Cancer Risk in Lynch Syndrome
Lynch syndrome is a common autosomal dominant genetic disease resulting from germline mutations in DNA mismatch repair genes; it is also called HNPCC syndrome. The lifetime risk of colon cancer in Lynch patients is about 70–80%, and Lynch syndrome accounts for 2–4% of all colorectal cancers. It can be clinically diagnosed by testing the MSH6, MSH2, MLH1, PMS2, and TACSTD1 genes. Patients carrying MLH1 or MSH2 mutations have the highest risk of colorectal cancer, with an average age of onset of 44.
Lynch syndrome is usually divided into type I and type II. Type I patients carry MLH1 or MSH2 mutations; the rest are type II. Type I mainly presents as familial clustering of colorectal cancer, while type II is also accompanied by various extraintestinal malignancies, such as endometrial cancer, ovarian cancer, gastric cancer, lung cancer, hepatobiliary duct cancer, and urinary system malignancies. A small number of Lynch syndrome patients also develop skin cancer (such as cutaneous adenocarcinoma, keratoacanthoma, and epithelioma) and brain tumors (usually glioblastoma). Therefore, in early screening, type I patients may only be screened for colorectal cancer, while type II patients should be screened simultaneously for endometrial cancer, ovarian cancer, gastric cancer, and so on.
Endometrial cancer is the most prevalent cancer in female Lynch syndrome patients besides bowel cancer; about 30–60% of Lynch syndrome patients develop endometrial cancer, with an average age of onset of 46–62. Female Lynch patients are also prone to ovarian cancer, with an incidence of 9–12% and an average age of onset of 42. The author once treated a Lynch syndrome patient who simultaneously developed two primary cancers: colon cancer and endometrial cancer; multiple members of her family had all developed colorectal cancer between the ages of 40 and 50.
Lynch syndrome patients also have a high lifetime risk of intestinal-type gastric cancer, with the highest risk in countries where gastric cancer is prevalent. In Japan, most Lynch syndrome patients are first diagnosed with gastric cancer rather than colorectal cancer. Overall, the risk of gastric cancer in Lynch syndrome patients is 11–19%.
If three or more family members in a family have colorectal cancer, endometrial cancer, gastric cancer, small intestine cancer, hepatobiliary duct cancer, or renal pelvis or ureter cancer, the direct relatives of that family have a very high risk of Lynch syndrome. Those who can afford it should undergo genetic sequencing before age 40 to determine whether they have Lynch syndrome, and regularly undergo early screening for bowel cancer, gastric cancer, endometrial cancer, ovarian cancer, and other cancers. Early screening is the most effective way to detect cancer early and gain the opportunity for surgical radical cure.
Although Lynch syndrome is also called hereditary nonpolyposis colorectal cancer, the tumors in Lynch syndrome patients usually originate from colonic polyps; it is just that most of these polyps are flat adenomas that are hard to detect during colonoscopy. These flat malignant adenomas easily metastasize in a short time, so Lynch syndrome patients between ages 30 and 40 should ensure at least one colonoscopy every two years, and after age 40 at least one colonoscopy every year. If several first-degree relatives have colorectal cancer, after age 40 one may consider two colonoscopies a year to detect early carcinogenesis as soon as possible. Gastroscopy can be done every 1–2 years to detect gastric cancer early.
Female Lynch syndrome patients also need regular screening for endometrial and ovarian cancer; it is recommended to screen for endometrial and ovarian cancer every 1–2 years. Endometrial cancer is mainly screened by ultrasound and gynecological examination; if endometrial thickening is found, diagnostic curettage may be performed. Ovarian cancer can be screened by uteroadnexal ultrasound, pelvic CT, or pelvic MRI. These two gynecological tumors can also be screened in conjunction with related tumor markers such as CA125. But some patients' tumor markers are not sensitive, so one cannot rely on tumor markers alone to screen for endometrial and ovarian cancer.
Lynch syndrome patients may also have other tumors, such as small intestine cancer, hepatobiliary duct cancer, ureteral and renal pelvis transitional cell carcinoma, pancreatic cancer, skin cancer, and brain tumors, but these tumors are not highly prevalent. Therefore, when doing cancer screening, one need not screen for these cancers every year so as not to increase the financial burden. But one may consider screening for the above cancers every 3 years after age 40.