Decoding the Enigma: Understanding and Diagnosing Hereditary Nonpolyposis Colorectal Carcinoma

Expert Reviewed By: ⁠Dr. Brandon Colby MD

Hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch syndrome, is a genetic condition that significantly increases the risk of developing colorectal cancer. It is the most common hereditary colorectal cancer syndrome, affecting approximately 1 in 300 people. This article aims to provide an overview of HNPCC, its diagnosis, and the role of genetic testing in managing the disease.

Understanding Hereditary Nonpolyposis Colorectal Carcinoma

HNPCC is caused by mutations in genes responsible for DNA mismatch repair, a process that corrects errors that occur during DNA replication. These mutations lead to an accumulation of DNA errors, increasing the risk of developing colorectal cancer. The condition is inherited in an autosomal dominant manner, which means that a person has a 50% chance of inheriting the mutated gene if one of their parents carries it. Individuals with HNPCC are also at an increased risk of developing other types of cancer, such as endometrial, ovarian, and stomach cancers.

Diagnosing Hereditary Nonpolyposis Colorectal Carcinoma

Diagnosing HNPCC can be challenging, as its symptoms are often similar to those of other colorectal diseases. A diagnosis is usually made based on personal and family medical history, clinical examination, and genetic testing. In some cases, a diagnosis may be confirmed by identifying a specific gene mutation, such as the truncating germline mutation in RPS20, a new colon cancer predisposition gene found in a familial colorectal cancer type X (FCCX) family (source).

Another diagnostic tool is the identification of microsatellite instability (MSI), a molecular hallmark of HNPCC. MSI is a condition in which the length of repetitive DNA sequences, called microsatellites, becomes unstable due to errors in DNA replication. A study investigating the molecular causes and consequences of MSI in endometrial carcinomas found hypermethylation of the MLH1 promoter region in 71% of MSI+ cases (source).

Genetic Testing for Hereditary Nonpolyposis Colorectal Carcinoma

Genetic testing plays a crucial role in the diagnosis and management of HNPCC. It can help identify individuals who carry a mutation in one of the known HNPCC-associated genes, such as MLH1, MSH2, MSH6, PMS2, or RPS20. By detecting these mutations, individuals at risk can be identified and appropriate screening and preventive measures can be implemented.

Benefits of Genetic Testing for HNPCC

There are several benefits to genetic testing for HNPCC, including:

• Early detection: Identifying individuals who carry a gene mutation associated with HNPCC allows for early implementation of colorectal cancer screening, which can lead to early detection and improved prognosis.
• Risk assessment: Genetic testing can provide valuable information about an individual’s risk of developing colorectal and other associated cancers, allowing for personalized risk management strategies.
• Family planning: Couples who are aware of their HNPCC carrier status can make informed decisions about family planning and the potential risks to their children.
• Emotional support: A definitive diagnosis can provide relief and emotional support to individuals and families affected by HNPCC, allowing them to better cope with the condition.

Limitations of Genetic Testing for HNPCC

While genetic testing for HNPCC can provide valuable information, there are some limitations to consider:

• False negatives: A negative genetic test result does not guarantee that an individual will not develop colorectal cancer, as not all gene mutations associated with HNPCC have been identified.
• Uncertain significance: Some genetic test results may be of uncertain significance, making it difficult to determine an individual’s risk of developing colorectal cancer.
• Cost and accessibility: Genetic testing for HNPCC can be expensive and may not be covered by insurance or readily available in all regions.

In conclusion, understanding and diagnosing hereditary nonpolyposis colorectal carcinoma is essential in the management of this genetic condition. Genetic testing plays a vital role in identifying individuals at risk and implementing appropriate screening and preventive measures. However, it is important to consider the limitations of genetic testing and discuss the results with a healthcare professional to ensure the best possible care and support.

About The Expert Reviewer

Dr. Brandon Colby MD is a US physician specializing in the personalized prevention of disease through the use of genomic technologies. He’s an expert in genetic testing, genetic analysis, and precision medicine. Dr. Colby is also the Founder of  and the author of ⁠⁠Outsmart Your Genes.

Dr. Colby holds an MD from the Mount Sinai School of Medicine, an MBA from Stanford University’s Graduate School of Business, and a degree in Genetics with Honors from the University of Michigan. He is an Affiliate Specialist of the American College of Medical Genetics and Genomics (⁠⁠ACMG), an Associate of the American College of Preventive Medicine (⁠⁠ACPM), and a member of the National Society of Genetic Counselors (⁠NSGC)