Mismatch Repair Proteins and Microsatellite Instability in Colorectal Carcinoma (MLH1, MSH2, MSH6 and PMS2): Histopathological and Immunohistochemical Study

Emera

et al. 2019

Egypt J Med Hum Genet

Background: Colorectal cancer (CRC) is the third most common cause of cancer-related deaths which contributes to a significant public health problem worldwide with 1.8 million new cases and almost 861,000 deaths in 2018 according to the World Health Organization. It exhibits 7.4% of all diagnosed cancer cases in the region of the Middle East and North Africa. Molecular changes that happen in CRCs are chromosomal instability, microsatellite instability (MSI), and CpG island methylator phenotype. The human RAS family (KRAS, NRAS, and HRAS) is the most frequently mutated oncogenes in human cancer appearing in 45% of colon cancers. Determining MSI status across CRCs offers the opportunity to identify patients who are likely to respond to targeted therapies such as anti-PD-1. Therefore, a method to efficiently determine MSI status for every cancer patient is needed. Results: KRAS mutations were detected in 31.6% of CRC patients, namely in older patients (p = 0.003). Codons 12 and 13 constituted 5/6 (83.3%) and 1/6 (16.7%) of all KRAS mutations, respectively. We found three mutations G12D, G12C, and G13D which occur as a result of substitution at c.35G>A, c.34G>T, and c.38G>A and have been detected in 4/6 (66.6%), 1/6 (16.7%), and 1/6 (16.7%) patients, respectively. Eleven (57.9%) patients had microsatellite instability-high (MSI-H) CRC. A higher percentage of MSI-H CRC was detected in female patients (p = 0.048). Eight patients had both MSI-H CRC and wild KRAS mutation with no statistical significance was found between MSI status and KRAS mutation in these studied patients. Conclusion: In conclusion, considering that KRAS mutations confer resistance to EGFR inhibitors, patients who have CRC with KRAS mutation could receive more tailored management by defining MSI status. MSI-high patients have enhanced responsiveness to anti-PD-1 therapies. Thus, the question arises as to whether it is worth investigating this association in the routine clinical setting or not. Further studies with a larger number of patients are needed to assess the impact of MSI status on Egyptian CRC care.

Section: Discussionmentioning

confidence: 52%

“…Previous studies found that MSI-H sporadic CRCs are the most often (about 70-95%) caused by alteration of the MLH1 gene via somatic promoter hypermethylation [18]. In other Egyptian studies, MSI-H was found in 37% and 30.8% of their patients [17,19]. This difference may be attributed due to different detective methods to some extent.…”

Section: Discussionmentioning

confidence: 88%

Clinicopathological features of Egyptian colorectal cancer patients regarding somatic genetic mutations especially in KRAS gene and microsatellite instability status: a pilot study

Emera

et al. 2019

Egypt J Med Hum Genet

“…The RAS gene is a predictive biomarker for the resistance to anti-EGFR monoclonal antibody (MoAb) treatment in mCRCs ( Amado et al, 2008 ; Punt, Koopman & Vermeulen, 2016 ). However, geographic and racial differences between Chinese and other countries were reported ( Huang et al, 2010 ; Ismael et al, 2017 ; Kim et al, 2007 ; Vasovcak et al, 2011 ; Ye et al, 2015 ), which need to be validated with large sample amounts. Furthermore, data regarding RAS mutation frequency and dMMR CRC is not consistent in China.…”

Section: Discussionmentioning

confidence: 99%

“…Correlations between dMMR status and clinicopathological characteristics were controversial ( Ismael et al, 2017 ; Jin et al, 2008 ; Ribic et al, 2003 ; Sinicrope et al, 2011 ). Reports from three independent Chinese groups ( Huang et al, 2010 ; Jin et al, 2008 ; Ye et al, 2015 ) indicated that dMMR had specific associations such as female gender, right sided colon tumors and mucious tumors.…”

Section: Discussionmentioning

confidence: 99%

Deficient mismatch repair and RAS mutation in colorectal carcinoma patients: a retrospective study in Eastern China

Zhang

Ran

et al. 2018

PeerJ

ObjectivesTo investigate the frequency and prognostic role of deficient mismatch repair (dMMR) and RAS mutation in Chinese patients with colorectal carcinoma.MethodsClinical and pathological information from 813 patients were reviewed and recorded. Expression of mismatch repair proteins was tested by immunohistochemistry. Mutation analyses for RAS gene were performed by real-time polymerase chain reaction. Correlations of mismatch repair status and RAS mutation status with clinicopathological characteristics and disease survival were determined.ResultsThe overall percentage of dMMR was 15.18% (121/797). The proportion of dMMR was higher in patients <50 years old (p < 0.001) and in the right side of the colon (p < 0.001). Deficient mismatch repair was also associated with mucinous production (p < 0.001), poor differentiation (p < 0.001), early tumor stage (p < 0.05) and bowel wall invasion (p < 0.05). The overall RAS mutation rate was 45.88%, including 42.56% (346/813) KRAS mutation and 3.69% (30/813) NRAS mutation (including three patients with mutations in both). KRAS mutation was significantly associated with mucinous production (p < 0.05), tumor stage (p < 0.05) and was higher in non-smokers (p < 0.05) and patients with a family history of colorectal carcinoma (p < 0.05). Overall, 44.63% (54/121) dMMR tumors harbored KRAS mutation, however, dMMR tumors were less likely to have NRAS mutation. Moreover, dMMR, KRAS and NRAS mutation were not prognostic factors for stage I–III colorectal carcinoma.ConclusionsThis study confirms that the status of molecular markers involving mismatch repair status and RAS mutation reflects the specific clinicopathological characteristics of colorectal carcinoma.

“…These mutations cause de ciencies in DNA repair, resulting in a high frequency of replication errors. Genetic analysis and detection of protein expression by immunohistochemistry (IHC) are important in diagnosing LS [5,6]. MTS is primarily related to mutations in MSH2 and is characterized by skin tumors (such as sebaceous adenomas, skin squamous cell carcinomas) [9].…”

Section: Introductionmentioning

confidence: 99%

A case of a new Lynch Syndrome variant with a deletion, c.1024_1026, in the MSH2 gene in a Chinese family

Zhao

Li²,

Lin

et al. 2020

Preprint

Background Multiple genetic variations have been identified in mismatch repair genes for Lynch Syndrome. However, diagnosis of Lynch Syndrome and its subtypes in patients with atypical cancer types still remains challenging. Little is known about Lynch syndrome-related renal carcinoma and related genes. We present a case of renal carcinoma with multiple primary skin tumors, with a new Lynch Syndrome variant with a deletion in a Chinese family. Case presentation: The patient was a 60-year-old Chinese male with a history of Lynch Syndrome-related renal carcinoma with repeatedly multiple primary skin tumors. Immunohistochemistry revealed loss of MSH2 and MSH6 proteins. Sequencing of mismatch repair genes revealed a previously unknown germline MSH2 mutation (c.1024_1026 del) resulting in an amino acid deletion (p. V342del). This variant was co-segregated among the carcinoma-affected family members. After 6 cycles of immunotherapy, a marked regression of the skin tumor was obtained. Conclusions We clarify the pathogenic significance of this new mutation and suggest immunotherapy for patients with this subtype of Lynch Syndrome.