Gene panel: (includes 38 genes)

Basic characteristics of the clinical phenotype:

Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC; OMIM #120435), is a hereditary cancer syndrome that results from 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. Mutations in MMR genes lead to genomic instability, characterized by a reduction or increase in the number of tandemly repeated sequences (microsatellites).

The microsatellite instability (MSI) leads to the occurrence of somatic mutations in oncogenes and/or in tumor suppressor genes, such as TGFβIIR, NF1 and others.

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.

 A clinical characteristics of Lynch syndrome, defined by the Amsterdam I criteria, includes a hereditary colorectal (Type I) or extracolonic (Type II) tumor in at least three relatives within at least two consecutive generations, with an age of onset before 50 years old in at least one of the relatives, and excluding cases of familial adenomatous polyposis (FAP).

Lynch syndrome is an autosomal dominant disorder with leading cause - a germline mutations in one of the four MMR genes: MLH1, MSH2, MSH6, and PMS2. Mutations in the MLH1 and MSH2 genes are in 80-90% of all patients with Lynch syndrome and are most often seen in families that strictly meet the Amsterdam I criteria.

Mutations in the MSH6 and PMS2 genes occur in almost all of the remaining patients and are characteristic of families with atypical symptoms for HNPCC, such as extracolonic carcinoma; and occur in patients with a low incidence of MHC. Mutations in another gene, EPCAM, are associated with Lynch syndrome. Germline mutations in this gene lead to inactivation of the nearby MSH2 gene by hypermethylation in approximately 1-3% of patients with Lynch syndrome.

The only described mutation in the EPCAM gene, that directly leads to HNPCC, involves a large deletion (Human Gene Mutation Database; www.insight-group.org). The cumulative risk of developing colon cancer for EPCAM deletions was determined to be 75% by age 70, and 12% for developing endometrial cancer in women.

Reason for Referral/ Clinical Significance:

Candidates for this test are all patients with multifocal, recurrent, and early-onset (before the age of 50) colorectal tumors or with a family history of colorectal carcinoma, but without evidence of the presence of relatives with FAP. Germline mutations in genes associated with Lynch syndrome are also associated with ovarian carcinoma.
This test is specifically intended for the analysis of inherited germline mutations and is not suitable for the testing of somatic mutations in tumor tissue.

Method: Next-generation sequencing (NovaSeq6000, Illumina).

The method involves bidirectional DNA sequencing of all coding exons and intron-exon boundaries of 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 bi-directional 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 from 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.