scholarly journals Lynch Syndrome Caused by Germline PMS2 Mutations: Delineating the Cancer Risk

2015 ◽  
Vol 33 (4) ◽  
pp. 319-325 ◽  
Author(s):  
Sanne W. ten Broeke ◽  
Richard M. Brohet ◽  
Carli M. Tops ◽  
Heleen M. van der Klift ◽  
Mary E. Velthuizen ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Lynch Syndrome ◽  
Family Members ◽  
Cumulative Risk ◽  
Mismatch Repair Gene ◽  
Genetic Modifiers ◽  
Analysis Model ◽  
Repair Gene ◽  
Mutation Carriers ◽  
Significant Difference

Purpose The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers. Methods Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome–associated cancers. Results The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis. Conclusion CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

Ten Years After Mutation Testing for Lynch Syndrome: Cancer Incidence and Outcome in Mutation-Positive and Mutation-Negative Family Members

2009 ◽  
Vol 27 (28) ◽  
pp. 4793-4797 ◽  
Author(s):  
Heikki J. Järvinen ◽  
Laura Renkonen-Sinisalo ◽  
Katja Aktán-Collán ◽  
Päivi Peltomäki ◽  
Lauri A. Aaltonen ◽  
...  
Keyword(s):  
At Risk ◽  
Lynch Syndrome ◽  
Cancer Incidence ◽  
Family Members ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mutation Carriers ◽  
Lynch Syndrome Family

PurposeColonoscopies with polypectomies and endometrial biopsies with transvaginal ultrasonography, repeated at 2- to 3-year intervals, are performed for prevention or early detection of cancer in patients with DNA mismatch repair gene mutation causing Lynch syndrome. The long-term effectiveness of surveillance was evaluated in Lynch syndrome family members tested approximately 10 years ago.Materials and MethodsCancer incidence and survival were determined after an 11.5-year follow-up in 242 mutation-positive and 367 mutation-negative participants. These participants in 57 Lynch syndrome families with 14 different mutations were at 50% risk. The median age was 36 years (range, 18 to 72 years) in mutation carriers and 42 years (range, 18 to 72 years) in mutation-negative participants, and none had had cancer of the Lynch syndrome type.ResultsCompliance was 95.9% for the colonic surveillance and 97.1% for the gynecologic surveillance. Colorectal cancer (CRC) occurred in 30 mutation-positive participants, and 74 participants had adenomas removed. Three patients died of CRC. Endometrial cancer (EC) occurred in 19 of 103 women at risk, and 48 women had prophylactic hysterectomy. Six of 112 women at risk had ovarian cancer. The overall cancer risk ratio (RR) in mutation carriers was 5.80 (95% CI, 3.4 to 9.5). Cancer mortality rate (RR = 2.28; 95% CI, 0.82 to 6.31) and overall death rate (RR = 1.26; 95% CI, 0.65 to 2.46) were not significantly increased.ConclusionLong-term compliance in surveillance for CRC and EC exceeded 95% in Lynch syndrome. All CRC deaths were not prevented as a result of noncompliance or missed lesions. Still, after 10 years of surveillance, no significant increase in mortality had occurred compared with mutation-negative relatives.

scholarly journals Cancer spectrum in DNA mismatch repair gene mutation carriers: results from a hospital based Lynch syndrome registry

2012 ◽  
Vol 11 (3) ◽  
pp. 441-447 ◽  
Author(s):  
Mala Pande ◽  
Chongjuan Wei ◽  
Jinyun Chen ◽  
Christopher I. Amos ◽  
Patrick M. Lynch ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Gene Mutation ◽  
Dna Mismatch Repair ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Mutation Carriers ◽  
Dna Mismatch Repair Gene

scholarly journals Associations of Height With the Risks of Colorectal and Endometrial Cancer in Persons With Lynch Syndrome

2020 ◽  
Author(s):  
Jesca G M Brouwer ◽  
Polly A Newcomb ◽  
Tanya M Bisseling ◽  
Jane C Figueiredo ◽  
John L Hopper ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Risk ◽  
Lynch Syndrome ◽  
Proportional Hazards ◽  
Pathogenic Mutation ◽  
Cox Proportional Hazards ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Using Data

Abstract People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998–2007) and the GEOLynch Cohort Study (2006–2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS.

scholarly journals Penetrance of Colorectal Cancer Among Mismatch Repair Gene Mutation Carriers: A Meta-Analysis

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Cathy Wang ◽  
Yan Wang ◽  
Kevin S Hughes ◽  
Giovanni Parmigiani ◽  
Danielle Braun
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Meta Analysis ◽  
Heterozygous Mutation ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
Risk Estimates ◽  
Specific Risk ◽  
Mutation Carriers

Abstract Background Lynch syndrome, the most common colorectal cancer (CRC) syndrome, is caused by germline mismatch repair (MMR) genes. Precise estimates of age-specific risks are crucial for sound counseling of individuals managing a genetic predisposition to cancer, but published risk estimates vary. The objective of this work is to provide gene-, sex-, and age-specific risk estimates of CRC for MMR mutation carriers that comprehensively reflect the best available data. Methods We conducted a meta-analysis to combine risk information from multiple studies on Lynch syndrome–associated CRC. We used a likelihood-based approach to integrate reported measures of CRC risk and deconvolved aggregated information to estimate gene- and sex-specific risk. Results Our comprehensive search identified 10 studies (8 on MLH1, 9 on MSH2, and 3 on MSH6). We estimated the cumulative risk of CRC by age and sex in heterozygous mutation carriers. At age 70 years, for male and female carriers, respectively, risks for MLH1 were 43.9% (95% confidence interval [CI] = 39.6% to 46.6%) and 37.3% (95% CI = 32.2% to 40.2%), for MSH2 were 53.9% (95% CI = 49.0% to 56.3%) and 38.6% (95% CI = 34.1% to 42.0%), and for MSH6 were 12.0% (95% CI = 2.4% to 24.6%) and 12.3% (95% CI = 3.5% to 23.2%). Conclusions Our results provide up-to-date and comprehensive age-specific CRC risk estimates for counseling and risk prediction tools. These will have a direct clinical impact by improving prevention and management strategies for both individuals who are MMR mutation carriers and those considering testing.

scholarly journals Cumulative risks of colorectal cancer in Han Chinese patients with Lynch syndrome in Taiwan

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Abram Bunya Kamiza ◽  
Wen-Chang Wang ◽  
Jeng-Fu You ◽  
Reiping Tang ◽  
Huei-Tzu Chien ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Cumulative Risk ◽  
Germline Mutations ◽  
Han Chinese ◽  
Chinese Patients ◽  
Mutation Carriers ◽  
Amsterdam Criteria ◽  
Cumulative Risks ◽  
Age And Sex

AbstractPatients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

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