Lynch syndrome is the most common form of hereditary colon cancer. This autosomal dominant disorder accounts for 2 to 3 percent of all colorectal cancers. Penetrance reaches up to 80%. Lynch syndrome is more challenging than FAP because there is no distinctive pre-malignant phenotype. Usually the diagnosis is suspected only due to a strong family history of colorectal cancer and other associated malignancies.
Patients with Lynch syndrome may present a small number of polyps early in life (usually in their 20ís or 30ís). Colorectal cancers tend to present in the proximal colon (up to 70%) and often are multiple, either presenting synchronously (~18%) or metachronously (~24%). Lynch tumors more commonly present certain histological features, such as: tumor-infiltrating lymphocytes, Crohn disease-like lymphocytic reaction, mucin production and signet ring differentiation, medullary growth pattern, and poorly differentiated histology.
Lynch syndrome is characterized by colorectal cancer at an early age and an increased risk of other related cancers, commonly endometrial, ovary, stomach, small bowel, brain, hepatobiliary tract, ureteral or renal pelvis. Affected individuals have an estimated risk of developing colorectal cancer that approaches 70% by the age of 70. The mean age at diagnosis of patients affected with Lynch syndrome is the mid 40s, however there is a wide range of ages at presentation ranging from 16 to 90 years. Different modifier genes could account for this inter-individual variation. Thus, p53 codon 72 or CYP17 (c-34T/C) variants resulted in important differences in colorectal cancer age of presentation in Lynch syndrome mutation carriers.
A reduced number of patients with Lynch syndrome can also present sebaceous gland adenomas and carcinomas, and multiple keratoacanthomas constituting a variant named Muir-Torre syndrome. Furthermore, approximately 30% of patients identified as having Turcot syndrome (polyposis and central nervous system tumors, usually glioblastomas) are caused by mutations usually responsible for Lynch syndrome tumors.
Genetic testing and Lynch syndrome
Lynch syndrome is caused by alterations in the main genes of the DNA mismatch repair system (MMR). Two gene families, mutS (including hMSH2, hMSH3, and hMSH6 genes ) and mutL (including h MLH1 , h MLH3 , h PMS1 and hPMS2 genes ) constitute this system. Germ-line mutations in the genes MLH1 and MSH2 are responsible for almost 90% of Lynch syndrome tumors . The remaining 10% of mutations are located in MSH6 or PMS2 genes. Mutations can be either point mutations, which can be studied through direct sequencing, or deletions, insertions, and rearrangements of large segments of DNA, which requires Multiple Ligation Probe Amplification (MLPA) or Conversion Analysis methods. For these studies, DNA is isolated from peripheral white blood cells.
The function of the proteins encoded by mismatch repair genes is to repair mismatches between nucleotides produced during DNA replication. Mutations in some of these genes result in malfunctioning of the DNA repair activity and ultimately in a widespread presence of errors all over the genome. These types of errors can usually be detected in microsatellite segments of DNA.
Microsatellites are short sequences, commonly of mononucleotide or dinucleotide repeats, present throughout the entire genome. When the MMR system is compromised, the integrity of these repeats can't be maintained. This phenomenon is called microsatellite instability (MSI) and it is one of the hallmarks of tumors from patients with Lynch syndrome.
It is important to bear in mind that 10-15% of sporadic colorectal cancer tumors also display MSI. In these cases it is almost always due to loss of MLH1 protein expression caused by gene silencing through promoter hypermethylation. These patients with sporadic colorectal cancer with MSI tumors are older, and mostly female. Recently, it has been shown that sporadic MSI tumors usually present a BRAF oncogene point mutation (V600E).
The fact that this BRAF mutation is commonly absent in Lynch syndrome tumors makes its study a good molecular tool to distinguish hereditary MSI tumors from their sporadic counterparts. When a tumor shows an MSI-H phenotype, immunohistochemical analysis of MLH1, MSH2, MSH6 and PMS2 commonly results in one of these proteins not being expressed. In Lynch syndrome cases, this lack of expression is due to a pathogenic mutation in the corresponding gene.
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