Background Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.
Methods We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan–Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period–specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.
Results Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).
Conclusion Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.
Risks of Primary Extracolonic Cancers Following Colorectal Cancer in Lynch Syndrome
Cumulative risks (percent) and corresponding 95% confidence intervals (CIs) of primary extracolonic cancers during the 10 and 20 years following diagnosis of colorectal cancer for carriers of mismatch repair gene mutations
|Cancer site||10 years||20 years|
|Risk, %||(95% CI)||Risk,%||(95% CI)|
|(0.87 to 3.17)||5.15||(2.86 to 7.68)|
|Urinary bladder||1.61||(0.65 to 2.75)||3.15||(1.37 to 5.20)|
|Small intestine||0.92||(0.28 to 1.73)||4.00||(1.92 to 6.41)|
|Stomach||0.66||(0.13 to 1.40)||1.15||(0.19 to 2.48)|
|Hepatobiliary tract†||0.83||(0.16 to 1.69)||1.42||(0.42 to 2.73)|
|Prostate||2.74||(0.86 to 4.77)||5.90||(2.69 to 9.76)|
|Endometrium||12.12||(7.66 to 17.11)||23.99||(16.79 to 32.84)|
|Breast||1.94||(0.58 to 3.83)||11.38||(0.63 to 16.69)|
|Ovary||0.94||(0.00 to 2.11)||2.08||(0.50 to 4.14)|
* Kidney etc. included kidney, renal pelvis, ureter and other and unspecified urinary organs.
† Hepatobiliary tract included liver and intrahepatic bile duct, gall bladder, and other and unspecified parts of biliary tract.
Patients who have had colorectal cancer and who are carriers of the DNA mismatch repair gene mutations that cause Lynch syndrome “have an increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers,” according to a study in the Journal of the National Cancer Institute.
Previous studies had shown that mutation carriers “are at a substantially increased risk of cancers of the colon, rectum, endometrium, stomach, ovary, ureter, renal pelvis, brain, small bowel, hepatobiliary tract, and pancreas,” the authors noted. A major inherited cancer syndrome, Lynch syndrome is also known as hereditary nonpolyposis colorectal cancer (HNPCC).
The study was based on data for 764 patients from the Colon Cancer Family Registry, evenly divided between men and women, who were carriers of the mismatch repair gene mutation and previously diagnosed with colorectal cancer. Most of the carriers (52%) were recruited in Australia and New Zealand, with 33% from the United States and 15% from Canada. The average age at diagnosis of colorectal cancer was 44 years.
Compared with the general population, following colorectal cancer, carriers of mismatch repair gene mutations had a 70-fold increased risk for cancer of the small intestine, a 13-fold increased risk for cancer of the kidney, renal pelvis, and ureter or urethra, a 7-fold increased risk for cancer of the bladder, a 6-fold increased risk for hepatobiliary tract cancer, and a nearly 6-fold increased risk for gastric cancer. Men had a 2-fold increased risk of prostate cancer. The most common primary cancer following colorectal cancer for women with Lynch syndrome was endometrial cancer, with a 40-fold increased risk compared to the general population. There were 20 breast cancers and 6 ovarian cancers in the study population.
“These new data provide further determination of cancer risks, potentially informing and justifying ongoing studies to create the evidence for effective screening methodologies and intervals in [mismatch repair] gene mutation carriers,” the researchers concluded. “Larger studies are needed to refine risk estimates separately for specific [mismatch repair] gene mutations to best inform policies on clinical risk management.” ■
- Lynch Syndrome and other non-polyposis inherited cancer syndromes (familyhistorybowelcancer.wordpress.com)
- Lynch Syndrome (familyhistorybowelcancer.wordpress.com)
- Hereditary Colorectal Cancer Syndromes (familyhistorybowelcancer.wordpress.com)
- Lynch Syndrome and Uterine Cancer Risk (everydayhealth.com)
- A dedicated service for the Management of Hereditary Colorectal Cancer Improves Adherence with Molecular Testing for Lynch Syndrome (familyhistorybowelcancer.wordpress.com)