Frequency Of Microsatellite Instability Research Articles

Abstract P1-06-11: Microsatellite instability in triple negative breast cancers

Abstract Background:Microsatellite instability (MSI) is a phenotype resulting from defect in mismatch repair genes. The Food and Drug Administration approved anti-programmed death 1 (PD-1) immune checkpoint inhibitor for any solid tumor with MSI-high (MSI-H). Some tumors had good response to PD-1 blockade and it is a promising treatment for a part of refractory breast cancers. Our goal was to determine the frequency of MSI in triple negative breast cancer (TNBC), one of the most clinically aggressive subtypes. Patients and Methods:This study included 228 patients with primary TNBC underwent resection without neoadjuvant chemotherapy between January 2004 and December 2014. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue. Tumor and control DNA were amplified by polymerase chain reaction at the following 5 microsatellite markers: NR-21, BAT-26, BAT-25, NR-24, MONO-27. We classified the tumors as microsatellite stable(MSS), MSI-low or MSI-H. Results: The mean age of patients was 59 years (range: 30-89) and all were women. T1 tumors were 57.9% and N0 were 67.5%. Meanwhile, the tumors with nuclear grade 3 were 66.2% and high Ki-67 (> 30%) were 66.7%. Among the 228 tumors, 222 tumors (97.4%) revealed MSS, of which 6 (2.6%) revealed MSI and 2 (0.9%) were MSI-H. Among the MSI tumors, T and N factor were showed as follows: T1: 2 tumors, T2: 3 tumors, T3: 1 tumor, N0: 5 tumors and N1: 1 tumor. Of two MSI-H tumors, one showed T1N0 and another showed T2N0. The both of them showed nuclear grade 3, high Ki-67 (> 30%) and had common following instable markers: NR-21, BAT-26 and BAT-25. Conclusions: Our results demonstrated that the frequency of MSI-H was 0.9% (2/228). MSI might not be useful as a biomarker for immune check point inhibitors. MSI should be combined with another biomarker such as tumor mutational burden in TNBC. Citation Format: Kurata K, Kubo M, Mori H, Kawaji H, Motoyama Y, Kuroki L, Yamada M, Kaneshiro K, Kai M, Nakamura M. Microsatellite instability in triple negative breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-06-11.

Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer

Introduction:Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method:A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results:Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.

No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis

Objective: Microsatellite instability (MSI) and a defective mismatch repair (MMR) system were described as beneficial tumor features for response to immune checkpoint therapy (PD-1 blockade). Meanwhile, the FDA approved PD-1/PD-L1 inhibition treatment for any solid tumor showing MSI and/or defects in the MMR system. For squamous cell carcinoma (SCC) of the penis, no data on the frequency of MSI and altered MMR protein expression are available to date. Therefore, we investigated the MSI status and the expression of MMR proteins in a large cohort of penile SCCs. Methods: The MSI status of 105 archival formalin-fixed, paraffin-embedded penile SCCs was analyzed using the 5 markers of the NCI consensus panel for MIS testing (BAT25, 26, D2S123, D17S250, and D5S346), or, in cases without representative nontumorous tissue using a validated panel of 5 quasimonomorphic mononucleotide repeat markers (BAT 25, 26 and NR21, 24, 27). The expression of the MMR proteins MLH1, MSH2, MSH6, and PMS2 was analyzed using immunohistochemistry and a tissue microarray of a subset of penile SCCs from our cohort (n = 75). Results: Overall, in 96/105 cases, at least 4 microsatellite markers gave interpretable results. None of the cases showed MSI. Immunohistochemistry for MMR proteins was analyzable in 70/75 cases. All cases showed a regular expression of the MMR proteins. Conclusion: MSI and defects in MMR protein expression are not regular features of penile SCC and might not act as biomarkers for PD-1/PD-L1 blockade therapy in penile carcinoma.

Small Bowel Carcinomas Associated with Immune-Mediated Intestinal Disorders: The Current Knowledge.

Small bowel carcinomas (SBC) are uncommon neoplasms, whose predisposing conditions include hereditary syndromes and immune-mediated intestinal disorders including coeliac disease (CD) and Crohn’s disease (CrD). Although both CD-associated SBC (CD-SBC) and CrD-associated SBC (CrD-SBC) arise from an inflammatory background, they differ substantially in tumour cell phenotype, frequency of microsatellite instability and nuclear β-catenin expression, as well as in prognosis. For these patients, high tumour-infiltrating lymphocyte density and glandular/medullary histotype represent independent positive prognostic factors. Dysplasia adjacent to SBC is rare and characterized by intestinal phenotype and nuclear β-catenin in CD, while it is frequent and typified by gastro-pancreatobiliary marker expression and preserved membranous β-catenin in CrD. Recent evidence suggests that Epstein-Barr virus-positive dysplasia and SBC, albeit exceptional, do exist and are associated with CrD. In this review, we summarize the novel pathological and molecular insights of clinical and therapeutic interest to guide the care of CD-SBC and CrD-SBC.

The Tendency of Having MSH2 and MSH6 Microsatellite Instability among Clinicopathological Features in Patients with Colorectal Cancer

Objective:This study aimed to identify micro-satellite instability (MSI) based on the expression of MMRp (MSH2 and MSH6) and to evaluate the association of MSI and with clinicopathological features in patients with colorectal cancer (CRC).Methods:MMRp expression in 80 tissue samples from patients with adenocarcinoma CRC were evaluated by using anti-MSH2 and -MSH6 antibodies. Loss of MSH2 and/or MSH6 expression was stated as MSI. The association between MSI status and clinicopathological features were analyzed by using binary logistic regression (p<0.05).Results:The frequency of MSI in patients with CRC varied, corresponding to 8.3% (6/72) MSH2 MSI, 36.1% (26/72) MSH6 MSI and 6.9% (5/72) MSH2-MSH6 MSI. Male patients (OR=1.98), with tumor located in colon (OR=1.47) and late stage tumor (OR=1.48) have a tendency of having MSH2 MSI. Male patients (OR=1.4), with tumor located in colon (OR=2.53) and poor tumor differentiation (OR=3.02) have a tendency to encounter MSH6 MSI. Male patients (OR=4.93) with late stage tumor (OR=1.69) have a tendency of having MSH2-MSH6 MSI.Conclusion:Patients more likely to have MSH2 MSI are males, and/or having tumor located in colon, and /or having late stage tumor. Patients more likely to have MSH6 MSI are males, and/or having tumor located in colon, and/or having tumor with poor differentiation. Patients who have greater tendency to have MSH2 and MSH6 MSI are males, and/or having late stage tumor.

Solid-type poorly differentiated adenocarcinoma of the stomach: clinicopathological and molecular characteristics and histogenesis.

Despite predominant microsatellite instability (MSI) in intestinal-type gastric carcinomas, we found the most frequent MSI in solid-type poorly differentiated adenocarcinoma (PDA). Although this tumor is classified as PDA, it is hypothesized to possess peculiar features among PDAs. The present study aimed to clarify the clinicopathological and molecular characteristics of this tumor. We examined the expression of p53, mismatch-repair proteins, and mucin core glycoproteins; microsatellite status; and mutations in KRAS and BRAF, as well as clinicopathological features, in 54 cases of PDA of the stomach (31 solid-type PDAs and 23 non-solid-type PDAs). The proportion (51.6%) of MSI in solid-type PDA was significantly higher than that in non-solid-type PDA (4.5%) (p = 0.00022). The proportion of absent expression of MLH1 (58.1%) and PMS2 (51.6%) in solid-type PDA was significantly higher than that in non-solid-type PDA (4.5 and 8%) (p < 0.0001). No differences were found in the mutations of KRAS and BRAF among PDAs. MSI-positive solid-type PDA was significantly associated with older age, female predominance, lower third location, concordant glandular component, and absent MLH1 and PMS2 expression. These results suggest that MSI-positive solid-type PDA has peculiar clinicopathological features and that MSI with absent MLH1 and PMS2 expression may play an important role in tumor development. In addition, from the viewpoint of histogenesis, MSI-positive solid-type PDA may originate from differentiated-type adenocarcinoma.

Familial aggregation of gastric cancer with microsatellite instability*

Background: Microsatellite instability (MSI) is currently a new molecular subtype of gastric cancer (GC). About 90% of GC cases appear sporadically. MSI seems to be responsible for both sporadic and familial GC. The aim of this study was to analyze the frequency of MSI in GC with familial history of GC.Methods: The MSI analysis was conducted using five quasi-monomorphic mononucleotide repeats: BAT-26, BAT-25, NR-24, NR-21 and NR-27. From our database, we analyzed 457 patients in terms of cancer history across family members, particularly focusing on GC.Results: MSI status in patients without familial history of GC was present in 22.1% of the cases, whereas in the patients with familial history of GC it was present in 28% of the cases (p = 0.220). For 1st or 2nd degree family members with GC, MSI was observed in 27.6% and in 30.8%, respectively (p = 0.812). MSI was observed in hereditary gastric cancer (HGC) in 33.3% and in familial gastric cancer (FGC) in 30%. No difference in survival rates was observed between the analyzed groups.Conclusions: In our publication, we could not find any link between familial background and the MSI status in GC patients. More detailed molecular and genetic analysis of subgroups of these patients is required.

IJU this issue

In this issue of International Journal of Urology, six Review Articles with three Editorial Comments, four Original Articles and two Urological Notes were published. Husmann (Rochester, USA) reviewed 385 patients that have experienced an enteric bladder augmentation as a result of spina bifida or bladder exstrophy, using either the ileum or colon. Based on the finding of increasing complications with body mass index, the author concluded long-term follow-up evaluations and the nutritional management of patients undergoing an enteric bladder augmentation are necessary to prevent the long-term sequela of this procedure. As the reviewer notes in the Editorial Comment, urologists should bear in mind that complicated surgeries are not a goal, but the start of a new daily care routine of their bladder. Takeuchi et al. (Fukuoka, Japan) reviewed the mechanism of immunological tolerance induced by cyclophosphamide (CY) and other immune factors in kidney transplantation. The authors established their own CY-induced experimental chimera mouse model consisting of intravenous injection of allogeneic bone marrow and spleen cells, followed by intraperitoneal injection of CY. In this model, they showed destruction of allo-reactive T cells by CY. Interestingly, they modified their tolerance system for the experimental treatment of malignancy. Inamoto et al. (Osaka, Japan) compared the oncological and quality of life results of bladder preservation therapy including trimodal therapy with that of radical cystectomy, and concluded that trimodal therapy has emerged as a potential alternative treatment option for muscle-invasive bladder cancer. As muscle-invasive bladder cancer is a systemic disease, trimodal therapy might become an attractive alternative when considering the combination or adjuvant setting of immuno-oncology drugs because of the abscopal effect as a result of radiation therapy. Several interesting Original Articles have been published. Nishioka et al. (Osaka, Japan) reported the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant from a Japanese multicenter study that enrolled 156 kidney transplant patients between 2009 and 2013. The authors concluded that two calcineurin inhibitors yielded equivalent efficacy, and high-dose (6 mg/kg at the start) mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression. This study is worthwhile, not only for showing the utility and safety of this regimen, but also for showing the commitment of Japanese urologists to kidney transplantation worldwide. Urakami et al. (Tokyo, Japan) studied DNA mismatch repair proteins for 143 patients with upper urinary tract urothelial cancer, and found seven (5%) had loss of mismatch repair proteins, so-called microsatellite instability (MSI). Malignant tumors show an inherent genetic instability that can be classified as MSI or chromosomal instability. Although the frequency of MSI was reportedly higher in upper urinary tract urothelial cancer than bladder cancer, the figure and clinical characteristics were almost identical to bladder cancer (9/100; 9%, all with a low grade without tumor progression; Yamamoto T. Clin Cancer Res 2006; 12: 2752). Study of the genetic status of MSI will be more important because of the higher mutational burden than chromosomal instability with a good response to immuno-oncology drugs. Unfortunately, other interesting papers could not be published in this issue due to limited space. None declared.

Frequency and prognostic utility of MSI and TILs in advanced noncolorectal GI malignancies.

313 Background: Mismatch repair gene mutation status not only has a role in pathogenesis but also has significant clinical implications with respect to treatment with checkpoint inhibitors. Additionally tumor infiltrating lymphocytes (TILs) are also emerging prognostic biomarker and are utilized in adoptive T-cell therapy as well. Methods: This is a retrospective cohort study of patients who were diagnosed with advanced unresectable non-colorectal GI (NCGI) cancers. Biopsy specimens of patients diagnosed between 2009 and 2015 at St. John Hospital and Medical Center were analyzed. Immunohistochemistry panels were performed on a representative tissue sections for microsatellite instability (MSI) testing. TILs were assessed on the hematoxylin and Eosin stained slide of the same tissue section. MSI was interpreted as stable or high and TILs were categorized as ≤5 and &gt; 5 per high power field. Descriptive statistics were generated using frequency distributions, medians and means. Kaplan-Meier analysis was performed to determine the impact of TILs and MSI on survival; differences by factor were assessed with the Log_Rank test. Results: We analyzed 114 patients; the mean age at diagnosis was 66.8 ± 10.7 years, 61.4% were male. All samples were MSI stable. The percentage of patients with TILs ≤ 5 was 46.5. When stratified by tumor stage, overall median survival by TILs level did not differ significantly. When stratified by type of tumor, overall median survival by TILs level was significantly different only for hepatocellular cancers (HCC) (≤ 5 TILs, 86 days vs. &gt; 5 TILs 312 days, p = 0.031) only, (see table). Conclusions: Our study shows that MSI-H tumors are very rare in advanced NCGI malignancies. TILs are definitely present in tumor microenvironment of NCGI malignancies. Though the number of patients of our study was small, there was a statistically significant difference in median overall survival of patients with HCC when stratified by TILs status.[Table: see text]

Frequency of Mismatch Repair Protein Deficiency in a Puerto Rican Population with Colonic Adenoma and Adenocarcinoma.

Microsatellite instability (MSI) results from genetic alterations involving the mismatch repair (MMR) genes MLH1, PSM2, MSH2, and MSH6. MSI has been implicated in both sporadic CRC and Lynch syndrome. The aim of the study was to assess the frequency of alterations in MMR protein expression in both primary colorectal cancer and precursor lesions among Puerto Rican patients. A retrospective study of 84 Puerto Rican patients was performed to assess the frequency of MMR protein expression alterations in both primary CRC and precursor lesions using tissue microarray and immunohistochemistry. The loss of expression of both MLH1 and PMS2 proteins was present in 6.3% of adenomas, 9.1% of adenomas with high-grade dysplasia and 9.4% of colon adenocarcinomas. Negative nuclear staining for both MSH2 and MSH6 proteins was found in 2.4% of colon adenocarcinomas. When compared to prior reports, this study suggests a lower frequency of MSI among the Puerto Rican population. The higher prevalence of MLH1 mutations correlates with previous studies of protein expression among the Hispanic community including Colombian, Uruguay and Brazilian populations.

Linking arsenite- and cadmium-generated oxidative stress to microsatellite instability in vitro and in vivo

Mismatch repair (MMR) corrects replicative errors and minimizes DNA damage that occurs frequently in microsatellites. MMR deficiency is manifested as microsatellite instability (MSI), which contributes to hypermutability and cancer pathogenesis. Genomic instability, including MSI and chromosomal instability, appears to be responsible for the carcinogenesis of arsenic and cadmium, common contaminants in our environment. However, few studies have addressed arsenic- or cadmium-induced MSI, especially its potential link with arsenic- or cadmium-generated oxidative stress, due to the lack of quantifiable MSI assays and cost-effective animal models. Here, using a dual-fluorescent reporter, we demonstrate that sub-lethal doses of cadmium or arsenite, but not arsenate, increased the MSI frequency in human colorectal cancer cells. Arsenite- and cadmium-induced MSI occurred concomitantly with increased levels of reactive species and oxidative DNA damage, and with decreased levels of MMR proteins. However, N-acetyl-l-cysteine (NAC) suppressed arsenite- and cadmium-induced MSI and oxidative stress while restoring the levels of MMR proteins in the cells. Similarly, MSI was induced separately by arsenite and cadmium, and suppressed by NAC, in zebrafish in a fluorescinated PCR-based assay with newly-developed microsatellite markers and inter-segmental comparisons. Of five selected antioxidants examined, differential effects were exerted on the MSI induction and cytotoxicity of both arsenite and cadmium. Compared to MMR-proficient cells, MMR-deficient cells were more resistant to arsenic-mediated and cadmium-mediated cytotoxicity. Our findings demonstrate a novel linkage between arsenite-generated and cadmium-generated oxidative stress and MSI induction. Our findings also caution that antioxidants must be individually validated before being used for preventing arsenite- and cadmium-induced MSI that is associated with cancer development.

Correlation between gastric carcinoma and ZAC gene-associated microsatellite instability and loss of heterozygosity.

The present study explored the association between loss of heterozygosity (LOH) or microsatellite instability (MSI) of the zinc finger regulator of apoptosis and cell-cycle arrest (ZAC) gene and the clinicopathological factors of gastric cancer. Samples of cancer and cancer-adjacent normal tissue from 30 patients with gastric cancer were collected. The genomic DNA was extracted from each and amplified with primers specific to ZAC microsatellite mutations, then run on a polyacrylamide gel for analysis. The CA197 microsatellite locus exhibited LOH in cancer sample 4. There was LOH in the 15AAAG locus in cancer sample 27 and cancer-adjacent tissue 23, and MSI at 15AAAG in cancer-adjacent tissue 27. There was MSI at the D6S1703 microsatellite locus in cancer-adjacent tissue 28. There was no LOH or MSI in the CA340 microsatellite locus in the gastric cancer or adjacent tissues analyzed. Thus, the frequency of LOH or MSI at ZAC gene-associated microsatellite loci for all patients was 13.3% (4/30). The present study has demonstrated that LOH and MSI events may contribute to the downregulation of ZAC; however, it is unlikely to be the primary cause, as it was only identified in 13.3% of cases.

Elucidation of the molecular and clinical impact of microsatellite instability in Brazilian colorectal cancer patients at Barretos Cancer Hospital.

e23185 Background: Colorectal cancer (CRC) has a high incidence and mortality in the world and in Brazil. The microsatellite instability (MSI) pathway is associated with a distinct mutational profile, which affects MSI target genes contributing to a different clinical impact. Reports have suggested that CRC aspects may be influenced by patients’ ancestry. This study aims to elucidate the molecular and clinical impact of MSI, and to determine Brazilian patients’ genetic ancestry. Methods: We enrolled 1013 patients. MSI was evaluated by molecular analysis, and MSI-H cases were further analyzed for alterations in 24 MSI-target genes, BRAF V600E, and MLH1 methylation. Genetic ancestry was evaluated by an AIMs panel. Results: MSI-H was observed in 10.5% of the cases. MSI-H cases were significantly associated with: right colon localization, staging II, absence of metastasis, mucinous histological type, III/undifferentiated histological grade, presence of synchronic tumor, no disease recurrence, and complete cure response. The most altered MSI target genes was HSP110, followed by ATM and EGFR. The frequency of BRAF V600E mutation was 26.4% and of MLH1 methylation was 72.3% in MSI-H cases. No significant overall survival (OS) differences were observed among the MSI statuses, neither when stratified by 5-FU treatments, nor by HSP110 mutational status. The average ancestry proportion was 74% of European, 12% of African, 7% of Native Americans, and 7% of East Asian. We observed that African ancestry is associated with increased chance of being MSI-H, and that in MSI-H cases, the lower the Asian ancestral component the greater the probability of patient survival. Conclusions: The MSI frequency of 10% identified in Brazilian CRC is in agreement with literature. MSI-H status was found correlated with clinic-pathological features associated with less aggressive tumors, although we did not find significant differences in patient’s OS. The European ancestral component was the most representative one, confirming population genetic studies. In conclusion, this study constituted the deepest and most extensive analyses of the MSI impact in the CRC Brazilian patients.

Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system

Background:Colorectal cancer (CRC) is a heterogeneous disease in terms of molecular carcinogenic pathways. Based on recent findings regarding the multiple serrated neoplasia pathway, we revised an eight-marker panel for a new CIMP classification system.Methods:1370 patients who received surgical resection for CRCs were classified into three CIMP subtypes (CIMP-N: 0–4 methylated markers, CIMP-P1: 5–6 methylated markers and CIMP-P2: 7–8 methylated markers). Our findings were validated in a separate set of high-risk stage II or stage III CRCs receiving adjuvant fluoropyrimidine plus oxaliplatin (n=950).Results:A total of 1287/62/21 CRCs cases were classified as CIMP-N/CIMP-P1/CIMP-P2, respectively. CIMP-N showed male predominance, distal location, lower T, N category and devoid of BRAF mutation, microsatellite instability (MSI) and MLH1 methylation. CIMP-P1 showed female predominance, proximal location, advanced TNM stage, mild decrease of CK20 and CDX2 expression, mild increase of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-P2 showed older age, female predominance, proximal location, advanced T category, markedly reduced CK20 and CDX2 expression, rare KRAS mutation, high frequency of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-N showed better 5-year cancer-specific survival (CSS; HR=0.47; 95% CI: 0.28–0.78) in discovery set and better 5-year relapse-free survival (RFS; HR=0.50; 95% CI: 0.29–0.88) in validation set compared with CIMP-P1. CIMP-P2 showed marginally better 5-year CSS (HR=0.28, 95% CI: 0.07–1.22) in discovery set and marginally better 5-year RFS (HR=0.21, 95% CI: 0.05–0.92) in validation set compared with CIMP-P1.Conclusions:CIMP subtypes classified using our revised system showed different clinical outcomes, demonstrating the heterogeneity of multiple serrated precursors of CIMP-positive CRCs.

No Change in Frequency of Microsatellite Instability in Colorectal Cancers over a Period of 15 or More Years

Microsatellite instability (MSI) is a molecular change resulting from inactivation of DNA mismatch repair systems, occurring with a reported incidence between 15% - 20% of all sporadic colorectal cancers. Our aim was to determine whether a change in the incidence of MSI in colorectal cancer had occurred at our institution over time. We assayed 106 cases from the mid-1990s and 69 cases from 15 or more years later for MSI. Those tumors with MSI were assayed for BRAF mutation and methylation. MSI was detected in 15 (14.2%) of the early cases and 11 (15.9%) of the later cases. For the two groups with MSI, a similar percentage was methylated and had a BRAF mutation. One tumor in each group was MSI, unmethylated, and BRAF wild type. Our data indicate consistency in the frequency of microsatellite unstable colorectal cancer across a time span of 15 or more years.

Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

ObjectiveHodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the...

Abstract 5013: A meta-analysis of MSI frequency and race in colorectal cancer

Abstract BACKGROUND: African Americans(AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in their tumors while others report lower frequency compared to Caucasians. AIM: To determine and evaluate the association of race and clinical factors with MSI rate through meta- analysis. METHODS: Twenty-two studies out of 15105 (1997-2015) were evaluated after a search in different literature databases, using keywords “colorectal cancer, microsatellite instability”. We used random effect meta-analysis to calculate the MSI frequency in all studies as well as in African American and Caucasian samples. Meta-regression analysis was used to assess the univariate effect of race, gender, age, tumor location and stage on MSI rate. RESULTS: The overall MSI frequency among CRCs was 17% (95%CI: 15%-19%, I2 = 91%). The MSI rate among racial groups were 12%, 12% and 14% in AAs, Hispanics and Caucasians respectively and was not significantly different. Sub-group analysis of studies with racial information indicates MSI OR (95% CI) of 0.78 (0.58-1.06) for AAs compared to Caucasians. CONCLUSION: CRCs demonstrate an MSI frequency of 17%. MSI frequency differences between AAs and Caucasians were not pronounced, suggesting other factors contribute to the racial disparity. There is a large variation in MSI rate between different studies. Methodology approaches and biological sources of this variation should be investigated. Citation Format: Hassan Ashktorab, Sadhna Ahuja, Lakshmi Kannan, Xavier Llor, Nathan Ellis, Rosa M. Xicola, Adeyinka O. Laiyemo, John M. Carethers, Hassan Brim, Mehdi Nouraie. A meta-analysis of MSI frequency and race in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5013.

High-risk and low-risk gastric cancer areas in Italy and its association with microsatellite instability.

The different pathological characteristics and prognoses between gastric cancer patients coming from high-risk (group A) and low-risk (group B) areas of Italy were analyzed. We investigated a suspected difference in microsatellite instability (MSI) between these two groups. MSI analyses of 452 gastric cancer patients were performed using five quasimonomorphic mononucleotide repeats NR-21, NR-24, NR-27, BAT-25, and BAT-26. MSI analysis was done by PCR usage. An allelic profile of these five mononucleotides was detected on an automated DNA sequencer ABI PRISM 3100 Genetic Analyser. Data were analyzed according to high-risk and low-risk gastric cancer areas. MSI was observed in 23.9% of all gastric cancer patients studied. Patients from group A showed a higher rate of MSI (28.4%) than from group B (13.5%) (p<0.001). We analyzed this association together with tumor location and Lauren classification: A nonsignificant differences were seen when analyzing cardia and non-cardia tumors (p=0.854) but significant for Lauren histotype (p=0.028). There was no statistical difference in survival between high-risk and low-risk areas (p=0.437), with a nonsignificant trend for better survival in the high-risk group, especially when measured over a longer period of time. Analyzing MSI or MSS in these groups, the survival curves were almost the same. A higher frequency of MSI in patients coming from high-risk areas may help explain geographical differences in gastric cancer. The trend of better survival in high-risk areas may be due to a higher rate of MSI gastric cancer patients.

A meta-analysis of MSI frequency and race in colorectal cancer.

PURPOSEAfrican Americans (AA) are at a higher risk of colorectal cancer (CRC) and some studies report a higher frequency of microsatellite instability (MSI) in this population while others report lower frequency compared to Caucasians.AIMTo determine and evaluate the association of race and clinical factors with MSI frequency through meta- analysis.METHODSTwenty-two studies out of 15,105 (1997-2015) were evaluated after a search in different literature databases, using keywords “colorectal cancer, microsatellite instability, African Americans, Caucasians and Hispanics”. We used random effect meta-analysis to calculate the MSI frequency in all studies as well as in African American and Caucasian samples. Meta-regression analysis was used to assess the univariate effect of race, gender, age, tumor location and stage on MSI frequency.RESULTSThe overall MSI frequency among CRCs was 17% (95%CI: 15%-19%, I²=91%). In studies with available race data, The MSI rate among AAs, Hispanics and Caucasians were 12%, 12% and 14% respectively and was not significantly different. Sub-group analysis of studies with racial information indicates MSI OR of 0.78 for AAs compared to Caucasians.CONCLUSIONCRCs demonstrate an overall MSI frequency of 17%. MSI frequency differences between AAs and Caucasians were not pronounced, suggesting that other factors contribute to the racial disparity. The methodological approaches and biological sources of the variation seen in MSI frequency between different studies need to be further investigated.

Microsatellite Instability as a Biomarker for PD-1 Blockade.

Initial results by Le and colleagues, which were published in the June 25, 2015 issue of the New England Journal of Medicine, report significant responses of cancers with microsatellite instability (MSI) to anti-PD-1 inhibitors in patients who failed conventional therapy. This finding fits into a broader body of research associating somatic hypermutation and neoepitope formation with response to immunotherapy, with the added benefit of relying on a simple, widely used diagnostic test. This review surveys the pathogenesis and prognostic value of MSI, diagnostic guidelines for detecting it, and the frequency of MSI across tumors, with the goal of providing a reference for its use as a biomarker for PD-1 blockade. MSI usually arises from either germline mutations in components of the mismatch repair (MMR) machinery (MSH2, MSH6, MLH1, PMS2) in patients with Lynch syndrome or somatic hypermethylation of the MLH1 promoter. The result is a cancer with a 10- to 100-fold increase in mutations, associated in the colon with poor differentiation, an intense lymphocytic infiltrate, and a superior prognosis. Diagnostic approaches have evolved since the early 1990s, from relying exclusively on clinical criteria to incorporating pathologic features, PCR-based MSI testing, and immunohistochemistry for loss of MMR component expression. Tumor types can be grouped into categories based on the frequency of MSI, from colorectal (20%) and endometrial (22%-33%) to cervical (8%) and esophageal (7%) to skin and breast cancers (0%-2%). If initial results are validated, MSI testing could have an expanded role as a tool in the armamentarium of precision medicine.