Differences in histological features and PD-L1 expression between sporadic microsatellite instability and Lynch-syndrome-associated disease in Japanese patients with colorectal cancer

2018 ◽  
Vol 23 (3) ◽  
pp. 504-513 ◽  
Author(s):  
Rin Yamada ◽  
Tatsuro Yamaguchi ◽  
Takeru Iijima ◽  
Rika Wakaume ◽  
Misato Takao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Japanese Patients ◽  
Histological Features

TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

2008 ◽  
Vol 31 (4) ◽  
pp. 12
Author(s):  
A J Hyde ◽  
D Fontaine ◽  
R C Green ◽  
M Simms ◽  
P S Parfrey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Population Based ◽  
Pathological Features ◽  
Predictive Tool ◽  
Entire Cohort ◽  
Dna Mismatch ◽  
Bethesda Guidelines ◽  
Revised Bethesda Guidelines

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

scholarly journals Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer

2014 ◽  
Vol 207 (10-12) ◽  
pp. 495-502 ◽  
Author(s):  
Eduardo Vilar ◽  
Maureen E. Mork ◽  
Amanda Cuddy ◽  
Ester Borras ◽  
Sarah A. Bannon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Diagnostic Biomarker

Clinicopathological features of microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) in Japanese patients.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 629-629
Author(s):  
Akihito Kawazoe ◽  
Kohei Shitara ◽  
Masaaki Noguchi ◽  
Shota Fukuoka ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Large Scale ◽  
Phase Ii Trial ◽  
Japanese Patients ◽  
Clinicopathological Features ◽  
Braf V600e

629 Background: Recently, anti-programmed death 1 (PD-1) antibody has shown promising efficacy in a phase II trial for patients with microsatellite instability-high (MSI-H) tumors, especially in those with metastatic colorectal cancer (mCRC). Currently, several clinical trials of anti-PD-1 antibody for patients with MSI-H mCRC are ongoing. However, little is known about the frequencies and clinicopathological features of MSI-H mCRC in Japanese patients. Methods: Patients with histologically confirmed adenocarcinoma of mCRC were eligible for this observational study. MSI status was analyzed in tumors using the MSI Analysis System (Promega) composed of 5 mononucleotide markers. KRAS, NRAS, BRAF and PIK3CA mutations were also evaluated using the multiplex kit. Results: A total of 232 patients were enrolled until August 31, 2015, of which MSI-H was detected in 5 patients (2.1%). Among five patients with MSI-H mCRC, median age was 45 years (28-75), four had tumors on right-sided colon, five had moderately differentiated adenocarcinoma, one had poorly differentiated adenocarcinoma, and three had stage IV disease at presentation. Overall survival for patients with MSI-H mCRC from the start of first-line systemic chemotherapy ranged from 8.1 to 62.0 month. All five patients with MSI-H mCRC had RAS wild-type tumors and two had BRAF V600E mutation. One patient with MSI-H mCRC was enrolled in a phase II trial of anti-PD-1 antibody. Conclusions: MSI-H mCRC is rare in Japanese patients. A large scale nationwide cancer genome screening project together with MSI status is required to evaluate more detailed clinicopathological features and facilitate the enrollment of patients with MSI-H mCRC for clinical trials with anti-PD-1 antibody.

Use of immunohistochemical versus microsatellite analyses as markers for colorectal cancer

2017 ◽  
Vol 43 (2) ◽  
pp. 134-141
Author(s):  
Utku Tantoğlu ◽  
Seher Yüksel ◽  
Cihangir Akyol ◽  
Haldun Doğan ◽  
Nükhet Kutlay ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immunohistochemical Analysis ◽  
Sporadic Colorectal Cancer ◽  
Molecular Tests ◽  
Antibody Panel ◽  
Mismatch Repair Proteins ◽  
Good Concordance

Abstract Objectives: Our aim was to determine how well immunohistochemical analysis identified colon cancer patients with microsatellite instability in Turkish patients. Material and methods: Subjects were patients that underwent surgery for colorectal cancer in our institution between 2006 and 2011. Patients were grouped as: (1) suspected Lynch syndrome (n=14), (2) familial colorectal cancer (n=14), and (3) sporadic colorectal cancer groups (n=14). Mismatch repair proteins were analyzed by a four antibody-panel immunohistochemistry. Microsatellite instability analysis was conducted on DNA samples using MSI-PCR followed by fragment analysis. Results: The immunohistochemistry and PCR results had good concordance in 35/42 patients. Both microsatellite instability and at least one mismatch repair protein deficiency were detected in 11 patients, and both microsatellite stability and normal expression of mismatch repair proteins were detected in 24 patients. Test results were discordant in seven of the patients. Conclusion: As it is not feasible to perform expensive molecular tests in healthcare units in many developing countries, the four antibody-panel immunohistochemistry is a reliable and affordable method for screening for colorectal cancer, including Lynch syndrome and sporadic cases when suspected.

Prognostic significance of KRAS and BRAF mutations in Japanese patients with colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14033-e14033
Author(s):  
Eiji Oki ◽  
Ryota Nakanishi ◽  
Koji Ando ◽  
Hiroshi Saeki ◽  
Takefumi Ohga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Molecular Mechanisms ◽  
Prognostic Significance ◽  
Japanese Patients ◽  
Genetic Alterations ◽  
Stage Ii ◽  
Anatomical Site

e14033 Background: Recent evidence highlights the potential prognostic and predictive value of BRAF and K-RAS gene alterations in patients with colorectal cancer. To determine whether differences exist in the molecular mechanisms driving colorectal cancer between Japanese and Western, we characterized Japanese patients with colorectal cancer by assessing genetic alterations involved in cancer progression and response to treatment. Methods: We retrospectively evaluated 254 Japanese diagnosed with colorectal cancer at our institution between 1994 and 2009. Mutations in KRAS codons 12 and 13 and BRAF codon 600 were identified by direct sequencing. Microsatellite instability (MSI) status was determined by genotyping in the 5 loci. Associations between KRAS or BRAF mutation and clinicopathological characteristics and prognosis were evaluated. Results: KRAS and BRAF mutation were detected in 33.5% and 6.7% of all patients, respectively. KRAS mutation was correlated with poor recurrence free survival (RFS) (p = 0.03), especially in stage II patients (p = 0.007). BRAF mutation was significantly correlated with the anatomical site of tumor (p < 0.001), tumor grade (p = 0.001) and high frequency of microsatellite instability (p < 0.001). BRAF mutation was also correlated with poor overall survival in all cases of patients (p = 0.009). Overall, the background of KRAS and BRAF mutation was almost similar between CRCs of Western countries and those of Japanese. However, KRAS mutation status was considered to be helpful to predict recurrence in Japanese patients with stage II CRC. Conclusions: Our findings indicate that BRAF and K-RAS mutation plays an important role in the tumorigenesis of colorectal cancer. These results indicate that molecular analysis for BRAF and K-RAS may be a useful biomarker for identifying patients with right-sided colon cancer with poor outcome who may benefit from a more individualized course of therapy.

Molecular Diagnostics of Colorectal Cancer

2011 ◽  
Vol 135 (5) ◽  
pp. 578-587
Author(s):  
Ahmed Bedeir ◽  
Alyssa M. Krasinskas
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Molecular Diagnostics ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Response To Therapy ◽  
Molecular Testing ◽  
Cancer Predisposition Syndrome ◽  
Standard Tool

Abstract Context.—Of all gastrointestinal tract epithelial malignancies, molecular diagnostics has impacted colorectal cancer the most. Molecular testing can detect sporadic and inherited colorectal cancers that arise through the microsatellite instability pathway and can determine the efficacy of targeted drug therapy. Objectives.—To review the microsatellite instability pathway of colorectal carcinoma carcinogenesis and to demonstrate the diagnostic utility of molecular testing in the detection of patients with Lynch syndrome, an inherited disorder of this pathway. Also, to review the significance of detection of KRAS and BRAF gene mutations in predicting the response to anti–epidermal growth factor receptor therapies. Data Sources.—This article is based on original publications and review articles that are accessible through the PubMed biomedical database (US National Library of Medicine). Conclusions.—In modern pathology practice, molecular testing is a standard tool that is used to diagnose an inherited colorectal cancer predisposition syndrome (Lynch syndrome) and to help predict outcome and response to therapy for patients with advanced colorectal cancer.

scholarly journals Lynch syndrome I: A case report

2008 ◽  
Vol 61 (1-2) ◽  
pp. 79-82
Author(s):  
Vesna Zivkovic ◽  
Vuka Katic ◽  
Jasmina Gligorijevic ◽  
Zlatibor Andjelkovic ◽  
Aleksandar Petrovic ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Case Report ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Clinical Stage ◽  
Family Members ◽  
Advanced Rectal Cancer ◽  
Degree Relative ◽  
Mmr Genes ◽  
Amsterdam Criteria

Introduction. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndromes J and II, accounts for about 5-8% of colorectal cancers. Lynch syndrome I is an autosomal domi?nant inherited disorder characterized by early onset of colorectal cancer, predominance of proximal and multiple tumors, and microsatellite instability. In order to identify HNPCC, the international "Amsterdam criteria" have been used. Case report. The proband was a 40-year-old male who was admitted to hospital with a diagnosis of advanced rectal cancer. Left colectomy was carried out. A histopathologic diagnosis of poorly differentiated adenocarcinoma of clinical stage Dukes C was made. The family talking was done and it was revealed that the pro-band had five family members (one of first degree relative) with colorectal cancer, and two successive generations affected. All malignancy were diagnosed before 45 years of age. In one family member, metachronous transverse cancer was revealed 12 years after surgery for cecal adenocarcinoma. Discussion and conclusion. The main molecular cause for HNPCC is constitutional mutation in one of the mismatch repair (MMR) genes that regulate the excision of errors occurring during DNA replication. The most often are mutations of MLHI and MSH2 genes, and microsatellite instability is present in about 90-95% HNPCC. In this report, we present a case of an HNPCC patient who met the Amsterdam criteria for Lynch syndrome I. Family members that fulfill the Amsterdam criteria should be investigated for mutation in MMR genes. The genetic tests are not routinely available, so colonoscopic screening of all asymptomatic family members older than 25 has been recommended.

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.

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