|
1
|
Liu B, Pan S, Gao XH. The current status of care for families with Lynch syndrome in China. Fam Cancer 2025; 24:29. [PMID: 40113638 DOI: 10.1007/s10689-025-00452-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 02/27/2025] [Indexed: 03/22/2025]
Abstract
Lynch syndrome is one of the most common hereditary cancer predisposition syndromes, which is caused by germline pathogenic variants in mismatch repair genes. It is associated with increased risks of colorectal cancer, endometrial cancer and various other types of cancer. With the rapid development in economy, medicine and genetic tests technology in recent decades, China had achieved significant advancements in the screening, diagnosis and treatment of Lynch syndrome. However, there are still a lot of challenges remaining unresolved. The major challenges include inconsistent access to genetic tests and counseling, regional disparities in healthcare quality, and limited implementation of clinical guidelines. This review will focus on the Chinese current status in the screening of Lynch syndrome, cancer surveillance, preventive measures, patients' willingness to take genetic tests and share genetic information, insurance coverage of medical cost, and national collaboration. At the end, we also summarize the major current research themes in Lynch syndrome in China.
Collapse
Affiliation(s)
- Baoshuai Liu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
| | - Shouyu Pan
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China
| | - Xian Hua Gao
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University, Shanghai, China.
- Hereditary Colorectal Cancer Center and Genetic Block Center of Familial Cancer, Changhai Hospital, Shanghai, China.
| |
Collapse
|
|
2
|
Qin PF, Yang L, Hu JP, Zhang JY. Breast cancer and rectal cancer associated with Lynch syndrome: A case report. World J Clin Oncol 2024; 15:1215-1221. [PMID: 39351452 PMCID: PMC11438856 DOI: 10.5306/wjco.v15.i9.1215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 07/28/2024] [Accepted: 08/05/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND The development mechanisms of Lynch syndrome (LS)-related breast cancer (BC) and rectal cancer are complex and variable, leading to personalized variations in diagnosis and treatment plans. CASE SUMMARY This paper presents a comprehensive review of clinical diagnosis and treatment data from a patient with LS-associated BC and rectal cancer. Moreover, screening data and management guidelines, as well as relevant literature on LS, are included in this report. This study summarizes the molecular pathogenesis, clinicopathological features, and screening and management protocols for LS-associated BC and rectal cancer. CONCLUSION Implementing early screening, prevention, and timely diagnosis and treatment measures is expected to reduce mitigate the incidence and mortality of LS-related BC and rectal cancer.
Collapse
Affiliation(s)
- Pei-Fang Qin
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Ling Yang
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Jun-Ping Hu
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| | - Jing-Yue Zhang
- Department of Laboratory Medicine, The People Hospital of Guigang, Guigang 537100, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
3
|
Zhan Z, Shi-jin L, Yi-ran Z, Zhi-long L, Xiao-xu Z, Hui D, Pan YL, Pan JH. High endothelial venules proportion in tertiary lymphoid structure is a prognostic marker and correlated with anti-tumor immune microenvironment in colorectal cancer. Ann Med 2023; 55:114-126. [PMID: 36503344 PMCID: PMC9754014 DOI: 10.1080/07853890.2022.2153911] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 11/27/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND High endothelial venules (HEV) and tertiary lymphoid structures (TLS) are associated with clinical outcomes of patients with colorectal cancer (CRC). However, because HEV are components of TLS, there have been few studies of the role of the HEV proportion in TLS (HEV/TLS). This study investigated the role of the HEV/TLS and its relationship with the tumor immune microenvironment in CRC. METHODS A retrospective analysis of 203 cases of tissue pathologically diagnosed as CRC after general surgery was performed at the First Affiliated Hospital of Jinan University from January 2014 to July 2017. Paraffin sections were obtained from the paracancerous intestinal mucosal tissues. The area of HEV and TLS and immune cells were detected by immunohistochemistry. We further divided the positive HEV expression group into the high HEV/TLS group and the low HEV/TLS group by the average area of HEV/TLS. After grouping, the data were also analyzed using the chi-square test, Kaplan-Meier method, and univariate and multivariate Cox proportional risk regression analyses. A correlation analysis of the HEV/TLS and immune cells as well as angiogenesis was performed. RESULTS Patients with a high HEV/TLS in CRC tissue were associated with longer OS, DFS and lower TNM stage. Meanwhile, CRC tissue with a high HEV/TLS showed a greater ability to recruit the CD3+ T cells, CD8+ T cells and M1 macrophages and correlated with less angiogenesis. Conclusively, high HEV/TLS links to the favorable prognosis of CRC patients and correlated with anti-tumor immune microenvironment, which can be a potential biomarker for prognosis of CRC patients. CONCLUSION A high HEV/TLS is associated with a favorable prognosis for CRC and is correlated with the anti-tumor immune microenvironment. Therefore, it is a potential biomarker of the CRC prognosis.KEY MESSAGESHigh HEV/TLS is associated with a favorable prognosis for CRC.High HEV/TLS correlated with the anti-tumor immune microenvironment of CRC and can serve as a novel prognostic biomarker.
Collapse
Affiliation(s)
- Zhao Zhan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liu Shi-jin
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhang Yi-ran
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Liu Zhi-long
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Zhao Xiao-xu
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Ding Hui
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Yun-long Pan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| | - Jing-hua Pan
- Department of General Surgery, the First Affiliated Hospital of Jinan University, Guangzhou, China
| |
Collapse
|
|
4
|
Aiob A, Kim YR, Kim K, Kim H, Kim YB, Kim DW, No JH, Seo SH, Suh DH, Park KU. A simplified two-marker immunohistochemistry strategy for Lynch syndrome screening in endometrial cancer patients. Obstet Gynecol Sci 2023; 66:537-544. [PMID: 37839795 PMCID: PMC10663397 DOI: 10.5468/ogs.23124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 06/22/2023] [Accepted: 08/22/2023] [Indexed: 10/17/2023] Open
Abstract
OBJECTIVE To examine the efficacy of MSH6 and PMS2 immunohistochemistry (IHC) as a screening method for Lynch syndrome in endometrial cancer patients. METHODS Through multidisciplinary discussions, an institutional MSH6 and PMS2 IHC-initiated cascade test (MSH6, PMS2 IHC→microsatellite instability [MSI] assay→germline mismatch repair [MMR] gene sequencing) was developed to screen for Lynch syndrome in endometrial cancer patients. Testing was performed on a consecutive cohort of 218 newly diagnosed endometrial cancer patients who underwent surgery at a tertiary hospital in the Republic of Korea between August 2018 and December 2020. The number of MMR deficiencies (MSH6 or PMS2 loss in IHC) and. RESULTS of subsequent tests (MSI assay and germline MMR gene sequencing) were examined. RESULTS MMR deficiency was detected in 52 of the 218 patients (24.0%). Among these 52 patients, 34 (65.0%) underwent MSI testing, of which 31 (91.0%) exhibited high MSI. Of the 31 patients with MSI-high status, 15 (48.0%) underwent germline MMR gene sequencing. Subsequently, Lynch syndrome was diagnosed in five patients (33.0%). CONCLUSION Lynch syndrome screening using MSH6 and PMS2 IHC-initiated cascade testing is a viable strategy in the management of endometrial cancer. A simplified strategy (MSH6 and PMS2 IHC→germline MMR gene sequencing) was proposed because most women with MMR deficiencies exhibited high MSI.
Collapse
Affiliation(s)
- Ala Aiob
- Department of Obstetrics and Gynecology, Galilee Medical Center, Nahariya, Azrieli Faculty of Medicine, Bar Ilan University, Safed,
Israel
| | - Yeo Rae Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Kidong Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Hyojin Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Yong Beom Kim
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Duck Woo Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Jae Hong No
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Soo Hyun Seo
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Dong Hoon Suh
- Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| | - Kyoung Un Park
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam,
Korea
| |
Collapse
|
|
5
|
Trujillo-Rojas MA, Ayala-Madrigal MDLL, Gutiérrez-Angulo M, González-Mercado A, Moreno-Ortiz JM. Diagnosis of patients with Lynch syndrome lacking the Amsterdam II or Bethesda criteria. Hered Cancer Clin Pract 2023; 21:21. [PMID: 37864171 PMCID: PMC10589993 DOI: 10.1186/s13053-023-00266-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 10/06/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history. MAIN BODY Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis. CONCLUSION Universal screening could be an option to address the problem of underdiagnosis.
Collapse
Affiliation(s)
- Miguel Angel Trujillo-Rojas
- Doctorado en Genética Humana e Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - María de la Luz Ayala-Madrigal
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - Melva Gutiérrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Av. Rafael Casillas Aceves #1200. Tepatitlán de Morelos, C.P. 47620, Jalisco, México
| | - Anahí González-Mercado
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - José Miguel Moreno-Ortiz
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México.
| |
Collapse
|
|
6
|
Chen J, Luo X, Wang G, Zhang J, Zhang Y. Analysis of m 6A methylation patterns and tumor microenvironment in endometrial cancer. Gene 2023; 852:147052. [PMID: 36395970 DOI: 10.1016/j.gene.2022.147052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/25/2022] [Accepted: 11/09/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND The N6-methyladenosine (m6A) modification is the most common epigenetic modification in eukaryotic mRNA. In recent years, lots of studies have shown that the tumor microenvironment (TME) plays a critical role in tumor growth and development. However, there are few studies on the interaction between m6A methylation and the TME in uterine corpus endometrial carcinoma (UCEC). METHODS Three distinct m6A modification patterns were based on 21 m6A regulators of UCEC patients and tumor-free individuals. We investigated the relationship between m6A modification patterns and associated features of the TME. Differentially expressed genes were selected and the m6A score was established to evaluate the prognosis and immunotherapeutic efficacy of UCEC patients. RESULTS We identified three different m6A modification patterns. The TME infiltrating characteristics were highly consistent with tumors with three distinct immune phenotypes. Besides, our analysis showed that the m6A score was shown to be useful in predicting clinical outcomes. Patients with the low m6A score seemed to have a better prognosis, a stronger immunotherapeutic response, and a higher tumor mutation burden. CONCLUSION Our study explored the influence of m6A modification and TME on the prognosis of cancer patients, which will contribute to the discovery of immunotherapy strategies to improve their prognosis.
Collapse
Affiliation(s)
- Junfeng Chen
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Xiaomei Luo
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Guocheng Wang
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Jing Zhang
- Department of Gynecological Oncology, The First Affiliated Hospital of Bengbu Medical College, Anhui, China.
| | - Yongli Zhang
- Department of Obstetrics and Gynecology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China.
| |
Collapse
|
|
7
|
Matsubayashi H, Oishi T, Sasaki K, Abe M, Kiyozumi Y, Higashigawa S, Niiya F, Sato J, Ishiwatari H, Imai K, Hotta K, Kishida Y, Takada K, Ono H, Yamazaki K, Yasui H, Kenmotsu H, Kado N, Kagawa H, Shiomi A, Sugiura T, Bando E, Nishimura S, Hatakeyama K, Serizawa M, Harada R, Sugino T. Discordance of microsatellite instability and mismatch repair immunochemistry occurs depending on the cancer type. Hum Pathol 2022; 135:54-64. [PMID: 36596344 DOI: 10.1016/j.humpath.2022.12.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 11/12/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023]
Abstract
Microsatellite instability (MSI) and deficiency of mismatch repair (dMMR) are key markers for predicting the response of immune checkpoint inhibitors (ICIs) and screening for Lynch syndrome (LS). This study examined the incidences of and factors associated with the concordance of MSI and MMR in human cancers. A total of 518 formalin-fixed cancer tissues were analyzed for MSI and MMR immunohistochemistry (IHC). MSI was analyzed by a PCR-based method using Promega markers. Concordance with MMR expression and factors associated with concordance were analyzed. In 2 colorectal cancer samples, MMR IHC failed due to inadequate staining conditions. In the remaining 516 cancers, a high level of MSI (MSI-H) was identified in 113 cases, and dMMR was identified in 112. The concordance of MSI and MMR IHC was 98.3%. Only 9 cases (4 pancreatobiliary, 3 colorectal, and 2 endometrial cancers) were discordant. Of the 113 MSI-H cases, 4 (3.5%) were proficient MMR (pMMR); of the 403 microsatellite stability (MSS) cases, 5 (1.2%) were dMMR. The independent factors associated with MSI-H/dMMR included meeting Amsterdam II criteria, assay purpose, and sampling method. Multivariate analysis revealed that cancer type (gastrointestinal cancers or others) was associated with concordance of MSI and MMR IHC. Three LS cases with pancreatic or endometrial cancer demonstrated MSS and dMMR, and one biliary cancer showed MSI-H and pMMR. Discordance between MSI and MMR IHC occasionally occurs in pancreaticobiliary and endometrial cancers. When suspected, both MSI and MMR IHC should be done to judge the ICI indication and screen for LS.
Collapse
Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan; Division of Endoscopy, Shizuoka, 411-8777, Japan.
| | - Takuma Oishi
- Division of Pathology, Shizuoka, 411-8777, Japan
| | - Keiko Sasaki
- Division of Pathology, Shizuoka, 411-8777, Japan
| | - Masato Abe
- Division of Pathology, Shizuoka, 411-8777, Japan
| | - Yoshimi Kiyozumi
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan
| | | | | | - Junya Sato
- Division of Endoscopy, Shizuoka, 411-8777, Japan
| | | | | | | | | | | | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka, 411-8777, Japan
| | | | - Hirofumi Yasui
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan; Division of Gastrointestinal Oncology, Shizuoka, 411-8777, Japan
| | - Hirotsugu Kenmotsu
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan; Division of Thoracic Oncology, Shizuoka, 411-8777, Japan
| | - Nobuhiro Kado
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan; Division of Gynecology, Shizuoka, 411-8777, Japan
| | - Hiroyasu Kagawa
- Division of Colon and Rectal Surgery, Shizuoka, 411-8777, Japan
| | - Akio Shiomi
- Division of Colon and Rectal Surgery, Shizuoka, 411-8777, Japan
| | - Teichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka, 411-8777, Japan
| | - Etsuro Bando
- Division of Gastric Surgery, Shizuoka, 411-8777, Japan
| | - Seiichiro Nishimura
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan; Division of Breast Surgery, Shizuoka, 411-8777, Japan
| | - Keiichi Hatakeyama
- Division of Clinical Research Center, Shizuoka Cancer Center, Shizuoka, 411-8777, Japan
| | - Masakuni Serizawa
- Division of Clinical Research Center, Shizuoka Cancer Center, Shizuoka, 411-8777, Japan
| | - Rina Harada
- Division of Genetic Medicine Promotion, Shizuoka, 411-8777, Japan
| | | |
Collapse
|
|
8
|
El Hussein S, Daver N, Liu JL, Kornblau S, Fang H, Konoplev S, Kantarjian H, Khoury JD. Microsatellite Instability Assessment by Immunohistochemistry in Acute Myeloid Leukemia: A Reappraisal and Review of the Literature. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2022; 22:e386-e391. [PMID: 34980577 DOI: 10.1016/j.clml.2021.12.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 12/06/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) is caused by defects in DNA mismatch repair (MMR) components. Inactivation of any MMR gene(s), including hMLH1, hMSH2, hMSH6, and hPMS2, can result in MSI. Immunohistochemistry (IHC) is a sensitive and specific screening tool for MSI that can detect loss of expression of one or more MMR components. Of the four MMR markers, hMLH1 and hMSH2 are considered most informative of MSI status. There has been renewed interest in MSI status in view of its favorable association with response to immune checkpoint inhibitors in some cancers. MMR expression patterns in acute myeloid leukemia (AML) have not been evaluated systematically. METHODS We used clinically-validated IHC assays to assess the expression of hMLH1, hMSH2, hMSH6, and/or hPMS2 in formalin-fixed paraffin-embedded tissue sections of bone marrow core biopsies from patients diagnosed with AML. Mutation profiling was performed using next-generation sequencing to assess for mutations in MMR genes. RESULTS The study group included 236 patients with AML, including a cohort treated on a clinical trial of azacitidine and nivolumab (NCT02397720). In addition, hMSH6, and/or hPMS2 expression was assessed in 99 AML patients with diploid karyotype. All patients, except two, had retained expression of all MMR markers assessed: One patient from the azacytidine+nivolumab group had zonal patchy loss of staining of hMLH1 and, to a lesser extent, a similar staining pattern of hMSH2; and one patient from the AML with diploid karyotype group had loss of hMSH2 but retained expression of hMLH1, hMSH6 and hPMS2. In addition, a retrospective analysis on a separate cohort of 139 patients with primary AML, on which next generation sequencing profiling was performed, identified 14 cases with alterations in MMR genes. CONCLUSION AND REMARKS MMR loss is a rare event in AML, thus does not appear to underlie response patterns to anti-PD1 therapy.
Collapse
Affiliation(s)
- Siba El Hussein
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology , University of Rochester Medical Center, Rochester, New York, USA
| | - Naval Daver
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing-Lan Liu
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan
| | - Steven Kornblau
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hong Fang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sergej Konoplev
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph D Khoury
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| |
Collapse
|
|
9
|
Noei Teymoordash S, Arab M, Bahar M, Ebrahimi A, Hosseini MS, Farzaneh F, Ashrafganjoei T. Screening of Lynch syndrome in endometrial cancer in Iranian population with mismatch repair protein by immunohistochemistry. CASPIAN JOURNAL OF INTERNAL MEDICINE 2022; 13:772-779. [PMID: 36420342 PMCID: PMC9659833 DOI: 10.22088/cjim.13.4.772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/26/2021] [Accepted: 01/01/2022] [Indexed: 01/25/2023]
Abstract
Background Lynch syndrome (LS) is one of the commonest genetic cancer syndromes, with an incidence rate of 1 per 250-1000 population. The aim of this study was to evaluate the frequency and characteristics of MMR deficiency in endometrial cancer in Iranian women. Methods One hundred endometrial carcinoma cases who referred to the gynecological oncology clinic of Imam Hossein Medical Center located in Tehran, Iran, from 2018 to 2020 were included in the study. Immunohistochemistry (IHC) evaluation was performed mainly on the hysterectomy specimens of all endometrial cancer (EC) patients to assess MMR proteins (MLH1, MSH2, MSH6, and PMS2) expression. Results A total of 23 out of 100 (23%) cases were identified through IHC screening to be MMR-deficient. The most common types were loss of MLH1/PMS2 (17.4%) and solitary MSH2 (17.4%) expressions followed by PMS2/MSH2 loss (13%). MMR deficiency (dMMR) histopathology was significantly overrepresented in patients with family history of cancer or Lynch syndrome (LS) associated cancers (p-values of 0.016 and 0.005, respectively). The rate of myometrial invasion and lower uterine segment involvement were also significantly higher in dMMR EC patients compared to MMR-intact EC (p-value of 0.021 and 0.018, respectively). Conclusion MMR deficiency, observed in 23% of endometrial cancer cases, was associated with higher rates of poor prognostic factors including myometrial invasion and lower uterine segment involvement. The presence of positive family history of cancer and family history of LS-associated cancer increased the probability of MMR-deficiency in endometrioid endometrial cancer to 47% and 70%, respectively.
Collapse
Affiliation(s)
- Somayyeh Noei Teymoordash
- Department of Obstetrics and Gynecology, Firoozgar Hospital, Iran University of Medical Sciences (IUMS), Tehran, Iran
| | - Maliheh Arab
- Department of Gynecology Oncology, Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Massih Bahar
- Familial and Hereditary Cancers Institute, Tehran, Iran
| | - Abdolali Ebrahimi
- Department of Pathology, Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Sadat Hosseini
- Preventative Gynecology Research Center (PGRC), Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Farah Farzaneh
- Preventative Gynecology Research Center (PGRC), Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Ashrafganjoei
- Preventative Gynecology Research Center (PGRC), Imam Hossein Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
10
|
Chen J, Wang G, Zhang D, Luo X, Zhang D, Zhang Y. Construction of novel hypoxia-related gene model for prognosis and tumor microenvironment in endometrial carcinoma. Front Endocrinol (Lausanne) 2022; 13:1075431. [PMID: 36589842 PMCID: PMC9797861 DOI: 10.3389/fendo.2022.1075431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Endometrial cancer is currently one of the three most common female reproductive cancers, which seriously threatens women's lives and health. Hypoxia disrupts the tumor microenvironment, thereby affecting tumor progression and drug resistance. METHODS We established hypoxia-related gene model to predict patient prognosis and 1-, 3-, and 5-year overall survival rates. Then, the expression level of hypoxia-related genes and survival data were extracted for comprehensive analysis by Cox regression analysis, and the model was established. RESULTS We analyzed the survival and prognosis of patients in the high and low-risk groups. The Kaplan-Meier curve showed that the low-risk group is associated with a better survival rate. The 1-, 3-, and 5-year AUC values of the model were 0.680, 0.698, and 0.687, respectively. Finally, we found that LAG3 may be a potential immune checkpoint for endometrial cancer. CONCLUSION We found four hypoxia-related genes (ANXA2, AKAP12, NR3C1, and GPI) associated with prognosis. The hypoxia-related gene model can also predict prognosis and tumor microenvironment in endometrial cancer.
Collapse
Affiliation(s)
- Junfeng Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Guocheng Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Donghai Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaomei Luo
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Da Zhang
- Department of Gynecological Oncology, Changchun Center Hospital, Changchun, Jilin, China
- *Correspondence: Yongli Zhang, ; Da Zhang,
| | - Yongli Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Yongli Zhang, ; Da Zhang,
| |
Collapse
|
|
11
|
Lee JHS, Li JJX, Chow C, Chan RCK, Kwan JSH, Lau TS, To KF, Yim SF, Yeung SY, Kwong J. Long-Term Survival and Clinicopathological Implications of DNA Mismatch Repair Status in Endometrioid Endometrial Cancers in Hong Kong Chinese Women. Biomedicines 2021; 9:biomedicines9101385. [PMID: 34680502 PMCID: PMC8533409 DOI: 10.3390/biomedicines9101385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 09/17/2021] [Accepted: 09/30/2021] [Indexed: 12/16/2022] Open
Abstract
To investigate the role of DNA mismatch repair status (MMR) in survival of endometrioid endometrial cancer in Hong Kong Chinese women and its correlation to clinical prognostic factors, 238 patients with endometrioid endometrial cancer were included. Tumor MMR status was evaluated by immunohistochemistry. Clinical characteristics and survival were determined. Association of MMR with survival and clinicopathological parameters were assessed. MMR deficiency (dMMR) was found in 43 cases (16.5%). dMMR was associated with poor prognostic factors including older age, higher stage, higher grade, larger tumor size and more radiotherapy usage. Long-term survival was worse in dMMR compared to the MMR proficient group. The dMMR group had more deaths, shorter disease-specific survival (DSS), shorter disease-free survival (DFS), less 10-year DSS, less 10-year DFS, and more recurrence. The 5-year DSS and 5-year DFS in the dMMR group only showed a trend of worse survival but did not reach statistical significance. In conclusion, dMMR is present in a significant number of endometrioid endometrial cancers patients and is associated with poorer clinicopathological factors and survival parameters in the long run. dMMR should be considered in the risk stratification of endometrial cancer to guide adjuvant therapy and individualisation for longer follow up plan.
Collapse
Affiliation(s)
- Jacqueline Ho Sze Lee
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (T.S.L.); (S.F.Y.); (S.Y.Y.); (J.K.)
- Correspondence: ; Tel.: +852-3505-2748
| | - Joshua Jing Xi Li
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (J.J.X.L.); (C.C.); (R.C.K.C.); (J.S.H.K.); (K.F.T.)
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (J.J.X.L.); (C.C.); (R.C.K.C.); (J.S.H.K.); (K.F.T.)
| | - Ronald Cheong Kin Chan
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (J.J.X.L.); (C.C.); (R.C.K.C.); (J.S.H.K.); (K.F.T.)
| | - Johnny Sheung Him Kwan
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (J.J.X.L.); (C.C.); (R.C.K.C.); (J.S.H.K.); (K.F.T.)
| | - Tat San Lau
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (T.S.L.); (S.F.Y.); (S.Y.Y.); (J.K.)
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (J.J.X.L.); (C.C.); (R.C.K.C.); (J.S.H.K.); (K.F.T.)
| | - So Fan Yim
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (T.S.L.); (S.F.Y.); (S.Y.Y.); (J.K.)
| | - Suet Ying Yeung
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (T.S.L.); (S.F.Y.); (S.Y.Y.); (J.K.)
| | - Joseph Kwong
- Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China; (T.S.L.); (S.F.Y.); (S.Y.Y.); (J.K.)
- School of Medicine, Faculty of Medicine and Health Sciences, Keele University, Newcastle-under-Lyme ST5 5BG, UK
| |
Collapse
|
|
12
|
Brothers C, Etchegary H, Curtis F, Simmonds C, Houston J, Young TL, Pullman D, Mariathas HH, Connors S, Hodgkinson K. Psychological Distress and Quality of Life in Participants Undergoing Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy Caused by TMEM43 p.S358L: Is It Time to Offer Population-Based Genetic Screening? Public Health Genomics 2021; 24:253-260. [PMID: 34500452 DOI: 10.1159/000517265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 05/18/2021] [Indexed: 11/19/2022] Open
Abstract
PURPOSE We have identified 27 families in Newfoundland and Labrador (NL) with the founder variant TMEM43 p.S358L responsible for 1 form of arrhythmogenic right ventricular cardiomyopathy. Current screening guidelines rely solely on cascade genetic screening, which may result in unrecognized, high-risk carriers who would benefit from preemptive implantable cardioverter-defibrillator therapy. This pilot study explored the acceptability among subjects to TMEM43 p.S358L population-based genetic screening (PBGS) in this Canadian province. METHODS A prospective cohort study assessed attitudes, psychological distress, and health-related quality of life (QOL) in unselected individuals who underwent genetic screening for the TMEM43 p.S358L variant. Participants (n = 73) were recruited via advertisements and completed 2 surveys at baseline, 6 months, and 1 year which measured health-related QOL (SF-36v2) and psychological distress (Impact of Events Scale). RESULTS No variant-positive carriers were identified. Of those screened through a telephone questionnaire, >95% felt positive about population-genetic screening for TMEM43 p.S358L, though 68% reported some degree of anxiety after seeing the advertisement. There were no significant changes in health-related QOL or psychological distress scores over the study period. CONCLUSION Despite some initial anxiety, we show support for PBGS among research subjects who screened negative for the TMEM43 p.S358L variant in NL. These findings have implications for future PBGS programs in the province.
Collapse
Affiliation(s)
- Cassidy Brothers
- Postgraduate Medical Education, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Holly Etchegary
- Unit of Clinical Epidemiology, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Fiona Curtis
- Provincial Medical Genetics Program, Eastern Regional Health Authority, St. John's, Newfoundland, Canada
| | - Charlene Simmonds
- Health Research Unit, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Jim Houston
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Terry-Lynn Young
- Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Daryl Pullman
- Centre for Bioethics, Memorial University, St. John's, Newfoundland, Canada
| | - Hensley H Mariathas
- Strategy for Patient-Oriented Research Unit, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Sean Connors
- Division of Cardiology, Eastern Regional Health Authority, St. John's, Newfoundland, Canada
| | - Kathleen Hodgkinson
- Unit of Clinical Epidemiology, Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada.,Provincial Medical Genetics Program, Eastern Regional Health Authority, St. John's, Newfoundland, Canada
| |
Collapse
|
|
13
|
Kim JB, Kim YI, Yoon YS, Kim J, Park SY, Lee JL, Kim CW, Park IJ, Lim SB, Yu CS, Kim JC. Cost-effective screening using a two-antibody panel for detecting mismatch repair deficiency in sporadic colorectal cancer. World J Clin Cases 2021; 9:6999-7008. [PMID: 34540955 PMCID: PMC8409214 DOI: 10.12998/wjcc.v9.i24.6999] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 05/24/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The microsatellite instability (MSI) test and immunohistochemistry (IHC) are widely used to screen DNA mismatch repair (MMR) deficiency in sporadic colorectal cancer (CRC). For IHC, a two-antibody panel of MLH1 and MSH2 or four-antibody panel of MLH1, MSH2, PMS2, and MSH6 are used. In general, MSI is known as a more accurate screening test than IHC. AIM To compare two- and four-antibody panels of IHC in terms of accuracy and cost benefit on the basis of MSI testing for detecting MMR deficiency. METHODS We retrospectively analyzed patients with CRC who underwent curative surgery between 2015 and 2017 at a tertiary referral center. Both IHC with four antibodies and MSI tests were routinely performed. The sensitivity and specificity of a four- and two types of two-antibody panels (PMS2/MSH6 and MLH1/MSH2) were compared on the basis of MSI testing for detecting MMR deficiency. RESULTS High-frequency MSI was found in 5.5% (n = 193) of the patients (n = 3486). The sensitivities of the four- and two types of two-antibody panels were 97.4%, 92.2%, and 87.6%, respectively. The specificities of the three types of panels did not differ significantly (99.6% for the four-antibody and PMS2/MSH6 panels, 99.7% for the MLH1/MSH2 panel). Based on Cohen's kappa statistic (κ), four- and two-antibody panels were in almost perfect agreement with the MSI test (κ > 0.9). The costs of the MSI test and the four- and two-antibody panels of IHC were approximately $200, $160, and $80, respectively. CONCLUSION Considering the cost of the four-antibody panel IHC compared to that of the two-antibody panel IHC, a two-antibody panel of PMS2/MSH6 might be the best choice in terms of balancing cost-effectiveness and accuracy.
Collapse
Affiliation(s)
- Jong Beom Kim
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Young Il Kim
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Yong Sik Yoon
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Jihun Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Seo Young Park
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Jong Lyul Lee
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Chan Wook Kim
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - In Ja Park
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Seok-Byung Lim
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Chang Sik Yu
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| | - Jin Cheon Kim
- Division of Colon and Rectal Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, South Korea
| |
Collapse
|
|
14
|
Zhao S, Chen L, Zang Y, Liu W, Liu S, Teng F, Xue F, Wang Y. Endometrial cancer in Lynch syndrome. Int J Cancer 2021; 150:7-17. [PMID: 34398969 DOI: 10.1002/ijc.33763] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/05/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022]
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited disease caused by germline pathogenic variants (PVs) in mismatch repair (MMR) genes. LS-associated endometrial cancer (LS-EC) is the most common extraintestinal sentinel cancer caused by germline PVs in MMR genes, including MLH1, MSH2, MSH6 and PMS2. The clinicopathologic features of LS-EC include early age of onset, lower body mass index (BMI), endometrioid carcinoma and lower uterine segment involvement. There has been significant progress in screening, diagnosis, surveillance, prevention and treatment of LS-EC. Many studies support universal screening for LS among patients with EC. Screening mainly involves a combination of traditional clinical criteria and molecular techniques, including MMR-immunohistochemistry (MMR-IHC), microsatellite instability (MSI) testing, MLH1 promoter methylation testing and gene sequencing. The effectiveness of endometrial biopsy and transvaginal ultrasound (TVS) for clinical monitoring of asymptomatic women with LS are uncertain yet. Preventive strategies include hysterectomy and bilateral salpingo-oophorectomy (BSO) as well as chemoprophylaxis using exogenous progestin or aspirin. Recent research has revealed the benefits of immunotherapy for LS-EC. The NCCN guidelines recommend pembrolizumab and nivolumab for treating patients with advanced or recurrent microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) EC.
Collapse
Affiliation(s)
- Shuangshuang Zhao
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Lingli Chen
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yuqin Zang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenlu Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Shiqi Liu
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fei Teng
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Fengxia Xue
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| | - Yingmei Wang
- Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.,Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
15
|
Stinton C, Jordan M, Fraser H, Auguste P, Court R, Al-Khudairy L, Madan J, Grammatopoulos D, Taylor-Phillips S. Testing strategies for Lynch syndrome in people with endometrial cancer: systematic reviews and economic evaluation. Health Technol Assess 2021; 25:1-216. [PMID: 34169821 PMCID: PMC8273681 DOI: 10.3310/hta25420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Lynch syndrome is an inherited genetic condition that is associated with an increased risk of certain cancers. The National Institute for Health and Care Excellence has recommended that people with colorectal cancer are tested for Lynch syndrome. Routine testing for Lynch syndrome among people with endometrial cancer is not currently conducted. OBJECTIVES To systematically review the evidence on the test accuracy of immunohistochemistry- and microsatellite instability-based strategies to detect Lynch syndrome among people who have endometrial cancer, and the clinical effectiveness and the cost-effectiveness of testing for Lynch syndrome among people who have been diagnosed with endometrial cancer. DATA SOURCES Searches were conducted in the following databases, from inception to August 2019 - MEDLINE ALL, EMBASE (both via Ovid), Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (both via Wiley Online Library), Database of Abstracts of Reviews of Effects, Health Technology Assessment Database (both via the Centre for Reviews and Dissemination), Science Citation Index, Conference Proceedings Citation Index - Science (both via Web of Science), PROSPERO international prospective register of systematic reviews (via the Centre for Reviews and Dissemination), NHS Economic Evaluation Database, Cost-Effectiveness Analysis Registry, EconPapers (Research Papers in Economics) and School of Health and Related Research Health Utilities Database. The references of included studies and relevant systematic reviews were also checked and experts on the team were consulted. REVIEW METHODS Eligible studies included people with endometrial cancer who were tested for Lynch syndrome using immunohistochemistry- and/or microsatellite instability-based testing [with or without mutL homologue 1 (MLH1) promoter hypermethylation testing], with Lynch syndrome diagnosis being established though germline testing of normal (non-tumour) tissue for constitutional mutations in mismatch repair. The risk of bias in studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, the Consolidated Health Economic Reporting Standards and the Philips' checklist. Two reviewers independently conducted each stage of the review. A meta-analysis of test accuracy was not possible because of the number and heterogeneity of studies. A narrative summary of test accuracy results was provided, reporting test accuracy estimates and presenting forest plots. The economic model constituted a decision tree followed by Markov models for the impact of colorectal and endometrial surveillance, and aspirin prophylaxis with a lifetime time horizon. RESULTS The clinical effectiveness search identified 3308 studies; 38 studies of test accuracy were included. (No studies of clinical effectiveness of endometrial cancer surveillance met the inclusion criteria.) Four test accuracy studies compared microsatellite instability with immunohistochemistry. No clear difference in accuracy between immunohistochemistry and microsatellite instability was observed. There was some evidence that specificity of immunohistochemistry could be improved with the addition of methylation testing. There was high concordance between immunohistochemistry and microsatellite instability. The economic model indicated that all testing strategies, compared with no testing, were cost-effective at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Immunohistochemistry with MLH1 promoter hypermethylation testing was the most cost-effective strategy, with an incremental cost-effectiveness ratio of £9420 per quality-adjusted life-year. The second most cost-effective strategy was immunohistochemistry testing alone, but incremental analysis produced an incremental cost-effectiveness ratio exceeding £130,000. Results were robust across all scenario analyses. Incremental cost-effectiveness ratios ranged from £5690 to £20,740; only removing the benefits of colorectal cancer surveillance produced an incremental cost-effectiveness ratio in excess of the £20,000 willingness-to-pay threshold. A sensitivity analysis identified the main cost drivers of the incremental cost-effectiveness ratio as percentage of relatives accepting counselling and prevalence of Lynch syndrome in the population. A probabilistic sensitivity analysis showed, at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year, a 0.93 probability that immunohistochemistry with MLH1 promoter hypermethylation testing is cost-effective, compared with no testing. LIMITATIONS The systematic review excluded grey literature, studies written in non-English languages and studies for which the reference standard could not be established. Studies were included when Lynch syndrome was diagnosed by genetic confirmation of constitutional variants in the four mismatch repair genes (i.e. MLH1, mutS homologue 2, mutS homologue 6 and postmeiotic segregation increased 2). Variants of uncertain significance were reported as per the studies. There were limitations in the economic model around uncertainty in the model parameters and a lack of modelling of the potential harms of gynaecological surveillance and specific pathway modelling of genetic testing for somatic mismatch repair mutations. CONCLUSION The economic model suggests that testing women with endometrial cancer for Lynch syndrome is cost-effective, but that results should be treated with caution because of uncertain model inputs. FUTURE WORK Randomised controlled trials could provide evidence on the effect of earlier intervention on outcomes and the balance of benefits and harms of gynaecological cancer surveillance. Follow-up of negative cases through disease registers could be used to determine false negative cases. STUDY REGISTRATION This study is registered as PROSPERO CRD42019147185. FUNDING This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 42. See the NIHR Journals Library website for further project information.
Collapse
Affiliation(s)
- Chris Stinton
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Mary Jordan
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Hannah Fraser
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Peter Auguste
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Rachel Court
- Warwick Medical School, University of Warwick, Coventry, UK
| | | | - Jason Madan
- Warwick Medical School, University of Warwick, Coventry, UK
| | - Dimitris Grammatopoulos
- Institute of Precision Diagnostics and Translational Medicine, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | | |
Collapse
|
|
16
|
Gupta S, Nichols CB, Phillips J, O'Sullivan S, Ayres C, Mohan GR, Leung Y, Stewart CJR, Tan A, Schofield L, Salfinger SG, Kiraly-Borri C, Pachter N, Cohen PA. Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry. Int J Gynecol Cancer 2021; 31:846-851. [PMID: 33858951 DOI: 10.1136/ijgc-2020-002299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 03/31/2021] [Accepted: 04/05/2021] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia. OBJECTIVE To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment. METHODS A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing. RESULTS Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years. CONCLUSIONS Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.
Collapse
Affiliation(s)
- Surabhi Gupta
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
| | - Cassandra B Nichols
- Genetic Services of Western Australia, Subiaco, Western Australia, Australia
| | - Jessica Phillips
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
| | - Sarah O'Sullivan
- Genetic Services of Western Australia, Subiaco, Western Australia, Australia
- WOMEN Centre, West Leederville, Western Australia, Australia
| | - Chloe Ayres
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
| | - Ganendra Raj Mohan
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
- Department of Gynaecological Oncology, St John of God Hospital Bendat Family Comprehensive Cancer Centre, Subiaco, Western Australia, Australia
| | - Yee Leung
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
- Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, Australia
| | - Colin J R Stewart
- PathWest, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
| | - Adeline Tan
- Clinipath Pathology, Osborne Park, Western Australia, Australia
| | - Lyn Schofield
- Genetic Services of Western Australia, Subiaco, Western Australia, Australia
| | - Stuart G Salfinger
- Department of Gynaecological Oncology, St John of God Hospital Bendat Family Comprehensive Cancer Centre, Subiaco, Western Australia, Australia
| | | | - Nicholas Pachter
- Genetic Services of Western Australia, Subiaco, Western Australia, Australia
- Internal Medicine, University of Western Australia, Crawley, Western Australia, Australia
| | - Paul A Cohen
- Department of Gynaecological Oncology, King Edward Memorial Hospital, Subiaco, Western Australia, Australia
- Department of Gynaecological Oncology, St John of God Hospital Bendat Family Comprehensive Cancer Centre, Subiaco, Western Australia, Australia
- Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, Australia
| |
Collapse
|
|
17
|
Yang N, Wu Y, Jin M, Jia Z, Wang Y, Cao D, Qin L, Wang X, Zheng M, Cao X, Jiang J. Microsatellite instability and Epstein-Barr virus combined with PD-L1 could serve as a potential strategy for predicting the prognosis and efficacy of postoperative chemotherapy in gastric cancer. PeerJ 2021; 9:e11481. [PMID: 34046266 PMCID: PMC8139270 DOI: 10.7717/peerj.11481] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 04/27/2021] [Indexed: 12/13/2022] Open
Abstract
Background Microsatellite instability (MSI) and Epstein-Barr virus (EBV)-positive molecular subtypes exhibit complex immune responses in gastric cancer (GC), and PD-L1 has emerged as a prognostic biomarker associated with the cancer immune microenvironment. This study aimed to determine the prognostic value of molecular subtypes and whether the addition of PD-L1 would accurately predict the prognosis and guide postoperative chemotherapy for GC patients. Methods We performed molecular subtyping of tissue microarray slides from 226 GC patients who were treated with radical gastrectomy. The MSI status and PD-L1 expression were evaluated through immunohistochemistry (IHC) and EBV status through situ hybridization. Multiplex polymerase chain reaction (PCR) was also performed on 50 cases to validate the accuracy of IHC in defining MSI status. Differences in overall survival (OS) were assessed using the Kaplan-Meier method, log-rank test and Cox proportional hazards regression model. Results Among the 226 GC patients, 52 (23.2%) patients were classified as the MSI subtype, 11 (4.9%) were EBV+ subtype, and 161 (71.9%) were MSS (Microsatellite stable) /EBV subtype according to TCGA analysis. Two patients were both positive for MSI and EBV infection. EBV+ cases showed higher PD-L1 positivity than MSI cases and MSS/EBV cases (81.8% vs. 50.0% vs. 35.4%, P = 0.003). Compared with the non-MSS/EBV (MSI or EBV+ cases) subgroup, GC patients with MSS/EBV were associated with the worst outcomes (HR = 1.610, 95% CI [1.0462.479], P = 0.031). MSS/EBV GCs alone could benefit from postoperative chemotherapy (HR = 0.452, 95% CI [0.2990.682], P<0.001), and PD-L1-positive expression could also predict a better prognosis (HR = 0.612, 95% CI [0.3890.962], P = 0.033) in this subgroup. Considering both chemotherapy efficacy and PD-L1 expression in the MSS/EBV subgroup, chemotherapy could improve the prognosis for PD-L1-negative MSS/EBV GCs (HR = 0.357, 95% CI [0.2170.587], P <0.001) but not PD-L1-positive MSS/EBV GCs. Conclusions Molecular subtyping combined with PD-L1 expression could serve as a potential strategy to better predict prognosis and guide postoperative chemotherapy of GC patients.
Collapse
Affiliation(s)
- Na Yang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yanhua Wu
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Meishan Jin
- Division of Pathology, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Zhifang Jia
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yueqi Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Donghui Cao
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lili Qin
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xueying Wang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China.,Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun, Jilin Province, China
| | - Min Zheng
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xueyuan Cao
- Department of Gastric and Colorectal Surgery, First Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jing Jiang
- Division of Clinical Research, First Hospital of Jilin University, Changchun, Jilin Province, China
| |
Collapse
|
|
18
|
Zhang M, Chen T. Overview on population screening for carriers with germline mutations in mismatch repair (MMR) genes in China. Hered Cancer Clin Pract 2021; 19:26. [PMID: 33933134 PMCID: PMC8088635 DOI: 10.1186/s13053-021-00182-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Accepted: 04/20/2021] [Indexed: 11/11/2022] Open
Abstract
DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.
Collapse
Affiliation(s)
- Min Zhang
- School of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Tianhui Chen
- Department of Cancer Prevention/Experimental Research Center, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
| |
Collapse
|
|
19
|
Gallon R, Gawthorpe P, Phelps RL, Hayes C, Borthwick GM, Santibanez-Koref M, Jackson MS, Burn J. How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies. Cancers (Basel) 2021; 13:406. [PMID: 33499123 PMCID: PMC7865939 DOI: 10.3390/cancers13030406] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; (P.G.); (R.L.P.); (C.H.); (G.M.B.); (M.S.-K.); (M.S.J.)
| |
Collapse
|
|
20
|
Yamamoto A, Yamaguchi T, Suzuki O, Ito T, Chika N, Kamae N, Tamaru JI, Nagai T, Seki H, Arai T, Tachikawa T, Akagi K, Eguchi H, Okazaki Y, Ishida H. Prevalence and molecular characteristics of DNA mismatch repair deficient endometrial cancer in a Japanese hospital-based population. Jpn J Clin Oncol 2021; 51:60-69. [PMID: 32844218 DOI: 10.1093/jjco/hyaa142] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The prevalence and molecular characteristics of defective DNA mismatch repair endometrial cancers in the Japanese population have been underexplored. Data supporting clinical management of patients with Lynch-like syndrome and germline variant of uncertain significance of mismatch repair genes are still lacking. METHODS Immunohistochemistry of mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed on formalin-fixed paraffin-embedded sections prepared from resected primary endometrial cancers in 395 women with a median age of 59 years. Genetic and/or epigenetic alterations of the mismatch repair genes were also investigated. RESULTS Loss of expression of one or more mismatch repair proteins was observed in 68 patients (17.2%). A total of 17 out of 68 patients (25%, 4.3% of all cases) were identified as candidates for genetic testing for Lynch syndrome after excluding 51 patients with MLH1 hypermethylated cancer. Fourteen of these 17 patients subjected to genetic testing were found to have Lynch syndrome (n = 5), germline variant of uncertain significance (n = 2) or Lynch-like syndrome (n = 7). Compared with patients with Lynch syndrome, those with germline variant of uncertain significance and Lynch-like syndrome tended to demonstrate an older age at the time of endometrial cancer diagnosis (P = 0.07), less fulfillment of the revised Bethesda guidelines (P = 0.09) and lower prevalence of Lynch syndrome-associated tumors in their first-degree relatives (P = 0.01). CONCLUSIONS This study provides useful information for management in patients with DNA mismatch repair endometrial cancer. Specifically, cancer surveillance as recommended in patients with Lynch syndrome might not be necessary in patients with germline variant of uncertain significance and Lynch-like syndrome and their relatives.
Collapse
Affiliation(s)
- Azusa Yamamoto
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Tatsuro Yamaguchi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.,Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.,Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Okihide Suzuki
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.,Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Tetsuya Ito
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Noriyasu Chika
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Nao Kamae
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.,Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Jun-Ichi Tamaru
- Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Tomonori Nagai
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Hiroyuki Seki
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Tomio Arai
- Department of Pathology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan
| | - Tetsuhiko Tachikawa
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Hidetaka Eguchi
- Diagnosis and Therapeutics of Intractable Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yasushi Okazaki
- Diagnosis and Therapeutics of Intractable Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan.,Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| |
Collapse
|
|
21
|
Pu J, Wang J, Qin Z, Wang A, Zhang Y, Wu X, Wu Y, Li W, Xu Z, Lu Y, Tang Q, Wei H. IGF2BP2 Promotes Liver Cancer Growth Through an m6A-FEN1-Dependent Mechanism. Front Oncol 2020; 10:578816. [PMID: 33224879 PMCID: PMC7667992 DOI: 10.3389/fonc.2020.578816] [Citation(s) in RCA: 108] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/07/2020] [Indexed: 12/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. N6-methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 and IGF2BP2 are key genes in the m6A signal pathway and have recently been shown to play important roles in cancer development and progression. In our work, higher METTL3 and IGF2BP2 expression were found in HCC tissues and were associated with a poor prognosis. In addition, IGF2BP2 overexpression promoted HCC proliferation in vitro and in vivo. Mechanistically, IGF2BP2 directly recognized and bound to the m6A site on FEN1 mRNA and enhanced FEN1 mRNA stability. Overall, our study revealed that METTL3 and IGF2BP2, acting as an oncogene, maintained FEN1 expression through an m6A-IGF2BP2-dependent mechanism in HCC cells, and indicated a potential biomarker panel for prognostic prediction in liver cancer.
Collapse
Affiliation(s)
- Jian Pu
- Department of General Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Jianchu Wang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Zebang Qin
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Anmin Wang
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Ya Zhang
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Xianjian Wu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yi Wu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Wenchuan Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Zuoming Xu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Yuan Lu
- Graduate College of Youjiang Medical University for Nationalities, Guangxi, China
| | - Qianli Tang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| | - Huamei Wei
- Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Guangxi, China
| |
Collapse
|
|
22
|
Testing for lynch syndrome in people with endometrial cancer using immunohistochemistry and microsatellite instability-based testing strategies - A systematic review of test accuracy. Gynecol Oncol 2020; 160:148-160. [PMID: 33190932 DOI: 10.1016/j.ygyno.2020.10.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Lynch syndrome is an inherited genetic condition that is associated with an increased risk of cancer, including endometrial and colorectal cancer. We assessed the test accuracy of immunohistochemistry and microsatellite instability-based testing (with or without MLH1 promoter methylation testing) for Lynch syndrome in women with endometrial cancer. METHODS We conducted a systematic review of literature published up to August 2019. We searched bibliographic databases, contacted experts and checked reference lists of relevant studies. Two reviewers conducted each stage of the review. RESULTS Thirteen studies were identified that included approximately 3500 participants. None of the studies was at low risk of bias in all domains. Data could not be pooled due to the small number of heterogeneous studies. Sensitivity ranged from 60.7-100% for immunohistochemistry, 41.7-100% for microsatellite instability-based testing, and 90.5-100% for studies combining immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation testing. Specificity ranged from 60.9-83.3% (excluding 1 study with highly selective inclusion criteria) for immunohistochemistry, 69.2-89.9% for microsatellite instability-based testing, and 72.4-92.3% (excluding 1 study with highly selective inclusion criteria) for testing strategies that included immunohistochemistry, microsatellite instability-based testing, and MLH1 promoter methylation. We found no statistically significant differences in test accuracy estimates (sensitivity, specificity) in head-to-head studies of immunohistochemistry versus microsatellite instability-based testing. Reported test failures were rare. CONCLUSIONS Sensitivity of the index tests were generally high, though most studies had much lower specificity. We found no evidence that test accuracy differed between IHC and MSI based strategies. The evidence base is currently small and at high risk of bias.
Collapse
|
|
23
|
Diagnostic Accuracy of Immunohistochemistry for Mismatch Repair Proteins as Surrogate of Microsatellite Instability Molecular Testing in Endometrial Cancer. Pathol Oncol Res 2020; 26:1417-1427. [PMID: 32377987 DOI: 10.1007/s12253-020-00811-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/30/2020] [Indexed: 12/27/2022]
Abstract
Microsatellite instability (MSI) defines one of the four molecular groups of endometrial carcinoma identified by The Cancer Genome Atlas (TCGA). Immunohistochemistry for mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, PMS2) has been proposed as a widely applicable technique to identify this group in the common practice. However, the diagnostic accuracy of such approach has never been calculated. We aimed to assess: 1) the diagnostic accuracy of MMR proteins immunohistochemistry as surrogate of MSI molecular testing in endometrial carcinoma; 2) whether a combination of only two MMR proteins may be used as a still cheaper test. A systematic review and meta-analysis of was performed by searching electronic databases from their inception to September 2019. All studies assessing endometrial carcinoma with both MMR proteins immunohistochemistry and MSI molecular testing were included. Diagnostic accuracy was assessed as sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-), diagnostic odds ratio (DOR) and area under the curve (AUC) on SROC curves. A subgroup analysis was performed for a combination of only two MMR proteins (MLH1-MSH2 vs MSH6-PMS2). Ten studies with 3097 patients were included. Out of these, 1110 were suitable for the meta-analysis. Immunohistochemistry for all the four MMR proteins showed sensitivity = 0.96, specificity = 0.95, LR + =17.7, LR- = 0.05, DOR = 429.77, and high diagnostic accuracy (AUC = 0.988). The combination of MLH1 and MSH2 showed sensitivity = 0.88, specificity = 0.96, LR + =22.36, LR- = 0.15, DOR = 200.69, and high diagnostic accuracy (AUC = 0.9838). The combination of MSH6 and PMS2 showed the same results as the complete panel of four MMR proteins. In conclusion, MMR proteins immunohistochemistry is a highly accurate surrogate of MSI molecular testing in endometrial carcinoma. A combination of MSH6 and PMS2 may allow reducing the cost without decrease in the diagnostic accuracy.
Collapse
|
|
24
|
Ju JY, Dibbern ME, Mahadevan MS, Fan J, Kunk PR, Stelow EB. Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies. Am J Clin Pathol 2020; 153:598-604. [PMID: 31844887 DOI: 10.1093/ajcp/aqz199] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. METHODS We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing. RESULTS We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. CONCLUSIONS Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.
Collapse
Affiliation(s)
- Jennifer Y Ju
- Departments of Pathology, University of Virginia, Charlottesville
| | - Megan E Dibbern
- Departments of Pathology, University of Virginia, Charlottesville
| | - Mani S Mahadevan
- Departments of Pathology, University of Virginia, Charlottesville
| | - Jinbo Fan
- Departments of Pathology, University of Virginia, Charlottesville
| | - Paul R Kunk
- Hematology/Oncology, University of Virginia, Charlottesville
| | - Edward B Stelow
- Departments of Pathology, University of Virginia, Charlottesville
| |
Collapse
|