Lynch syndrome is the most common inherited condition that increases the risk of several cancers, most notably colorectal cancer (CRC) and endometrial cancer. It's primarily characterized by a significantly higher lifetime risk for these cancers, along with an elevated risk for other malignancies.
Understanding the Basics
Lynch syndrome, previously known as hereditary non-polyposis colorectal cancer (HNPCC), is a genetic disorder caused by mutations in genes that are responsible for DNA mismatch repair (MMR). These MMR genes normally correct errors that occur when DNA is copied in cells. When these genes are not working properly, errors accumulate, potentially leading to cancer development.
Key Features of Lynch Syndrome
- Inherited Condition: It's passed down from parents to children.
- Increased Cancer Risk: Primarily colorectal and endometrial cancers, but also includes ovarian, stomach, small bowel, urinary tract, brain, and skin cancers.
- Early Onset: Cancers associated with Lynch syndrome tend to develop at a younger age than sporadic (non-inherited) cancers.
- DNA Mismatch Repair Deficiency: Caused by mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) or the EPCAM gene.
Genetic Basis
The core of Lynch syndrome lies in mutations affecting the following genes:
- MLH1, MSH2, MSH6, PMS2: These are the primary mismatch repair (MMR) genes. Mutations in any of these genes disrupt the DNA repair process.
- EPCAM: Deletions in the EPCAM gene can lead to inactivation of the MSH2 gene.
These mutations lead to microsatellite instability (MSI) in tumor cells, which is a hallmark of Lynch syndrome-associated cancers.
Clinical Manifestations
The most prominent clinical features of Lynch syndrome are the increased risks for specific cancers:
- Colorectal Cancer (CRC): Significantly elevated lifetime risk.
- Endometrial Cancer: High lifetime risk in women.
- Other Cancers: Increased risk of ovarian, stomach, small bowel, urinary tract, brain, and skin cancers (sebaceous adenomas and keratoacanthomas).
Diagnosis
Diagnosis of Lynch syndrome typically involves:
- Personal and Family History: Assessment of cancer history in the individual and their family. The Amsterdam criteria and revised Bethesda guidelines help identify individuals who may be at risk.
- Tumor Testing:
- Immunohistochemistry (IHC): Detects the presence or absence of MMR proteins in tumor tissue.
- Microsatellite Instability (MSI) Testing: Determines if there is instability in microsatellite sequences in the tumor DNA.
- Genetic Testing: Confirms the diagnosis by identifying a mutation in one of the MMR genes or EPCAM.
Management
Individuals with Lynch syndrome require a comprehensive management plan that includes:
- Increased Surveillance: Regular colonoscopies, upper endoscopies, and endometrial biopsies to detect cancers early.
- Prophylactic Surgery: Hysterectomy and bilateral salpingo-oophorectomy (removal of the uterus and ovaries) may be considered for women to reduce the risk of endometrial and ovarian cancer.
- Chemoprevention: Aspirin has shown some promise in reducing the risk of colorectal cancer.
- Genetic Counseling: To inform individuals and families about the risks and management options.
In summary, Lynch syndrome is a significant genetic condition characterized by an inherited predisposition to various cancers, with a strong emphasis on colorectal and endometrial cancer. Early diagnosis and management are crucial for improving outcomes for affected individuals.
