Lynch syndrome is an inherited condition that elevates the risk for several types of cancer. It is caused by specific genetic mutations that are passed down through families. The primary cancer associated with this syndrome is colorectal cancer, but the condition also predisposes individuals to other malignancies. Understanding the genetic nature of Lynch syndrome is the first step in recognizing its potential impact on an individual’s health and that of their relatives.
The Genetic Foundation of Lynch Syndrome
Lynch syndrome is the result of an inherited mutation in genes responsible for a process called DNA mismatch repair (MMR). These genes—MLH1, MSH2, MSH6, and PMS2—produce proteins that act like a spell-checker for your DNA, correcting errors that occur when cells divide. When one of these genes carries a mutation, the repair system is compromised, allowing errors to accumulate in the DNA, which can lead to uncontrolled cell growth and cancer.
In some cases, the syndrome is not caused by a direct mutation within one of the four main MMR genes. Instead, it results from a deletion in a nearby gene called EPCAM. This deletion prevents the adjacent MSH2 gene from functioning correctly, leading to the same breakdown in the DNA repair process.
The inheritance pattern for Lynch syndrome is autosomal dominant. This means a mutation needs to be inherited from only one parent to increase cancer risk. Each child of a parent with a Lynch syndrome mutation has a 50% chance of inheriting that same genetic variant. The condition affects both males and females equally.
Associated Cancer Risks
The genetic changes in Lynch syndrome significantly increase a person’s lifetime risk of developing certain cancers. The lifetime risk for colorectal cancer in individuals with Lynch syndrome can be as high as 80%. For women with the syndrome, the lifetime risk of developing endometrial cancer can reach up to 60%. These cancers also tend to develop at a much younger age than in the general population.
Beyond the colon and endometrium, Lynch syndrome elevates the risk for a range of other malignancies. These include:
- Cancers of the ovary, stomach, and small intestine
- Cancers of the pancreas, biliary tract, and urinary tract
- Certain types of brain tumors, typically glioblastomas
- Specific skin growths like sebaceous adenomas and carcinomas
- Prostate cancer in men with the condition
The exact level of risk for these various cancers can differ depending on which specific gene—MLH1, MSH2, MSH6, or PMS2—is affected by the mutation. For instance, mutations in MLH1 and MSH2 carry the highest cancer risks, while mutations in MSH6 and PMS2 are associated with more moderate, though still elevated, risks and often later onset of cancer.
The Diagnostic Process
The diagnostic process for Lynch syndrome often starts when a doctor identifies a concerning pattern of cancer in an individual or their family. This might involve cancers developing at a young age, multiple family members on the same side of the family with Lynch-associated cancers, or an individual having more than one type of these cancers. To formalize this assessment, clinicians may use tools like the Amsterdam criteria, a set of guidelines based on family cancer history.
If a doctor suspects Lynch syndrome, the next step involves testing a tumor sample from a previously diagnosed cancer. Two main tests are used for this: microsatellite instability (MSI) and immunohistochemistry (IHC). MSI testing looks for instability in short, repeated segments of DNA within the tumor, a hallmark of a faulty mismatch repair system. IHC testing checks if the tumor cells are producing the four mismatch repair proteins; the absence of one or more of these proteins points toward a defect in the corresponding gene.
An abnormal result from either MSI or IHC testing strongly suggests Lynch syndrome, but it is not a definitive diagnosis. The final step is to confirm the inherited cause with germline genetic testing, performed on a blood sample. This test analyzes the individual’s DNA to find the specific pathogenic variant in one of the Lynch syndrome genes or a deletion in the EPCAM gene. Identifying the precise mutation confirms the diagnosis and provides information for at-risk family members.
Proactive Management and Surveillance
Receiving a Lynch syndrome diagnosis allows individuals to take proactive steps to manage their cancer risks through enhanced surveillance and preventive measures. A primary part of this management is frequent colonoscopy. Individuals are advised to begin colonoscopies every one to two years, often starting in their early to mid-20s, or two to five years before the earliest age of a colorectal cancer diagnosis in their family. This regular screening allows for the detection and removal of precancerous polyps before they can develop into cancer.
Screening for other associated cancers is also a part of the management plan. This may include annual upper endoscopies to check the stomach and small intestine, particularly for those with a family history of gastric cancer. For women, surveillance for gynecological cancers can involve transvaginal ultrasounds and endometrial biopsies. These screenings help in detecting cancers at an earlier, more treatable stage.
In addition to surveillance, risk-reducing options are available. Daily aspirin therapy can decrease the risk of colorectal cancer in individuals with Lynch syndrome. For women who have completed childbearing, prophylactic surgeries such as a hysterectomy to remove the uterus and a salpingo-oophorectomy to remove the ovaries and fallopian tubes can significantly reduce the risk of developing endometrial and ovarian cancers. These decisions are highly personal and are made in consultation with healthcare providers.