Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)

Cancer, a journey with many twists and turns, presents challenges of all shapes and sizes. For those diagnosed, it may feel like a daunting mountain to climb. And for those with familial conditions predisposing them to cancer, the path may seem uncertain. But remember, every cloud has a silver lining. With advancements in medical science, hope is always on the horizon.

Lynch syndrome (LS), previously known as hereditary nonpolyposis colorectal cancer (HNPCC) is a genetic cancer syndrome that increases the risk of colorectal, uterine and several other cancers throughout the life span of an individual. Recent advances in genetics, treatment, and even future for a possible preventive intervention for those with from Lynch syndrome have come to light.

However, all hope is not lost. Being aware of this genetic condition paves the way for better monitoring for cancer, of which the chances of successful treatment are significantly higher if detected early.

We hope that a better understanding of Lynch syndrome can empower you and your family when faced with the disease, whether now or in future.

Lynch syndrome is the most common hereditary colorectal cancer that accounts for about 1 in 279 individuals with underlying germline mutation and roughly 3–5% of all colorectal cancers in the United States.

Mutation in mismatch repair genes

Lynch syndrome is caused by germline mutations in DNA mismatch repair genes. These are genes that code important proteins that repair errors in the DNA during replication. In LS, the mismatch repair genes affected are MLH1, MSH2/EPCAM, MSH6 and PMS2. Mutation in these genes leads to a either an altered functioning or complete deficiency of mismatch repair proteins, and this in turn promotes mutations throughout the genome, including inactivating mutations in tumor suppressors genes, leading to rapid development of precancers and cancers.

LS is an autosomal dominant condition; every cell contains two copies of each gene, and an autosomal dominant disease means that only one mutated copy of the gene is required for the disease to be present. As such, if a parent has LS, the chances of the syndrome being inherited by the child is 50%.

Lynch syndrome tumors

Compared to other sporadic colorectal cancers or familial adenoma polyposis (FAP), tumors in LS are more poorly differentiated and resemble Crohn’s disease, an inflammatory bowel disease. The tumors are mucoid and bear signet-like features, and have also been identified with infiltrating lymphocytes within the tumor.

Due to the poor differentiation and an underlying hypermutator phenotype, LS also shows accelerated carcinogenesis, in which the 8–10 years it normally takes for an adenoma to become carcinogenic is shortened to 2–3 years. The cancer is also likely to develop in multiple locations in the proximal colon (the ascending and transverse colon) as well as other organs and can quickly recur even after surgery.

Other cancers

Besides colorectal cancer, Lynch syndrome can also predispose an individual to other cancers, including:

• Endometrial cancer
• Gastric (stomach) cancer
• Ovarian cancer
• Pancreatic cancer
• Cancer of the ureter and renal pelvis
• Biliary tract cancer
• Brain cancer (usually glioblastoma as seen in Turcot syndrome)
• Small intestine cancers
• Sebaceous gland adenomas
• Keratoacanthoma (as seen in Muir-Torre syndrome)

Lynch syndrome is estimated to occur in every 1 to 279 individuals in the US, making it one of the most common genetic predispositions to cancer.

Earlier, we mentioned that LS is caused by mutations in DNA mismatch repair genes. DNA mismatch repair is responsible for keeping the integrity of the genome during cell duplication and DNA replication. With a loss of DNA mismatch repair ability, cells start to accumulate mutations throughout the genome that are also exaggerated at repetitive DNA sequences called microsatellite DNA. Hence, microsatellite instability (MSI) is the hallmark of all LS-related cancers.

Microsatellite instability

Microsatellites are sections of repeated DNA that change in length and become unstable if repair of damaged DNA does not work properly. These repetitive sequences can be found in coding and non-coding regions of DNA. In such cases, mutations throughout the genome including those in microsatellite sequences can cause phenotypic changes and diseases.

Identifying individuals and families

In colorectal cancer, DNA mismatch repair gene mutations can be passed down through germline cells or can occur in sporadic cases when a further loss of second allele of mismatch repair gene during carcinogenesis leads to the manifestation of mismatch repair defects and shows microsatellite instability in the tumor tissue. However, given that MSI is found in all cases of LS, it is one of the key identifiers in determining if individuals have LS. In individuals that test positive for MSI, further genetic testing that checks for mutations in the mismatch repair genes will then confirm if the colorectal cancer is hereditary.

Generally, a diagnosis of LS is confirmed once microsatellite instability or mismatch repair protein deficit is seen in tumor tissues sequences and a mismatch repair gene mutation is confirmed in the non-tumor regions from the same individual. About 15% of overall colorectal cancers show microsatellite instability, but only 2-3% of all colorectal cases are due to LS. Other cases that show MSI are due to a loss of mismatch repair genes during sporadic carcinogenesis.

In addition to MSI, other factors are also taken into consideration when determining if the colorectal cancer present is due to LS. This includes the age of onset; in sporadic colorectal cancer the age of onset is approximately 63 years, while that of LS is 45 years or younger.

Once an individual with LS has been identified, immediate biological family members (parents, siblings) should also be tested to determine if they are also carriers of the LS germline mutation.

Like in other hereditary colorectal cancers, identification of at-risk individuals can be lifesaving through early screening and detection. The American Society for Clinical Oncology (ASCO) recommends the following screening guidelines for people with Lynch syndrome.

Colorectal cancer: Colonoscopy every 1 to 2 years, beginning between the ages of 20 to 25 or 5 years younger than the earliest age at diagnosis in the family, whichever is sooner.

Gastric cancer: Upper endoscopy every 3 to 5 years, in addition to testing for Helicobacter pylori infection at a baseline exam with treatment if positive.

Endometrial and ovarian cancer: Yearly female pelvic examination, pelvic ultrasound, endometrial biopsy, from age 30 to 35. Patients may want to consider having preventive surgery to remove the uterus and ovaries when childbearing is completed.

Another set of guidelines, known as the Bethesda Guidelines, was developed to outline the criteria by which colorectal tumors would be tested for MSI. Testing criteria includes (verbatim):

• Colorectal cancer diagnosed in a patient who is less than 50 years of age.
• Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age.
• Colorectal cancer with the MSI-H histology diagnosed in a patient who is less than 60 years of age.
• Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 years.
• Colorectal cancer diagnosed in two or more first- or second-degree relatives with HNPCC-related tumors, regardless of age.

In addition, based on other gastroenterology guidelines, the following recommendations may be made:

• Annual total body skin examination
• Consideration of a daily aspirin, which has been linked to a significantly reduced risk of colorectal cancer in individuals with Lynch syndrome
• Screening for other cancers linked with Lynch syndrome may be recommended depending on a person’s family history, though the effectiveness of such screening remains unproven.

Remember, it is possible to still lead a relatively normal life if you test positive for LS. It is not a death sentence.