scholarly journals Combined Microsatellite Instability, MLH1 Methylation Analysis, and Immunohistochemistry for Lynch Syndrome Screening in Endometrial Cancers From GOG210: An NRG Oncology and Gynecologic Oncology Group Study

2015 ◽  
Vol 33 (36) ◽  
pp. 4301-4308 ◽  
Author(s):  
Paul J. Goodfellow ◽  
Caroline C. Billingsley ◽  
Heather A. Lankes ◽  
Shamshad Ali ◽  
David E. Cohn ◽  
...  
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Gynecologic Oncology ◽  
Gynecologic Oncology Group ◽  
Methylation Analysis ◽  
Screening Practice ◽  
Mutation Carriers ◽  
Number Of Patients ◽  
Mlh1 Methylation

Purpose The best screening practice for Lynch syndrome (LS) in endometrial cancer (EC) remains unknown. We sought to determine whether tumor microsatellite instability (MSI) typing along with immunohistochemistry (IHC) and MLH1 methylation analysis can help identify women with LS. Patients and Methods ECs from GOG210 patients were assessed for MSI, MLH1 methylation, and mismatch repair (MMR) protein expression. Each tumor was classified as having normal MMR, defective MMR associated with MLH1 methylation, or probable MMR mutation (ie, defective MMR but no methylation). Cancer family history and demographic and clinical features were compared for the three groups. Lynch mutation testing was performed for a subset of women. Results Analysis of 1,002 ECs suggested possible MMR mutation in 11.8% of tumors. The number of patients with a family history suggestive of LS was highest among women whose tumors were classified as probable MMR mutation (P = .001). Lynch mutations were identified in 41% of patient cases classified as probable mutation (21 of 51 tested). One of the MSH6 Lynch mutations was identified in a patient whose tumor had intact MSH6 expression. Age at diagnosis was younger for mutation carriers than noncarriers (54.3 v 62.3 years; P < .01), with five carriers diagnosed at age > 60 years. Conclusion Combined MSI, methylation, and IHC analysis may prove useful in Lynch screening in EC. Twenty-four percent of mutation carriers presented with ECs at age > 60 years, and one carrier had an MSI-positive tumor with no IHC defect. Restricting Lynch testing to women diagnosed at age < 60 years or to women with IHC defects could result in missing a substantial fraction of genetic disease.

An alternative approach to identify women at risk for colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1513-1513
Author(s):  
Amanda S. Bruegl ◽  
Bojana Djordjevic ◽  
Shannon Neville Westin ◽  
Pamela T. Soliman ◽  
Amanda C. Brandt ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Gynecologic Oncology ◽  
Positive Family History ◽  
Dna Mismatch ◽  
Increased Risk ◽  
History Of ◽  
Mlh1 Methylation

1513 Background: Hereditary colorectal cancer (CRC) is preventable; however, identification of individuals at sufficiently high risk to warrant heightened surveillance is difficult. Lynch Syndrome (LS) is an inherited cancer syndrome due to germline mutation in a DNA mismatch repair gene. For women with LS, the lifetime risk of endometrial cancer (EC) is 64% and CRC is 54%. Fifty percent of women with LS will present with EC or ovarian cancer prior to CRC. Therefore, women with LS associated EC represent an ideal group for CRC prevention. The optimal method to identify women with LS associated EC is not known. The purpose of this study was to determine the utility of Amsterdam II and Society of Gynecologic Oncology (SGO) Criteria (modified Bethesda criteria that use EC as the sentinel cancer) in identifying women with LS associated EC. Our ultimate goal is to identify women at increased risk of CRC. Methods: Immunohistochemistry (IHC) for DNA mismatch repair proteins and MLH1 methylation analyses were used to identify LS associated EC among 388 women. EC was designated as LS if there was loss of mismatch repair protein expression. Absence of MLH1 methylation was required to confirm LS in tumors with MLH1 protein loss. Results: Fifty-nine (15.2%) of the EC patients tested had LS. These patients are summarized in the table. Conclusions: Clinical criteria to detect LS identify 17/59 (29%) - 44/59 (74%) of women who present with EC first. EC with MSH2 loss is most likely to occur in younger women and women with positive family history of EC and CRC, features classically associated with LS. In general, the MSH6 mutation is associated with older age at diagnosis and fewer familial CRCs, however, we found a large number of MLH1 (50%) and PMS2 (86%) cases diagnosed at greater than 50 years with no family history of CRC. Our data suggest that classic clinical screening criteria are inadequate to detect patients with LS who present with EC, potentially missing up to 25% of these patients. [Table: see text]

Universal endometrial cancer tumor typing: How much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population?

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17119-e17119
Author(s):  
Ryan Kahn ◽  
Sushmita Gordhandas ◽  
Brandon Paul Maddy ◽  
Becky Baltich Nelson ◽  
Gulce Askin ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Large Scale ◽  
Screening Method ◽  
Cochrane Library ◽  
Predictive Values ◽  
Msi Analysis ◽  
Weighted Prevalence ◽  
Mlh1 Methylation

e17119 Background: Universal tumor testing for defective DNA mismatch repair (MMR) is recommended for all women diagnosed with endometrial cancer (EC) to identify those with underlying Lynch syndrome (LS). However, since its implementation in 2013, the effectiveness of this screening method on identifying individuals with LS across the population has not been well studied. The aim of this study was to evaluate outcomes of MMR immunohistochemistry (IHC), MLH1 methylation, and microsatellite instability (MSI) analysis among EC patients. Methods: We conducted a complete systematic search of online databases PubMed, Embase, Medline, and Cochrane Library between 1990-2018. A DerSimonian–Laird random-effects model meta-analysis was utilized to estimate the weighted prevalence of LS diagnoses. Results: The comprehensive search produced 3,427 publications. 29 peer-review studies met the inclusion criteria. 6,649 EC patients were identified, 206 (3%) were confirmed to have LS following positive universal tumor molecular screening.5,917 patients underwent tumor IHC, 28% had abnormal staining. 3,140 patients underwent MSI analysis, 31% had MSI instability. Among EC patients with deficient IHC staining or positive MSI analysis, the weighted prevalence of LS was 15% and 19% respectively. 1159 patients exhibited loss of MLH1 staining, 143 (13.7%) were found to be MLH1 methylation negative, 32 demonstrated a germline MLH1 mutation (2.8% of all MLH1 absent staining; 22.4% of all MLH1 methylation negative). 43% of EC patients diagnosed with LS via tumor typing would have been missed by family history-based screening alone. Conclusions: Despite widespread implementation of universal tumor testing in EC, data regarding results have previously been limited. For the first time, this study provides large-scale predictive values that will help practitioners evaluate abnormal results in the context of LS and aid in patient counseling. [Table: see text]

Brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed non-serous, non-mucinous ovarian cancers

2022 ◽  
pp. ijgc-2021-003082
Author(s):  
Soyoun Rachel Kim ◽  
Alicia Tone ◽  
Raymond Kim ◽  
Matthew Cesari ◽  
Blaise Clarke ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Extended Family ◽  
Screening Strategy ◽  
Newly Diagnosed ◽  
Predictive Values ◽  
Family History Questionnaire ◽  
Sensitivity Specificity

ObjectivesWhile ovarian cancer is the third most common Lynch syndrome-associated cancer in women, there is no established screening strategy to identify Lynch syndrome in this population. The objective of this study was to assess whether the 4-item brief Family History Questionnaire can be used as a screening tool to identify women with ovarian cancer at risk of Lynch syndrome.MethodsIn this prospective cohort study, participants with newly diagnosed non-serous, non-mucinous ovarian cancer completed the brief Family History Questionnaire, extended Family History Questionnaire, and had tumors assessed with immunohistochemistry for mismatch repair proteins, MLH1 methylation, and microsatellite instability testing. All underwent universal germline testing for Lynch syndrome. Performance characteristics were compared between the brief Family History Questionnaire, extended Family History Questionnaire, immunohistochemistry±MLH1 methylation, and microsatellite instability testing.ResultsOf 215 participants, 169 (79%) were evaluable with both the brief Family History Questionnaire and germline mutation status; 12 of these 169 were confirmed to have Lynch syndrome (7%). 10 of 12 patients (83%) with Lynch syndrome were correctly identified by the brief Family History Questionnaire, compared with 6 of 11 (55%) by the extended Family History Questionnaire, 11 of 13 (85%) by immunohistochemistry±MLH1 methylation, and 9 of 11 (82%) by microsatellite instability testing. The sensitivity, specificity, positive predictive values, and negative predictive values of the brief Family History Questionnaire were 83%, 65%, 15%, and 98%, respectively. A combined approach with immunohistochemistry and the brief Family History Questionnaire correctly identified all 12 patients with Lynch syndrome. The brief Family History Questionnaire was more sensitive than the extended Family History Questionnaire and took <10 min for each patient to complete.ConclusionsThe brief Family History Questionnaire alone or combined with immunohistochemistry may serve as an adequate screening strategy, especially in centers without access to universal tumor testing.

scholarly journals Rectal Cancer Diagnosed after Cesarean Section in Which High Microsatellite Instability Indicated the Presence of Lynch Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-5
Author(s):  
Tomohiro Okuda ◽  
Hiroshi Ishii ◽  
Sadao Yamashita ◽  
Sakura Ijichi ◽  
Seiki Matsuo ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Family History ◽  
Cesarean Section ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Birth Canal ◽  
Emergency Cesarean ◽  
History Of ◽  
Revised Bethesda Guidelines

We report a case of rectal cancer with microsatellite instability (MSI) that probably resulted from Lynch syndrome and that was diagnosed after Cesarean section. The patient was a 28-year-old woman (gravid 1, para 1) without a significant medical history. At 35 gestational weeks, vaginal ultrasonography revealed a 5 cm tumor behind the uterine cervix, which was diagnosed as a uterine myoma. The tumor gradually increased in size and blocked the birth canal, resulting in the patient undergoing an emergency Cesarean section. Postoperatively, the tumor was diagnosed as rectal cancer with MSI. After concurrent chemoradiation therapy, a lower anterior resection was performed. The patient’s family history revealed she met the criteria of the revised Bethesda guidelines for testing the colorectal tumor for MSI. Testing revealed that the tumor did indeed show high MSI and, combined with the family history, suggested this could be a case of Lynch syndrome. Our findings emphasize the importance of considering the possibility of Lynch syndrome in pregnant women with colorectal cancer, particularly those with a family history of this condition. We suggest that the presence of Lynch syndrome should also be considered for any young woman with endometrial, ovarian, or colorectal cancer.

scholarly journals Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study

2016 ◽  
Vol 34 (25) ◽  
pp. 3062-3068 ◽  
Author(s):  
D. Scott McMeekin ◽  
David L. Tritchler ◽  
David E. Cohn ◽  
David G. Mutch ◽  
Heather A. Lankes ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Mismatch Repair ◽  
Gynecologic Oncology ◽  
Progression Free Survival ◽  
Prognostic Indicators ◽  
Gynecologic Oncology Group ◽  
Free Survival ◽  
Gynecology And Obstetrics ◽  
Mlh1 Methylation ◽  
Lymphovascular Space Invasion

Purpose The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. Methods Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. Results A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. Conclusion MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors.

Phase III Study of Cisplatin With or Without Paclitaxel in Stage IVB, Recurrent, or Persistent Squamous Cell Carcinoma of the Cervix: A Gynecologic Oncology Group Study

2004 ◽  
Vol 22 (15) ◽  
pp. 3113-3119 ◽  
Author(s):  
David H. Moore ◽  
John A. Blessing ◽  
Richard P. McQuellon ◽  
Howard T. Thaler ◽  
David Cella ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Response Rate ◽  
Gynecologic Oncology ◽  
Phase Iii ◽  
Gynecologic Oncology Group ◽  
Number Of Patients ◽  
Significant Difference ◽  
Stage Ivb

Purpose To determine whether cisplatin plus paclitaxel (C+P) improved response rate, progression-free survival (PFS), or survival compared with cisplatin alone in patients with stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix. Patients and Methods Eligible patients with measurable disease, performance status (PS) 0 to 2, and adequate hematologic, hepatic, and renal function received either cisplatin 50 mg/m2 or C+P (cisplatin 50 mg/m2 plus paclitaxel 135 mg/m2) every 3 weeks for six cycles. Tumor measurements and quality-of-life (QOL) assessments were obtained before each treatment cycle. Results Of 280 patients entered, 6% were ineligible. Among 264 eligible patients, 134 received cisplatin and 130 received C+P. Groups were well matched with respect to age, ethnicity, PS, tumor grade, disease site, and number of cycles received. The majority of all patients had prior radiation therapy (cisplatin, 92%; C+P, 91%). Objective responses occurred in 19% (6% complete plus 13% partial) of patients receiving cisplatin versus 36% (15% complete plus 21% partial) receiving C+P (P = .002). The median PFS was 2.8 and 4.8 months, respectively, for cisplatin versus C+P (P < .001). There was no difference in median survival (8.8 months v 9.7 months). Grade 3 to 4 anemia and neutropenia were more common in the combination arm. There was no significant difference in QOL scores, although a disproportionate number of patients (cisplatin, n= 50; C+P, n = 33) dropped out of the QOL component, presumably because of increasing disease, deteriorating health status, or early death. Conclusion C+P is superior to cisplatin alone with respect to response rate and PFS with sustained QOL.

scholarly journals Utility of MLH1 Methylation Analysis in the Clinical Evaluation of Lynch Syndrome in Women with Endometrial Cancer

2014 ◽  
Vol 20 (11) ◽  
pp. 1655-1663 ◽  
Author(s):  
Amanda Bruegl ◽  
Bojana Djordjevic ◽  
Diana Urbauer ◽  
Shannon Westin ◽  
Pamela Soliman ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Lynch Syndrome ◽  
Clinical Evaluation ◽  
Methylation Analysis ◽  
Mlh1 Methylation

Performance characteristics of brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed ovarian cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e22525-e22525
Author(s):  
Rachel Soyoun Kim ◽  
Alicia Tone ◽  
Raymond Kim ◽  
Matthew Cesari ◽  
Blaise Clarke ◽  
...  
Keyword(s):  
Family History ◽  
Lynch Syndrome ◽  
Screening Tool ◽  
Extended Family ◽  
Gynecologic Oncology ◽  
Performance Characteristics ◽  
Newly Diagnosed ◽  
Predictive Values ◽  
Family History Questionnaire ◽  
Genetic Assessment

e22525 Background: Ovarian cancer (OC) is the third most common Lynch syndrome (LS)-associated cancer in women but there is no established screening strategy to identify LS in this population. An adequate family history may identify patients suspected of LS, prompting a referral to genetic assessment. We have previously validated the 4-item brief Family History Questionnaire (bFHQ) in endometrial cancers. The objective of this study was to assess whether bFHQ can be used as a screening tool to identify women with OC at risk of LS. Methods: Prospective cohort study recruited women with newly diagnosed non-serous/non-mucinous OC from three cancer centers in Ontario, Canada. Participants completed bHFQ, extended Family History Questionnaire (eFHQ; encompassing Amsterdam II criteria, Society of Gynecologic Oncology 20-25% criteria and Ontario Ministry of Health criteria), immunohistochemistry (IHC) for mismatch repair (MMR) proteins and universal germline testing for LS. The performance characteristics were compared between bFHQ, eFHQ, and IHC. Results: Of 215 participants, 169 (79%) were evaluable with both bFHQ and germline mutation status; 12 of these 169 were confirmed to have LS (7%). Nine of 12 patients (75%) with LS were correctly identified by bFHQ, compared to 6 of 11 (55%) by eFHQ and 11 of 13 (85%) by IHC. The sensitivity, specificity, positive predictive values and negative predictive values of bFHQ were 75%, 66%, 15% and 98%, compared to 55%, 92%, 35% and 96% for eFHQ and 85%, 90%, 39% and 99% for IHC respectively. IHC was the most sensitive and specific approach. The 4-item bFHQ was more sensitive than eFHQ and took less than 10 minutes for each patient to complete. Conclusions: Patient-administered bFHQ may serve as an adequate screening tool to triage women with OC for further genetic assessment for LS, especially in centers without access to universal tumor testing for IHC for MMR.[Table: see text]

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