In addition to having an increased risk rates of cancers related to BRCA mutations, 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, also known as hereditary non-polyposis colorectal cancer (HNPCC), accounts for approximately five percent of colorectal cancer cases. Lynch syndrome is caused by a mutation in one of several genes that repair errors in DNA: MLH1, MSH2, MSH6, PMS2 or an EPCAM deletion. Individuals with this condition have a greatly increased chance of developing colorectal cancer, as well as several other cancers, especially at a younger age. Other cancers associated with Lynch syndrome include other gastrointestinal cancers (pancreas, small bowel, stomach cancer), urological cancers (bladder, kidney, ureter), endometrial cancer, ovarian cancer, prostate cancer, sebaceous gland neoplasms, and brain tumors.
In addition to Lynch syndrome, constitutional mismatch repair deficiency (CMMRD) syndrome is another rare disorder that is associated with PMS2, MLH1, MSH2, and MSH6 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, endometrial cancer, as well as cancer of the small intestine and urinary tract.
Familial Adenomatous Polyposis (FAP)
FAP accounts for approximately one percent of all colorectal cancer. Classic FAP is characterized by a preponderance of polyps, early age of onset of polyps, and an increased risk of developing colon cancer. It is caused by mutations in 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.
One specific APC mutation, I1307K is found in approximately seven percent of Ashkenazi Jews. The I1307K mutation does not cause classic FAP, but it does increase an individual’s risk of colon cancer two-fold. Ashkenazi Jews with an I1307K APC mutation have a 10 to 20% lifetime risk of colorectal cancer.
Other Hereditary Cancer Syndromes
There are many other cancer syndromes caused by inherited mutations. But in general, they are not found at higher rates in individuals of Jewish descent compared to the general population.
- Hereditary Diffuse Gastric Cancer (HDGC): HDGC is caused by having a mutation in the CDH1 gene. It is associated with stomach, lobular breast, and colon cancer.
- Li Fraumeni Syndrome: Li Fraumeni syndrome is caused by having a hereditary mutation in the TP53 gene. It is associated with several cancers, including sarcomas, brain tumors, leukemia, adrenal, and breast cancer that can develop as early as in childhood.
- Cowden Syndrome: Cowden syndrome is caused by having a hereditary mutation in the PTEN gene. It is associated with breast cancer, thyroid (follicular) cancer, and endometrial cancer.
- Von Hippel Lindau Syndrome: Von Hippel Lindau syndrome is associated with having a mutation in the VHL gene. It is associated with an increased risk of kidney cancer and benign blood vessel tumors.
- Multiple Endocrine Neoplasm Syndrome: Multiple endocrine neoplasm syndrome is associated with an increased risk of tumors of the endocrine organs (pancreas, thyroid, pituitary, adrenal), which can be benign or cancerous.
