Helping Those Genetically Predisposed to Colorectal Cancer

By Sonia Kupfer, MD

While the majority of colorectal cancer cases arise sporadically, we know that around 5% are caused by hereditary syndromes associated with specific genetic abnormalities.

By identifying which individuals are genetically predisposed to colorectal cancer, we can take proactive steps to manage their health, as well as their family members.

Moreover, we can use our knowledge of these genetic alterations in hereditary syndromes to better understand colorectal cancer pathogenesis and, ultimately, use this information to guide treatment.

Hereditary syndromes tend to affect individuals at younger ages (<50 years) and are often found in multiple family members over several generations.


Some individuals develop multiple primary tumors. Genetic testing is used to identify germline mutations, meaning those that have been passed on to offspring by their parents. Thanks to advances in next-generation sequencing technology, genetic testing is becoming faster, easier, and more robust.

The most common hereditary colorectal cancer syndrome is Lynch Syndrome.

This condition is characterized by mutations in mismatch repair genes (MLH1, MSH2, MSH6 and PMS2). Defective mismatch repair leads to a “mutator phenotype” affecting the genes that govern growth and regulation.

Individuals with germline mutations in one of these genes are at greatly elevated risk of cancers, including colorectal and endometrial cancers as well as urothelial, ovarian, gastric, small bowel, pancreatic, biliary and brain cancers.

When a patient has colorectal cancer, we test the tumor’s genetics for defective mismatch repair so we can screen for Lynch Syndrome and also make informed decisions about the patient’s prognosis and best course of treatment.

For example, certain tumors characterized by a molecular feature known as microsatellite instability carry a better prognosis and do not respond to the commonly used chemotherapy regimen 5-FU.

For individuals with Lynch Syndrome, we recommend intensive surveillance regimens to screen for associated cancers.

One of the other hereditary syndromes associated with colorectal cancer is familial adenomatous polyposis (FAP).

This rare condition is due to germline mutations in the APC gene and classically leads to 100s to 1000s of colorectal adenomas.

APC is important in Wnt-signaling that, when disturbed, leads to abnormal cell proliferation and ultimately chromosomal instability. If the colon is not surgically removed, virtually all FAP patients will develop colorectal cancer.

FAP patients are also at risk for additional cancers including duodenal, thyroid and desmoid tumors. The APC gene is also mutated in the vast majority of sporadic colorectal cancers.

A more recently described adenomatous polyposis syndrome is MYH-associated polyposis (MAP). MAP leads to colonic adenomas albeit less than the amount of polyps seen in classic FAP.

Similar as in FAP, endoscopic and/or surgical management are the mainstay of treatment in MAP. We offer genetic testing for both FAP and MAP.

Finally, a less well-characterized syndrome is serrated polyposis, in which multiple large and proximally located serrated polyps are found. A genetic basis for this disorder has not yet been identified. Endoscopic and/or surgical management are key in the treatment of serrated polyposis.

At the University of Chicago, we specialize in the management of hereditary colorectal cancer and provide personalized care for individuals at increased risk for colorectal cancer. Together, a multi-disciplinary team of gastroenterologists, oncologists, surgeons and genetic counselors provides them with comprehensive and evidence-based care.

In addition, our GI Cancer Risk and Prevention program is supported by a robust registry and tissue bank for research purposes. Our team has recently led research on the validation of models to predict Lynch Syndrome.

We have also participated in the development of a new next-generation sequencing panel test for hereditary colorectal cancer. This panel offers a powerful, cost-effective means of genetic testing for Lynch and polyposis syndromes that eliminates the need for repetitive testing and multiple follow-up clinical visits.

As our genetic researchers continue to define mutations associated with sporadic and inherited disease, more genes that modify a person’s risk for developing colorectal cancer will likely be identified in the near future.

Understanding how these genetic alterations influence colorectal cancer should allow us to develop better individualized risk and prevention methods.

Sonia Kupfer, MD, is a skilled specialist in all types of digestive system disorders. As a physician in the Center for Clinical Cancer Genetics and the Celiac Center, she is particularly focused on diagnosing and treating patients with genetic disorders such as hereditary gastrointestinal cancer syndromes and celiac disease.

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