Gene panel (includes 43 genes)

Basic characteristics of the clinical phenotype

Hereditary gastrointestinal tumors are malignant formations which affect the digestive tract with a hereditary component. Gastrointestinal tumors include, but are not limited to, neoplasias in the stomach, liver, and colon and rectum. Various hereditary syndromes are associated with the development of these types of tumors. The selected gene panel examines genes involved in the following autosomal dominant hereditary syndromes/dispositions: Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer – HNPCC; OMIM #120435), Hereditary Diffuse Gastric Cancer (HDGC; OMIM #137215), Gastrointestinal Stromal Tumor (GIST; OMIM #606764), juvenile polyposis syndrome (JPS; OMIM #174900), PTEN hamartoma tumor syndrome (PHTS; OMIM # 158350), Peutz-Jeghers syndrome (PJS; OMIM #175200), familial adenomatous polyposis 1 (FAP1; OMIM # 175100), CHEK2-associated tumors, and Li-Fraumeni syndrome (LFS; OMIM #151623). Autosomal recessive syndromes have also been associated with an increased risk of developing gastrointestinal neoplasia, even in the presence of only one mutated gene. Genes associated with this type of disease have been associated with the development of MUTYH-associated familial adenomatous polyposis 2 (MAP; OMIM #608456), Ataxia Telangiectasia (AT; OMIM #208900), Bloom Syndrome (BLM; OMIM #210900), and Mosaic Variegated Aneuploidy syndromes (MVA1; OMIM # 257300, MVA2; OMIM #614114, MVA3; OMIM #617598).

Lynch syndrome occurs as a result of germline mutations in DNA mismatch repair (MMR) genes. They are responsible for the correction of small errors that occur in the DNA nucleotide sequence (mismatches) during DNA replication. As a result, Lynch syndrome is characterized by an early onset and a very high risk of developing cancer, particularly in the right colon, but also in the endometrium, ovaries, stomach, bile ducts, kidneys, bladder, ureter, and brain.

Hereditary diffuse gastric cancer is a highly penetrant type of gastric cancer. Patients with HDGC are usually aged around 40 years and are characterized by a cumulative risk of developing cancer of 67% for men and 83% for women by the age of 80 years. The reason for its development are mutations in the CDH1 gene. Approximately 10% of gastric cancer patients show a family history, and 1-3% of the cases are proven to be hereditary. Mutations in CDH1 can also lead to the development of lobular breast cancer.

Gastrointestinal stromal tumors are rare mesenchymal tumors originating from the gastrointestinal tract or abdomen, specific for the KIT protein. In most cases, GIST spontaneously arises as a result of a spontaneous mutation in the KIT gene. In addition, there are descriptions and cases of families possessing germline mutations in the aforementioned gene.

Juvenile polyposis syndrome is rare syndrome, which leads to the inheritance of hamartose-polyposis syndrome with an increased predisposition to the development of colorectal tumors. In addition to polyposis, 10-20% of JPS patients also have disorders that do not affect the colon, such as congenital heart defects, cleft palate, microcephaly, etc. Despite the fact that a single juvenile polyp in the total cell population has very low malignant potential, patients with UPS have a 68% chance of developing gastrointestinal cancer by age 60.

PTEN Hamartoma syndrome is a group of clinically related conditions all resulting from mutations in the tumor suppressor gene PTEN. In this syndrome, syndromes such as Cowden, Bannayan-Riley-Ruvalcaba, Proteus, Proteus-like, and VACTERL Association with Hydrocephalus are united, united by the characteristics common to all of them such as excessive size of the hamatom, macrocephaly and vascular changes. Patients with a germline PTEN mutation have a 5-10 times higher risk of developing cancer much earlier (<30 years of age) than the general population.

Familial adenomatous polyposis is characterized clinically by the development of hundreds to thousands of adenomatous polyposis in the colon and/or rectum. Without treatment, almost all patients with FAP1 will develop colorectal carcinoma (CRC) by the age of 40. In addition, patients with FAP1 are predisposed to desmoid tumors, tumors affecting the small intestine and thyroid gland, hepatoblastoma, and medulloblastoma.

Peutz-Jeghers syndrome is characterized by hamartomatous polyps in the gastrointestinal tract and melanin pigmentation around the mouth, eyes, nostrils, buccal mucosa, fingers and toes, and other areas. Compared to the general population, patients with PJS have an increased risk of developing malignancies in the small intestine and in various extra-intestinal sites, including breast, ovaries, testes, and others. Approximately 75% of PJS patients have a family history, while the remainder are sporadic cases.

Li-Fraumeni syndrome is a rare inherited disorder which affects children and young adults due to germline mutations in the TP53 gene. Germline mutations in hCHK2, a putative tumor suppressor gene associated with LFS, have been found in patients with familial LFS. The mean age of onset of malignancies in individuals with LFS is between 20 and 45 years of age, which is approximately 2–3 decades earlier than that seen in the general population.

MUTYH-associated polyposis (MAP) is an autosomal recessive disease caused by mutations in the MUTYH gene. Individuals with MAP by the age of 55 develop the clinical features of the disease with the development of multiple (from 10 to 1000) colorectal adenomas, some of which are or will become carcinomas.

Ataxia Telangiectasia is characterized by a very early onset of progressive ataxia affecting the cerebellum, conjunctival telangiectasias, immune deficiency, frequent infections, and others, and an increased risk of cancers, particularly leukemia and lymphoma. Patients with AT have homozygous or complex heterozygous mutations in the ATM gene, and heterozygous carriers of mutations in this gene have an increased risk of developing breast cancer, gastric and colorectal carcinoma, and diseases of the cardiovascular system.

Reason for Referral/ Clinical Significance:

Candidates for this test are all patients with a clinical (medical) or family history suggesting that the etiology of the disease is due to hereditary genetic changes. The test is offered to patients in whom the most common mutations are not detected using Sanger sequencing of the most commonly affected genes.

This test is specifically intended for the analysis of inherited germline mutations and is not suitable for the study of somatic mutations in tumor tissue.

Method: Next-generation sequencing.

The method involves bi-directional DNA sequencing of all coding exons and intron-exon boundaries of the target genes. The laboratory offers Sanger sequencing of a single exon or a pair of exons in the patient's relatives to determine carrier status in cases where the mutation is known (Test #182).

Sensitivity of the method: depends on GC and AT content, as well as the presence of segmentally duplicated genes

What does the test involve?

· DNA isolation and sample storage.

· Parallel sequencing including bidirectional DNA sequencing of all coding exons and intron-exon boundaries of the target genes

· Bioinformatic analysis of sequencing data. For each patient, only data for the gene(s) of interest were analyzed.

· Forming a written result of the genetic test.

· Diagnostic interpretation of results and genetic counseling.

Biological material: Venous blood or DNA isolated from venous blood.

For more information, please visit the "Biological material requirements and transport information" section.