Extracolonic Cancers Following CRC in Lynch Syndrome
Extracolonic Cancers Following CRC in Lynch Syndrome
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.
There were approximately 10 million cancer survivors in the United States in 2001 (approximately 3.5% of the general population), and 22% of these had a colorectal cancer. Several epidemiological studies have shown that risk of primary cancers following colorectal cancer is substantially greater than the risk of first primary cancers for the general population. Possible reasons for an increased risk of cancers following a first cancer could be the long-term effects of treatment for the first cancer and an overall greater predisposition to cancer due to patient characteristics (both genetic and environmental factors) and gene–environment and gene–gene interactions. Cancers following a first cancer may be identified earlier because of increased surveillance.
A major inherited cancer syndrome is Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. 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. Several studies have quantified the risks of these cancers in Lynch syndrome; however, there have been relatively few studies of the risks of primary cancers following colorectal cancer in Lynch syndrome patients. Knowledge of the risks of cancers for MMR gene mutation carriers presenting with colorectal cancer has the potential to impact patient management and subsequent proposed surveillance. In this study, we have estimated risks of the primary extracolonic cancers following colorectal cancer for MMR gene mutation carriers.
Abstract and Introduction
Abstract
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.
Introduction
There were approximately 10 million cancer survivors in the United States in 2001 (approximately 3.5% of the general population), and 22% of these had a colorectal cancer. Several epidemiological studies have shown that risk of primary cancers following colorectal cancer is substantially greater than the risk of first primary cancers for the general population. Possible reasons for an increased risk of cancers following a first cancer could be the long-term effects of treatment for the first cancer and an overall greater predisposition to cancer due to patient characteristics (both genetic and environmental factors) and gene–environment and gene–gene interactions. Cancers following a first cancer may be identified earlier because of increased surveillance.
A major inherited cancer syndrome is Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. 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. Several studies have quantified the risks of these cancers in Lynch syndrome; however, there have been relatively few studies of the risks of primary cancers following colorectal cancer in Lynch syndrome patients. Knowledge of the risks of cancers for MMR gene mutation carriers presenting with colorectal cancer has the potential to impact patient management and subsequent proposed surveillance. In this study, we have estimated risks of the primary extracolonic cancers following colorectal cancer for MMR gene mutation carriers.
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