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Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

ABSTRACT: OBJECTIVE:Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. METHODS:The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM? were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. RESULTS:Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM?, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. CONCLUSION:This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.

SUBMITTER: Takeda T

PROVIDER: S-EPMC5920216 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

Takeda Takashi T Tsuji Kosuke K Banno Kouji K Yanokura Megumi M Kobayashi Yusuke Y Tominaga Eiichiro E Aoki Daisuke D

Journal of gynecologic oncology 20180130 3

<h4>Objective</h4>Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history.<h4>Methods</h4>The subjects were 129 patients with ovar ...[more]

PMID: 29400022

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Project description:ImportanceThe data describing cancer risks associated with Lynch syndrome are variable.ObjectivesTo quantify the prevalence of families that fulfill the Amsterdam I or II criteria for Lynch syndrome in the Utah population and investigate the risk of colonic and extracolonic cancers in family members and their relatives.Design, setting, and participantsIn a population-based study, 202 families with Amsterdam I and II criteria–positive pedigrees in the Utah Population Database were identified. Of these, all cancer diagnoses in members of families with Amsterdam criteria and their first-degree, second-degree, and first-cousin relatives were located through linkage to the Utah Cancer Registry. The study was conducted from May 1 to June 30, 2016.Main outcomes and measuresStandardized morbidity ratios (SMRs) were estimated by comparing the observed rates of cancer in relatives with population-expected rates estimated internally from the Utah Population Database.ResultsA total of 202 families meeting Amsterdam criteria for Lynch syndrome accounted for 2.6% of all colorectal cancers in the state; of these, 59 met both the Amsterdam I and Amsterdam II criteria. Cancers observed in significant excess in the first-degree relatives of Amsterdam criteria pedigrees included colorectal (SMR, 10.10; 95% CI, 9.43-10.81), endometrial (SMR, 5.89; 95% CI, 5.09-6.78), stomach (SMR, 2.90; 95% CI, 2.02-4.03), small intestine (SMR, 7.72; 95% CI, 5.17-11.08), prostate (SMR, 1.94; 95% CI, 1.73-2.17), kidney (SMR, 3.22; 95% CI, 2.45-4.16), urinary bladder (SMR, 1.62; 95% CI, 1.22-2.12), thyroid (SMR, 2.26; 95% CI, 1.55-3.17), and non-Hodgkin lymphoma (SMR, 2.10; 95% CI, 1.64-2.65). Risks of colorectal and endometrial cancers were also found to be elevated in second-degree (SMR, 4.31; 95% CI, 3.98-4.65 and SMR, 2.70; 95% CI, 2.30-3.14, respectively) and first-cousin (SMR, 1.85; 95% CI, 1.70-2.00 and SMR, 1.50; 95% CI, 1.29-1.73, respectively) relatives of families with Amsterdam criteria.Conclusions and relevanceIn this population-based study of cancer risk in families fulfilling the Amsterdam criteria, many of the cancers previously reported to be associated with Lynch syndrome were observed, several previously unreported cancer associations were noted, and the risk of colorectal and endometrial cancer were markedly increased in first-, second-, and even third-degree relatives of these families. This study provides clinicians with population-based, unbiased data to counsel members of families meeting the Amsterdam criteria regarding their elevated risks of cancer and the importance of cancer screening.

Project description:BackgroundFor women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS.MethodsWomen with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result.ResultsOf 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%.ConclusionsSequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.

Project description:Importance:Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. Objective:To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS. Design, Setting, and Participants:Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS. Main Outcomes and Measures:Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS. Results:In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection. Conclusions and Relevance:Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

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Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

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Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.

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