Lynch Syndrome With Germline MSH2 Mutation in a Patient With Primary Anaplastic Glioneuronal Tumor

e22077 Background: Different predictive models for Lynch syndrome have recently been developed and their comparative performance in a clinic-based cohort has not been assessed. We aimed to analyze the accuracy of the MMRpro, Barnetson, and PREMM1,2 models to predict MLH1/MSH2 mutation carrier status in 564 unrelated probands with clinical suspicion of hereditary colorectal cancer and compare it with Wijnen model and clinical criteria. Methods: Overall, 538 individuals (95%) underwent mismatch repair (MMR) deficiency screening before germline genetic testing (sequencing with or without large rearrangement analysis) and 26 (5%) performed direct genetic testing. Prediction scores for all individuals were calculated by each model. Sensitivity, specificity, positive predictive value (PPV), and the areas under the receiver operating characteristics curves (AUC) for all models were calculated and compared with the Revised Bethesda Guidelines (RBG). Results: 114 individuals (20%) were mutation carriers (63 MLH1, 51 MSH2). The AUC was 0.95 (95% CI: 0.93–0.97) for MMRpro, 0.87 (95% CI 0.83–0.91) for the Barnetson model, 0.87 (95% CI 0.83–0.91) for PREMM1,2, and 0.75 (95% CI 0.69–0.80) for the Wijnen model (p<0.001). Testing thresholds and specificity at 100% and 90% sensitivity for each model were: 0.001/17% and 0.33/89% for MMRpro, 0.01/9% and 0.07/59% for Barnetson, 0.05/5% and 0.11/58% for PREMM1,2. Sensitivity and specificity of RBG were 86% and 14%, respectively. Calibration was 0.92, 1.05, 0.50, and 1.25 for PREMM1,2,Barnetson, Wijnen, and MMRpro, respectively. Conclusions: In a population of individuals at risk of Lynch syndrome, the MMRpro model has the largest AUC, although the Barnetson and PREMM1,2 model also show adequate discrimination. Any of the models perform better than the RBG and provide quantitative risk estimation of finding a MLH1/MSH2 mutation useful in genetic counselling. No significant financial relationships to disclose.

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Genotype-Phenotype Comparison of German MLH1 and MSH2 Mutation Carriers Clinically Affected With Lynch Syndrome: A Report by the German HNPCC Consortium

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.7333 ◽

2006 ◽

Vol 24 (26) ◽

pp. 4285-4292 ◽

Cited By ~ 97

Author(s):

Timm Goecke ◽

Karsten Schulmann ◽

Christoph Engel ◽

Elke Holinski-Feder ◽

Constanze Pagenstecher ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Germline Mutations ◽

Time Span ◽

Msh2 Mutation ◽

Mutation Carriers ◽

Phenotype Comparison ◽

Rectal Cancers ◽

Prostate Cancers ◽

Colorectal Cancer Patients

Purpose Lynch syndrome is linked to germline mutations in mismatch repair genes. We analyzed the genotype-phenotype correlations in the largest cohort so far reported. Patients and Methods Following standard algorithms, we identified 281 of 574 unrelated families with deleterious germline mutations in MLH1 (n = 124) or MSH2 (n = 157). A total of 988 patients with 1,381 cancers were included in this analysis. Results We identified 181 and 259 individuals with proven or obligatory and 254 and 294 with assumed MLH1 and MSH2 mutations, respectively. Age at diagnosis was younger both in regard to first cancer (40 v 43 years; P < .009) and to first colorectal cancer (CRC; 41 v 44 years; P = .004) in MLH1 (n = 435) versus MSH2 (n = 553) mutation carriers. In both groups, rectal cancers were remarkably frequent, and the time span between first and second CRC was smaller if the first primary occurred left sided. Gastric cancer was the third most frequent malignancy occurring without a similarly affected relative in most cases. All prostate cancers occurred in MSH2 mutation carriers. Conclusion The proportion of rectal cancers and shorter time span to metachronous cancers indicates the need for a defined treatment strategy for primary rectal cancers in hereditary nonpolyposis colorectal cancer patients. Male MLH1 mutation carriers require earlier colonoscopy beginning at age 20 years. We propose regular gastric surveillance starting at age 35 years, regardless of the familial occurrence of this cancer. The association of prostate cancer with MSH2 mutations should be taken into consideration both for clinical and genetic counseling practice.

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Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins

Journal of Translational Medicine ◽

10.1186/s12967-019-1961-9 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 1

Author(s):

Amira Jaballah-Gabteni ◽

Haifa Tounsi ◽

Maria Kabbage ◽

Yosr Hamdi ◽

Sahar Elouej ◽

...

Keyword(s):

Dna Repair ◽

Lynch Syndrome ◽

Dna Repair Genes ◽

Msh2 Mutation ◽

Lynch Syndrome Family ◽

Discordant Twins ◽

Repair Genes

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Novel MSH2 Mutation in the First Report of a Vietnamese–American Kindred with Lynch Syndrome

Gynecologic Oncology Reports ◽

10.1016/j.gore.2015.02.003 ◽

2015 ◽

Vol 12 ◽

pp. 31-33

Author(s):

Ramez N. Eskander ◽

Henry T. Lynch ◽

Sandra M. Brown ◽

Lawrence D. Wagman ◽

Krishnansu S. Tewari

Keyword(s):

Lynch Syndrome ◽

First Report ◽

Msh2 Mutation ◽

Vietnamese American

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Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Journal of Medical Genetics ◽

10.1136/jmg.2010.076992 ◽

2010 ◽

Vol 47 (7) ◽

pp. 464-470 ◽

Cited By ~ 98

Author(s):

R. S. van der Post ◽

L. A. Kiemeney ◽

M. J. L. Ligtenberg ◽

J. A. Witjes ◽

C. A. Hulsbergen-van de Kaa ◽

...

Keyword(s):

Bladder Cancer ◽

Lynch Syndrome ◽

Urothelial Bladder Cancer ◽

Msh2 Mutation ◽

Mutation Carriers ◽

Urothelial Bladder

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Short-Term Risk of Colorectal Cancer in Individuals With Lynch Syndrome: A Meta-Analysis

Journal of Clinical Oncology ◽

10.1200/jco.2014.55.8536 ◽

2015 ◽

Vol 33 (4) ◽

pp. 326-331 ◽

Cited By ~ 24

Author(s):

Mark A. Jenkins ◽

James G. Dowty ◽

Driss Ait Ouakrim ◽

John D. Mathews ◽

John L. Hopper ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Meta Analysis ◽

Age Groups ◽

Cancer Risks ◽

Short Term ◽

Dna Mismatch ◽

Msh2 Mutation ◽

Number Needed To Screen ◽

Mutation Carriers

Purpose For carriers of germline mutations in DNA mismatch repair genes, the most relevant statistic for cancer prevention is colorectal cancer (Lynch syndrome) risk, particularly in the short term. Methods We conducted a meta-analysis of all independent published Lynch syndrome studies reporting age- and sex-dependent colorectal cancer risks. We estimated 5-year colorectal cancer risk over different age groups, separately for male and female mutation carriers, and number needed to screen to prevent one death. Results We pooled estimates from analyses of 1,114 Lynch syndrome families (508 with MLH1 mutations and 606 with MSH2 mutations). On average, one in 71 male and one in 102 female MLH1 or MSH2 mutation carriers in their 20s will be diagnosed with colorectal cancer in the next 5 years. These colorectal cancer risks increase with age, peaking in the 50s (one in seven males and one in 12 females), and then decrease with age (one in 13 males and one in 19 females in their 70s). Annual colonoscopy in 16 males or 25 females in their 50s would prevent one death from colorectal cancer over 5 years while resulting in almost no serious complications. In comparison, annual colonoscopy in 155 males or 217 females in their 20s would prevent one death while resulting in approximately one serious complication. Conclusion For MLH1 or MSH2 mutation carriers, current guidelines recommend colonoscopy every 1 to 2 years starting in their 20s. Our findings support this regimen from age 30 years; however, it might not be justifiable for carriers who are in their 20s.

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