Efficient Screening Strategy for Lynch Syndrome in Japanese Endometrial Cancer

Abstract

Lynch syndrome (LS) is an inherited disorder caused by a germline mutation in the DNA mismatch repair (MMR) genes and is associated with increased risk of various cancers, particularly colorectal cancer and endometrial cancer (EC). It is significant to identify LS in EC patients for prediction and prevention of the succeeding other associated cancers. However, useful LS screening guidelines for EC have not been established. The purpose of our study is to devise an efficient and practical screening strategy for LS in EC. We designed original criteria, named "APF criteria," with lenient terms (Age of onset < 50, or Personal or Family history of associated cancers) and applied it to unselected EC patients. We performed immunohistochemistry (IHC) and the methylation assay of MutL homolog 1 (MLH1) gene promoter using the tumors of patients who met our criteria, and thus selected "suspected LS" as the candidates for genetic analyses. Of 360 EC patients, 187 (51.9%) met the APF criteria, and the tumor specimens were available from 182 out of the 187 patients. IHC revealed that expression of at least one MMR protein was absent in cell nuclei of 54 (29.6%) tumors. Of 20 tumors lacking MLH1 protein expression, 14 cases were judged sporadic EC because of the hypermethylated MLH1 promoter. We thus selected 40 (11.1%) of 360 EC patients as "suspected LS." Our strategy that consists of clinical triage and the molecular analyses is expected to improve the screening efficiency and reduce the cost of LS identification in EC.

Isolated Loss of PMS2 Immunohistochemical Expression is Frequently Caused by Heterogenous MLH1 Promoter Hypermethylation in Lynch Syndrome Screening for Endometrial Cancer Patients

“…We performed MMR-IHC on the tumor of patients who met our criteria in our previous study. 29 Additional IHC was performed on the tumor of patients who did not meet our criteria in this study. Performing the MLH1 methylation assay and MMR germline mutation testing on cases with IL-PMS2, we investigated the association between MLH1-PHM and IL-PMS2.…”

“…In a previous study, we proposed a screening strategy for LS in 360 newly diagnosed EC patients with lenient triage (original criteria) using selective IHC and optional MLH1 promoter methylation analysis. 29 We performed IHC on samples from all 360 of these participants and detected 10 cases (2.8%) of IL-PMS2. Most of them were accompanied by MLH1 IHC abnormalities (such as heterogenous or weak staining).…”

The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

“…In total, 14,770 tumors underwent tumor-based triage with IHC (n = 10,460) and/or MSI (n = 4310). Concurrent testing with both IHC and MSI was sufficiently reported in ten studies 16,27 Heterogeneity: I 2 = 85%, τ 2 = 0.2427, p < 0.01 González et al 39 Yoon et al 63 Riggi et al 58 Rubio et al 60 Ferguson et al 37 Najdawi et al 69 Long et al 67 Batte et al 14 Hartnett et al 42 Djordjevic et al 35 Backes et al 26 Watkins et al 73 Frolova et al 15 Egoavil et al 36 Mas-Moya et al 17 Bruegl et al 28 Resnick et al 57 Mills et al 53 Buchanan et al 29 Joehlin-Price et al 44 Goodfellow et al 40 Hampel et al 41 Dillon et al 13 Kato et al 45 Cossio et al 34 Woo et al 72 Lin et al 49 Pecorino et al 56 Kost et al 66 Matthews et al 51 Chu et al 68 Ring et al 71 Garg et al 38 Lu et al 50 Walsh et al 62 Rabban et al 18 Leenen et al 47 Sugawara et al 61 Tan et al 65 Moline et al 54 Lee et al 46 Berends et al 27 (n = 5594) all...…”

Comparative Polymorphism of BAT-26 between Healthy Individuals and Cancer Patients and Its Cancer Risk Implication for Local Chinese

“…The authors of the above research aimed to study MSI and patterns of variation in markers or molecular and clinicopathological features using the BAT-26 locus in cancer patients, especially HNPCC patients, but showed less interest in the polymorphism of BAT- LS is an inherited disorder caused by germline mutations in the DNA mismatch repair genes and the disorder increases the risk of various cancer types, particularly CRC and endometrial cancer (24). So CRC and endometrial cancer patients were included and combined as one group in our study.…”