Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability

Amira, Arfaoui Toumi; Trabelsi, Med Mehdi; Blel, Ahlem; Aloui, Raoudha; Majid, Ben Hmida; Amel, Hamza; Zermani, R; Nadia, Kourdaa

doi:10.1007/s13277-014-1831-2

Cited by 20 publications

(12 citation statements)

References 31 publications

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“…Therefore, a more accuracy and cost-effective test protocol is expected to arise from a combination of these methods. In our study, in consistent with previous studies,18–20 there was a moderate consistency between the IHC method for MMR detection and the PCR method for MSI assessment, indicating that combining the results of the IHC and PCR methods is a feasible strategy to obtain more promising results than that of considering either method alone. However, some tumors were MSI-H, but were classified as MMR-D, and some MSS were classified as MMR-D by IHC.…”

Section: Discussionsupporting

confidence: 91%

Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population

Yan¹,

Hu²,

Xie³

et al. 2016

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Colorectal cancers (CRCs) exhibiting microsatellite instability (MSI) have special biological behavior. The clinical predictors for MSI and its survival relevance for the Chinese population were still unclear. Seven hundred ninety-five CRC patients were retrospectively assessed. Mismatch repair (MMR) proteins (MSH2, MSH6, PMS1, and MLH1) expression was detected by immunohistochemistry using tumor tissues of all patients. DNA MSI status was analyzed by polymerase chain reaction in 182 samples randomly selected from the 795 cases. Among all CRC tumor tissues, 97 cases (12.2%) were with an MMR protein-deficient (MMR-D) phenotype, whereas 698 cases (87.8%) were with an MMR proteins intact (MMR-I) phenotype. A total of 21 (11.5%) CRCs were identified as having high microsatellite instability, 156 (85.7%) tumors were having microsatellite stability (MSS), and five (2.7%) were having low microsatellite instability. Importantly, MMR status was demonstrated to be moderately consistent with MSI status (κ=0.845, 95% confidence interval [CI] 0.721, 0.969). Unconditional logistic regression analysis revealed age, number of lymph node, tumor diameter, and tumor site as predictors for MSI with a substantial ability to discriminate different MSI status by area under curve of 80.62% using receiver operation curve. Compared with MMR-I, MMR-D was an independent prognostic factor for longer overall survival (hazard ratio =0.340, 95% CI 0.126, 0.919; P=0.034). MMR-D is an independent prognostic factor for better outcome. Our results may provide evidence for individualized diagnosis and treatment of CRC, but this will require further validation in larger sample studies.

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Section: Discussionsupporting

confidence: 91%

Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population

Yan¹,

Hu²,

Xie³

et al. 2016

OTT

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“…We found that dMMRP tumors tended to present at an earlier stage in consistency with several previous studies of MMRP-deficient colorectal cancer [25,35,37,39]. In this study, there was no significant association between the stage of the primary tumor (T stage) or distant metastasis (M stage) and MMRP deficiency.…”

Section: Gastroenterology Research and Practicesupporting

confidence: 92%

Frequency of Mismatch Repair Protein (MMRP) Deficiency among Young Jordanians Diagnosed with Colorectal Carcinoma (CRC)

Maraqa

Al-Shbool

Abu-Shawer

et al. 2020

Gastroenterology Research and Practice

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Purpose. Microsatellite instability (MSI) caused by mismatch repair protein (MMRP) deficiency is detected in 15% of sporadic colorectal cancers (CRCs). Our aim is to investigate the frequency of MMRP deficiency in young CRC patients, using immunohistochemical analysis. Methods. This study targeted cases of CRC at King Hussein Cancer Center from 2004 until 2012 in patients 45 years of age or younger at the time of diagnosis. Clinicopathological data was obtained from 155 patients’ records. Immunohistochemistry for MLH1, MSH2, PMS2, and MSH6 proteins was performed on paraffin-embedded tissue containing carcinoma. Results. The median age of patient at diagnosis was 38 years. A total of 29 (19%) cases showed deficient MMRP(dMMRP)expression. Loss of expression of PMS2 was seen in 17 cases, 12 cases of which showed loss of MLH1 expression. Loss of expression of MSH6 was seen in 10 cases, 9 of which showed loss of MSH2 expression. One case (3.4%) showed loss of all four MMR proteins, and another case (3.4%) showed loss of PMS2/MLH1 and MSH6. There was a significant association between abnormal MMR protein expression and tumor location proximal to splenic flexure (p value 0.000), pathologic features suggestive of microsatellite instability (p value 0.000), P53 negativity (p value 0.000), and stage (p value 0.02). Patients with dMMRP CRC appeared to have a significantly better overall survival compared to patients with proficient MMRP(pMMRP)(p value 0.02). Loss of MSH2/MSH6 was significantly associated with positive family history of cancer (p value = 0.020). Conclusions. The prevalence of dMMRP tumors in this age group appears to be similar to international literature. dMMRP tumors tends to be associated with earlier stages and better outcomes compared to pMMRP cases. dMMRP can serve as a biomarker for better prognosis. These results are of value in directing the clinical management of young patients with CRC.

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“…So far, very few clinical studies and genetic reports conducted on patients with LS in Tunisia have been published [19, 20]. Moussa et al [20] have identified pathogenic mutations in MMR genes in only 11/31 LS suspected Tunisian families.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins

et al. 2019

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Background Lynch syndrome (LS) is a highly penetrant inherited cancer predisposition syndrome, characterized by autosomal dominant inheritance and germline mutations in DNA mismatch repair genes. Despite several genetic variations that have been identified in various populations, the penetrance is highly variable and the reasons for this have not been fully elucidated. This study investigates whether, besides pathogenic mutations, environment and low penetrance genetic risk factors may result in phenotype modification in a Tunisian LS family. Patients and methods A Tunisian family with strong colorectal cancer (CRC) history that fulfill the Amsterdam I criteria for the diagnosis of Lynch syndrome was proposed for oncogenetic counseling. The index case was a man, diagnosed at the age of 33 years with CRC. He has a monozygotic twin diagnosed at the age of 35 years with crohn disease. Forty-seven years-old was the onset age of his paternal uncle withCRC. An immunohistochemical (IHC) labeling for the four proteins (MLH1, MSH2, MSH6 and PMS2) of the MisMatchRepair (MMR) system was performed for the index case. A targeted sequencing of MSH2 , MLH1 and a panel of 85 DNA repair genes was performed for the index case and for his unaffected father. Results The IHC results showed a loss of MSH2 but not MLH1, MSH6 and PMS2 proteins expression. Genomic DNA screening, by targeted DNA repair genes sequencing, revealed an MSH2 pathogenic mutation (c.1552C>T; p.Q518X), confirmed by Sanger sequencing. This mutation was suspected to be a causal mutation associated to the loss of MSH2 expression and it was found in first and second degree relatives. The index case has smoking and alcohol consumption habits. Moreover, he harbors extensive genetic variations in other DNA-repair genes not shared with his unaffected father. Conclusion In our investigated Tunisian family, we confirmed the LS by IHC, molecular and in silico investigations. We identified a novel pathogenic mutation described for the first time in Tunisia. These results come enriching the previously reported pathogenic mutations in LS families. Our study brings new arguments to the interpretation of MMR expression pattern and highlights new risk modifiers genes eventually implicated in CRC. Twins discordance reported in this work underscore that disease penetrance could be influenced by both genetic background and environmental factors. Electronic supplementary material The online version of this article (10.1186/s12967-019-1961-9) contains supplementary material, which is available to authorized users.

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Immunohistochemical expression pattern of MMR protein can specifically identify patients with colorectal cancer microsatellite instability

Cited by 20 publications

References 31 publications

Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population

Prediction of biological behavior and prognosis of colorectal cancer patients by tumor MSI/MMR in the Chinese population

Frequency of Mismatch Repair Protein (MMRP) Deficiency among Young Jordanians Diagnosed with Colorectal Carcinoma (CRC)

Identification of novel pathogenic MSH2 mutation and new DNA repair genes variants: investigation of a Tunisian Lynch syndrome family with discordant twins

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