely, compared to what happens in most cases, one of the malignant tumors associated with the aforementioned inherited disease.

Screening Test for Early Cancer Diagnosis

As stated in a previous step of this article, it is good that people with Lynch syndrome periodically undergo (based on what the treating doctor established) some screening tests for the early detection of some malignant tumors associated with their condition .

Screening tests indicated in the presence of Lynch syndrome include:

• For men and women over the age of 25, colonoscopy every 1-2 years and digestive endoscopy combined with the Helicobacter Pylori test every 2-5 years.
• For women aged 30-35 years and only in the case of a family history of tumors of the genital system, the pelvic exam, pelvic ultrasound and endometrial biopsy, all three annually.

Therapy

Lynch syndrome is an incurable condition, as there is no treatment capable of eliminating the mutation that supports it.

Therefore, those born with Lynch syndrome are destined to live with it and with the greatest risk of developing a series of dangerous malignant tumors.

Is There a Therapy for Tumors Associated with Lynch Syndrome?

People with one of the tumors associated with Lynch syndrome can rely on the same treatments provided in the absence of the aforementioned inherited condition. In practical terms, this means that a carrier of Lynch syndrome who develops colorectal cancer will receive the same care as non-carriers of Lynch syndrome who develop the same tumor.

Prognosis

Lynch syndrome is a medical condition that has a good chance of having implications (the associated malignant tumors) with a fatal outcome.

Therefore, the prognosis in the case of Lynch syndrome is to be considered not benevolent .

Prevention

Lynch syndrome is an impossible condition to prevent .

Did you know that ...

Some experiments, worthy of further study, have suggested that regular intake of aspirin by Lynch syndrome carriers would preserve the latter from the onset of colorectal cancer.