Genetic testing for hereditary endometrial cancer

Endometrial cancer (EC), also known as uterine body cancer, is a series of malignant tumors that occur in the endometrium or the inner layer of the uterus. Among malignant tumors of the female reproductive system, its incidence is second only to cervical cancer, and its mortality rate is the third largest gynecological tumor after ovarian cancer and cervical cancer. Endometrial cancer is associated with obesity and excessive estrogen secretion, and its incidence tends to increase slowly with age and body mass index.

The five-year survival rate of endometrial cancer detected early is very high, and the prognosis is also good. People with a family history of endometrial cancer, colorectal cancer, ovarian cancer, etc. should undergo corresponding genetic testing to prevent or intervene as early as possible.

The genes of hereditary endometrial cancer are mainly several mismatch repair genes related to Lynch syndrome, such as MLH1, MSH2, MSH6, and PMS2. There are also some genes related to the risk of endometrial cancer, mainly estrogen sensitivity-related genes such as BRCA1 and BRCA2.

1. BRCA1

The protein encoded by BRCA1 is a nuclear phosphoprotein that plays an important role in maintaining genome stability and inhibiting tumors. BRCA1 gene mutations affect almost all organs or tissues related to estrogen. BRCA1 gene mutations lead to hereditary breast cancer-ovarian cancer syndrome and also lead to a relatively high risk of endometrial cancer. The risk of endometrial cancer in BRCA1 gene mutation carriers is twice that of the general population.

2. BRCA2 gene

BRCA2 is another hereditary breast cancer-ovarian cancer syndrome gene. BRCA2 plays an important role in maintaining genome stability and suppressing tumors, especially in the repair of double-stranded DNA in the homologous recombination pathway. Like BRCA1, BRCA2 gene mutations also affect almost all estrogen-related tissues or organs. The risk of endometrial cancer in BRCA2 gene mutation carriers is 1.75 times that of the general population.

3. MLH1 gene

MLH1 is a DNA mismatch repair gene whose mutations are widely present in hereditary non-polyposis colorectal cancer (HNPCC). Mutations in this gene are associated with Lynch syndrome, an autosomal dominant genetic disease. Lynch syndrome is not only associated with HNPCC, but also increases the risk of endometrial cancer, ovarian cancer, gastric cancer, pancreatic cancer, kidney cancer, and bladder cancer. The cumulative risk of endometrial cancer in individuals with MLH1 deletion is 33%, and some point mutations also increase the risk of endometrial cancer.

4. MSH2 gene

MSH2, like MLH1, is a DNA mismatch repair gene, and its mutation is widely present in hereditary non-polyposis colon cancer (HNPCC). Mutations in this gene are associated with Lynch syndrome, an autosomal dominant genetic disease. Some point mutations in the MSH2 gene increase the risk of endometrial cancer. The cumulative risk of endometrial cancer in individuals with MSH2 deficiency is 51%, and the cumulative risk is 55% for combined EPCAM-MSH2 deficiency.

5. MSH6 gene

The MSH6 gene belongs to the MutS family of DNA mismatch repair. Mutations in this gene may cause colorectal cancer and endometrial cancer. The average age of early-onset endometrial cancer and early-onset colorectal cancer caused by this gene mutation is 56.5 years and 51.2 years, respectively. The cumulative risk of endometrial cancer in individuals with MSH6 deletion is 34%.

6. PMS2 gene

The PMS2 gene is a DNA mismatch repair gene that forms a heterodimer with MLH1 and binds to mismatched bases with other compounds. The cumulative risk of endometrial cancer in individuals with PMS2 deficiency is approximately 20%.