June 8, 2011 — A study of patients with Lynch syndrome revealed that mutations in the MLH1 and MSH2 genes are associated with higher colorectal and endometrial cancer risk, whereas mutations in the MSH6 gene are associated with lower risk. Results of the study were published in the June 8 issue of JAMA.
Lynch syndrome is responsible for 3% to 5% of colorectal cancer cases. It is an autosomal dominant disorder that can be traced to germline mutations in 4 mismatch repair genes. Almost 90% of these mutations are located in the MLH1 and MSH2 genes, and about 10% are found in MSH6 and PMS2.
Patients with the condition are at greater risk for early-onset colorectal and endometrial cancer, as well as tumors of the ovaries, small bowel, urothelium, biliary tract, and stomach. There are guidelines for managing patients with mismatch repair mutations, but key uncertainties remain, including the optimal age for beginning colonoscopy screening and consideration of gynecological risk-reducing surgery.
The authors, led by Valérie Bonadona, MD, PhD, from the Université Lyon 1, Centre National de la Recherche Scientifique UMR5558, Villeurbanne, and Centre Léon Bérard, Lyon, France, and colleagues from the French Cancer Genetics Network, set out to estimate age-specific cumulative risks for various cancers. The study included 537 families with segregating mutated genes (248 with MLH1, 256 with MSH2, and 33 with MSH6) who were recruited from 40 French cancer genetics clinics that participate in the Estimation des Risques de Cancer chez les porteurs de mutation des gènes mismatch repair (ERISCAM) study.
The researchers used the genotype restricted likelihood method to estimate age-specific cumulative cancer risks. The 3 mutated genes were associated with significantly different estimated cumulative cancer risks (P = .01). By age 70 years, participants had estimated cumulative cancer risks for colorectal cancer of 41% (95% confidence interval [CI], 25% - 70%) for MLH1 mutation carriers, 48% (95% CI, 30% - 77%) for MSH2 mutation carriers, and 12% (95% CI, 8% - 22%) for MSH6 mutation carriers.
Endometrial cancer risks were 54% (95% CI, 20% - 80%), 21% (95% CI, 8% - 77%), and 16% (95% CI, 8% - 32%), respectively. Ovarian cancer risks were 20% (95% CI, 1% - 65%), 24% (95% CI, 3% - 52%), and 1% (95% CI, 0% - 3%), respectively.
By age 40 years, estimated cumulative risks were less than 2% (95% CI, 0% - 7%) for endometrial cancer and less than 1% (95% CI, 0% - 3%) for ovarian cancer. None of the other tumor types had a greater than 3% estimated lifetime risk for any of the gene mutations.
Limitations of the trial include its retrospective design, leading to wide confidence intervals, which were especially apparent in the older age groups; patient recruitment from cancer genetics centers, which may not represent the population at large; and a heterogeneous mutational spectrum.
The study suggests that the current surveillance guidelines are sufficient for patients with Lynch syndrome who bear mutations in MLH1 or MSH2, but "MSH6 mutation carriers seem to have a lower risk for colorectal, endometrial, and ovarian cancer and this risk does not seem to be significantly higher than average until a later age," write Rosa M. Xicola, PhD, and Xavier Llor, MD, PhD, from the Department of Medicine and Cancer Center, University of Illinois at Chicago, the authors of an accompanying editorial, agreeing with the study conclusions.
"Therefore," they write, "in this group, it is probably unnecessary to begin colonoscopy surveillance at age 30 years, or transvaginal ultrasound and endometrial aspirate from 30 to 35 years, as has been recommended, more so if no other affected family member has developed these cancers at a relatively young age."
The editorial authors also note that it may be reasonable to postpone prophylactic oophorectomy until after age 40 years, as the risks do not appear to rise until after this age, when both oophorectomy and hysterectomy should be seriously considered.
The study was funded by the Fondation de France. The authors have disclosed no relevant financial relationships. The editorialists report having financial relationships with the Sirazi Foundation and receiving internal grants from the Department of Medicine and Cancer Center of the University of Illinois at Chicago.
JAMA. 2011;305:2304-2310, 2351-2351. Article abstract Editorial extract
Lynch syndrome is responsible for 3% to 5% of colorectal cancer cases. It is an autosomal dominant disorder that can be traced to germline mutations in 4 mismatch repair genes. Almost 90% of these mutations are located in the MLH1 and MSH2 genes, and about 10% are found in MSH6 and PMS2.
Patients with the condition are at greater risk for early-onset colorectal and endometrial cancer, as well as tumors of the ovaries, small bowel, urothelium, biliary tract, and stomach. There are guidelines for managing patients with mismatch repair mutations, but key uncertainties remain, including the optimal age for beginning colonoscopy screening and consideration of gynecological risk-reducing surgery.
The authors, led by Valérie Bonadona, MD, PhD, from the Université Lyon 1, Centre National de la Recherche Scientifique UMR5558, Villeurbanne, and Centre Léon Bérard, Lyon, France, and colleagues from the French Cancer Genetics Network, set out to estimate age-specific cumulative risks for various cancers. The study included 537 families with segregating mutated genes (248 with MLH1, 256 with MSH2, and 33 with MSH6) who were recruited from 40 French cancer genetics clinics that participate in the Estimation des Risques de Cancer chez les porteurs de mutation des gènes mismatch repair (ERISCAM) study.
The researchers used the genotype restricted likelihood method to estimate age-specific cumulative cancer risks. The 3 mutated genes were associated with significantly different estimated cumulative cancer risks (P = .01). By age 70 years, participants had estimated cumulative cancer risks for colorectal cancer of 41% (95% confidence interval [CI], 25% - 70%) for MLH1 mutation carriers, 48% (95% CI, 30% - 77%) for MSH2 mutation carriers, and 12% (95% CI, 8% - 22%) for MSH6 mutation carriers.
Endometrial cancer risks were 54% (95% CI, 20% - 80%), 21% (95% CI, 8% - 77%), and 16% (95% CI, 8% - 32%), respectively. Ovarian cancer risks were 20% (95% CI, 1% - 65%), 24% (95% CI, 3% - 52%), and 1% (95% CI, 0% - 3%), respectively.
By age 40 years, estimated cumulative risks were less than 2% (95% CI, 0% - 7%) for endometrial cancer and less than 1% (95% CI, 0% - 3%) for ovarian cancer. None of the other tumor types had a greater than 3% estimated lifetime risk for any of the gene mutations.
Limitations of the trial include its retrospective design, leading to wide confidence intervals, which were especially apparent in the older age groups; patient recruitment from cancer genetics centers, which may not represent the population at large; and a heterogeneous mutational spectrum.
The study suggests that the current surveillance guidelines are sufficient for patients with Lynch syndrome who bear mutations in MLH1 or MSH2, but "MSH6 mutation carriers seem to have a lower risk for colorectal, endometrial, and ovarian cancer and this risk does not seem to be significantly higher than average until a later age," write Rosa M. Xicola, PhD, and Xavier Llor, MD, PhD, from the Department of Medicine and Cancer Center, University of Illinois at Chicago, the authors of an accompanying editorial, agreeing with the study conclusions.
"Therefore," they write, "in this group, it is probably unnecessary to begin colonoscopy surveillance at age 30 years, or transvaginal ultrasound and endometrial aspirate from 30 to 35 years, as has been recommended, more so if no other affected family member has developed these cancers at a relatively young age."
The editorial authors also note that it may be reasonable to postpone prophylactic oophorectomy until after age 40 years, as the risks do not appear to rise until after this age, when both oophorectomy and hysterectomy should be seriously considered.
The study was funded by the Fondation de France. The authors have disclosed no relevant financial relationships. The editorialists report having financial relationships with the Sirazi Foundation and receiving internal grants from the Department of Medicine and Cancer Center of the University of Illinois at Chicago.
JAMA. 2011;305:2304-2310, 2351-2351. Article abstract Editorial extract
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