Individuals of Ashkenazi Jewish ancestry have among the highest rates of colorectal cancer (CRC) of any ethnic group.
In the general population, the lifetime risk of CRC is about five percent. In the Ashkenazi Jewish populations, this risk is two to three times greater.
About 10 percent of colorectal cancer is hereditary. Two known hereditary cancer syndromes account for a significant proportion of hereditary colorectal cancer: Lynch syndrome and familial adenomatous polyposis (FAP). The mutations associated with these syndromes are inherited in an autosomal dominant pattern, which means affected individuals have a 50% chance of passing on the gene mutation to the next generation. Having a cancer gene mutation does not mean a person will definitely have cancer, but it does increase their cancer risk.
Lynch Syndrome
Lynch syndrome (previously known as hereditary non-polyposis colorectal cancer (HNPCC)) accounts for approximately five percent of CRC cases. Lynch syndrome is caused by a pathogenic variant in one of several genes that repair errors in DNA – MLH1, MSH2, MSH6, PMS2 – or a fifth called EPCAM that can impact the function of the MSH2 gene. Individuals with this condition have a greatly increased chance of developing CRC, as well as several other cancers, especially at a younger age. Other cancers associated with Lynch syndrome include:
| Cancer Risk | Chance of developing cancer by age 80 (Risks vary by gene) |
General population chance to develop cancer |
|---|---|---|
| Colorectal | 8 – 60% | 4% |
| Uterine (Endometrial) | 13 – 60% | 3% |
| Ovarian | 1 – 40% | 1.4% |
| Kidney/Ureter | 2% – 30% | 2% |
| Bladder | 2-13% | 2% |
| Stomach | 5-9% | 1% |
| Small Bowel | 1-11% | <1% |
| Pancreas | 2-6% | 2% |
| Bile duct/Biliary Tract | Elevated | <1% |
| Prostate | 12-24% | 12% |
| Brain | Elevated | <1% |
| Skin (Sebaceous Gland Tumors) | Elevated | <1% |
Pathogenic variants in the MSH2 and MSH6 genes are more common in the Ashkenazi Jewish population.
In addition to Lynch syndrome, constitutional mismatch repair deficiency (CMMRD) is another rare disorder that is associated with the Lynch syndrome genes. CMMRD syndrome greatly increases the risk of developing cancer in children and young adults. Most individuals with this condition typically develop cancer before age 18. Cancers associated with CMMRD syndrome include colorectal cancer, leukemia, lymphoma, and brain tumors. Several benign tumors can be seen with CMMRD.
Surveillance and management for Lynch syndrome
Active surveillance and management – watching for warning signs and staying on top of your health – as well as lifestyle modifications, can significantly decrease one’s cancer risk. Your personal health and family history will help determine at what age and how frequently to utilize these strategies. Management strategies offered for Lynch syndrome include:
- Colonoscopies every 1-3 years
- Upper endoscopies every 2-4 years
- Urinalysis every year
- Endoscopic ultrasound and magnetic resonance cholangiopancreatography every year
- Dermatologic exams every year
- Individuals assigned female at birth – consideration of risk-reducing removal of the uterus, ovaries, and fallopian tubes
Familial Adenomatous Polyposis (FAP)
FAP accounts for approximately one percent of all colorectal cancer. Classic FAP is characterized by a preponderance of develop hundreds to thousands precancerous colon polyps (called adenomas), early age of onset of polyps, and an increased risk of developing colon cancer. In addition, people can develop polyps in stomach and small bowel, there is an increase risk for other gastrointestinal cancers as well as thyroid cancer. People with FAP can also develop benign abdominal tumors. It is caused by mutations in the APC gene. Some individuals have a milder form of the condition, called attenuated familial adenomatous polyposis (attenuated FAP). Those with the attenuated form typically have fewer colon polyps and develop cancer later in life compared to individuals with classic FAP.
While FAP is not more common in the Ashkenazi Jewish population, there is one specific change in the APC called I1307K that is found in approximately 6-7% percent of Ashkenazi Jews. This variant is called a ‘risk allele’ because it causes a 2-3 fold increased risk (~10-20%) for colon cancer, it does NOT cause FAP or attenuated FAP. Individuals that have the I307K risk allele are recommended to have colonoscopies every 5 years instead of every 10.
Hereditary Mixed Polyposis Syndrome
Hereditary mixed polyposis syndrome (HMPS) is a rare inherited gastrointestinal cancer predisposition syndrome characterized by the development of multiple colorectal polyps of mixed types, including adenomatous, hyperplastic, serrated, and juvenile-like polyps, often within the same individual. Affected individuals typically present in adulthood with numerous colonic polyps and have an increased risk of colorectal cancer, sometimes at a relatively young age, although the exact lifetime cancer risk is not as well defined as in other polyposis syndromes. HMPS is most commonly associated with pathogenic variants or duplications affecting the GREM1 gene, particularly a specific upstream duplication described in individuals of Ashkenazi Jewish ancestry. Management generally involves enhanced colorectal surveillance with frequent colonoscopy and polypectomy, and in cases of severe polyp burden or cancer, surgical intervention may be considered.
