MSI Group Research Articles

Resectable gastric cancer: should we apply a tailored surgical strategy according to microsatellite status?

BackgroundMicrosatellite instability (MSI-H) represents a small subgroup of gastric cancer (GC) with a favorable prognostic and predictive significance. This study aimed to investigate locoregional nodes involvement, overall survival (OS) and disease-free survival (DFS), and the interplay between molecular subtypes and histological profiles in relation to survival outcomes in MSI versus MSS GC. MethodsThis study included 72 GC patients treated with surgery with or without chemotherapy from 2017 to 2023. Clinicopathological characteristics, OS and DFS were compared between LN-positive and negative patients, stratified by microsatellite status, treatments, molecular profiles, tumor cell types. ResultsMSI GC was more common in older patients (79.0 versus 70.2 years, p<0.001), predominantly females (73.68% vs. 43.32%, p=0.023), and associated with intestinaltype histology (94.5% vs. 49%, p=0.002). Positive LN and lymphovascular invasion were lower in the MSI group (2.73 vs. 4.15 p=0.366; 36.8% vs. 64.5% p=0.039). MSI showed slightly better OS and DFS (84.2% vs. 66% p=0.108; 84.62% vs. 63.89% p=0.120). MSI GC also had improved OS and DFS in both LNs positive (OS 72.7% vs. 61.3% p=0.255; DFS 75% vs. 50% p=0.148) and LNs negative groups (OS 100% vs. 85.7% p=0.149; DFS 100% vs. 85.7% p=0.376). In patients not receiving chemotherapy, MSI/intestinal-type had the highest OS and DFS (77% and 87.5%), whereas MSS/mixed-type group had the poorest (25% and 100%)(p=0.024 and p=0.290). With chemotherapy, MSI/intestinal-type had the highest OS and DFS (100% and 100%), whereas MSS/mixed-type group had the poorest (66.7% and 50%)(p=0.741 and p=0.397, respectively). ConclusionsMSI GCs have a significantly lower risk of locoregional lymph node involvement and better OS and DFS compared to MSS tumors. Secondly, treatment responses diverge based on MSI status: patients with MSI tumors benefit more from upfront surgical interventions, while those with MSS, particularly mixed histotypes, demonstrate improved outcomes with preoperative chemotherapy. These results advocate for a tailored therapeutic approach that considers microsatellite status, Lauren classification as well as clinical conditions of patients.

Prognostic significance of microsatellite instability in patients with resectable gastric cancer

BackgroundMicrosatellite instability (MSI) gastric cancer (GC) generally has a better prognosis than microsatellite-stable (MSS) GC and has been associated with nonsurvival benefit with the addition of chemotherapy (CMT) compared with surgery alone. However, patients with MSI have distinct clinicopathological characteristics. This study aimed to compare the survival outcomes between patients with MSI GC and those with MSS GC. In addition, this study analyzed the survival outcomes of patients with MSI GC who received CMT. MethodsThis study reviewed all patients with GC who underwent curative gastrectomy. Patients were divided into MSI group and the MSS group. Propensity score matching (PSM) was used to match clinicopathological factors. ResultsAmong the 378 patients enrolled, 78 (20.6%) had MSI. Older age (P < .001), subtotal gastrectomy (P = .008), pN0 (P = .020), and earlier pTNM stage (P = .012) were associated with MSI GC. Survival analysis showed better disease-free survival (DFS) and overall survival (OS) of patients in the MSI group (P = .012 and P = .019, respectively). After PSM, 78 patients were matched to each group. All variables assigned to the scores were well matched, and both groups became equivalent. After the matching, the differences in DFS and OS according to MSI/MSS status were estimated to be larger than before (DFS: 63.3% vs 41.4%; P = .002; OS: 65.8% vs 42.5%; P = .002). Regarding patients referred for CMT, there was no difference in DFS and OS between patients with MSI GC who underwent CMT and those who underwent surgery alone (P = .255 and P = .178, respectively). ConclusionEven after controlling for clinicopathological characteristics, MSI was identified as a prognostic factor for patient survival. MSI GC showed no significant survival benefit with the addition of CMT.

Abstract 3084: Aldob regulates fructose metabolism to confer ferroptosis and immune response in colorectal cancer harboring microsatellite instability

Abstract Microsatellite instability (MSI) is a genetic alteration that occurs during cancer progression, specifically in colorectal cancer. Objective evidence demonstrates that colorectal cancer patients with MSI have better survival rates than those without MSI. Moreover, patients with both dMMR and MSI respond equally well to immunotherapy. We evaluated the MSI status of colorectal cancer specimens and identified an activation of aldolase B (ALDOB), the primary regulator of fructose metabolism, in the MSI group. Our analysis of the cancer cell panel revealed that the expression level of ALDOB in MSI+ cells (HCT116 and LoVo) was significantly higher than that in the microsatellite stable (MSS) group (SW480 and HT29). We also discovered a significant negative correlation between ALDOB and numerous dMMR-related genes, such as MLH1 and MSH2. We investigated how fructose concentration and pathway activation affected MSI occurrence. Our results demonstrated that abnormal fructose metabolism leaded to SLC7A11-mediated ferroptosis. SLC7A11 functioned as the active subunit and generated glutathione, GPX4, and lipid epoxides in response to transported cystine. This may explain the better clinical outcomes observed in colorectal patients with MSI. On the other hand, we also observed that ALDOB could increase certain immune ratios, such as CD4+ T cells and B cells. This aligns with the implementation of immunotherapy in the MSI community, which has been proven to yield positive effects. Consistent results were still being shown. Our study revealed significant increases in various chemokines and cytokines in media conditioned with fructose. It was interesting to note that fructose resulted in more significant changes than glucose. Based on the gathered evidence, it could be posited that ALDOB plays a crucial role as a promoter of fructose metabolism, leading to the induction of ferroptosis and immune responses in MSI colorectal cancer. The findings shed new light on known consequences and provide new avenues of information. Citation Format: Yu-Chan Chang, Chi-Long Chen. Aldob regulates fructose metabolism to confer ferroptosis and immune response in colorectal cancer harboring microsatellite instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3084.

Analysis of clinicopathological features and prognosis of sporadic synchronous multiple primary colorectal cancers

Analysis of clinicopathological features and prognosis of sporadic synchronous multiple primary colorectal cancers

Relationship between molecular markers and lymphadenectomy and lymphovascular space invasion in endometrial cancer.

Relationship between pathologic parameters, surgical parameters, or lymph node status with oncologic outcomes is not fully elucidated in endometrial cancer (EC). We want to investigate the molecular classification of uterine cancer in the Turkish population and its relationship between lymphadenectomy and lymph node metastasis. In this study, 100 patients' clinical and pathologic data diagnosed with EC were analyzed. Pathologic and molecular parameters were investigated and compared them with clinical parameters. According to the molecular analysis, 16 patients (16%) had p53 mutation, 3 patients (3%) were classified as POLE mutant group, 38 (38%) patients in the MSI group, and the remaining 43 patients (43%) into the no specific mutation profile (NSMP) group. Lymph node metastasis rate was significantly higher in copy number high (CNH) group compared to the others. In the CNH group, 29 of 437 (6.6%) dissected lymph nodes had metastasis. The median OS was the highest in the POLE group (72months) and lowest in the CNH group (36months). Endometrial cancer patients showed significantly different overall and disease-free survival according to the molecular subtypes and it was consistent with the literature, Lymph node metastasis risk was the highest in CNH group. MSI status is important for the lymph node metastasis risk but not all abnormalities, especially PMS2 and MLH1 expression changes showed the highest risk.

Prognostic significance and immune landscape of a fatty acid metabolism-related gene signature in colon adenocarcinoma.

Background: Fatty acid metabolism (FAM), as a hallmark of caner, plays important roles in tumor initiation and carcinogenesis. However, the significance of fatty acid metabolism-related genes in colon adenocarcinoma (COAD) are largely unknown. Methods: RNA sequencing data and clinical information were downloaded from the Cancer Genome Atlas (TCGA) cohort. Univariate and multivariate Cox regression analyses were utilized to construct a fatty acid metabolism-related gene signature. Kaplan-Meier survival and receiver operating characteristic (ROC) analyses were used to verify the performance of this signature. GEO datasets were applied to validate the signature. Maftools package was utilized to analyze the mutation profiles of this signature. Correlation between the risk signature and stemness scores was compared by RNA stemness score (RNAss). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set variation analysis (GSVA) were performed to explore the potential functions and signaling pathways. Immune landscape of the signature was explored by analyzing different immune cells infiltration, immune functions and microsatellite instability. A nomogram was constructed by combining the risk signature and multiple clinical factors. Expression levels and prognostic values of the risk genes were revealed in the cancer genome atlas and GEO databases. Moreover, the expression the risk genes were measured in cell lines using real time quantitative PCR (qRT-PCR). Results: Eight fatty acid metabolism-related genes (CD36, ENO3, MORC2, PTGR1, SUCLG2, ELOVL3, ELOVL6 and CPT2) were used to construct a risk signature. This signature demonstrated better prognostic value than other clinicopathological parameters, with AUC value was 0.734 according to the cancer genome atlas database. There was negative correlation between the riskscore and RNA stemness score. The patients in the high-risk group demonstrated higher infiltration of M0 macrophages, and less infiltration of activated CD4 memory T cells and Eosinophils. There were more MSI patients in the high-risk group than those in the low-risk group (38% vs. 30%). The risk scores of patients in the MSI group were slightly higher than those in the microsatellite stability group. Gene ontology, kyoto encyclopedia of genes and genomes and gene set variation analysis enrichment analyses showed that several metabolism-related functions and signaling pathways were enriched. A nomogram showed good predictive capability of the signature. Moreover, qRT-PCR revealed upregulated expression of ENO3, MORC2, SUCLG2 and ELOVL6, and downregulated expression of CPT2 in all examined colon adenocarcinoma cell lines. Conclusion: This study provided novel insights into a fatty acid metabolism-related signature in the prognosis an immune landscape of colon adenocarcinoma patients.

558P Molecular subtyping endometrial carcinoma in Chinese population applying an NGS-based classifier and its association with prognosis

Molecular subtypes of EC is widely recognized and applied in clinics. While, it is still less recognized the distribution and prognostic value of molecular subtypes of endometrial carcinoma in Chinese population. An NGS-based classification strategy with reference to these two classifiers was developed and applied for the first time to explore the prognostic correlation of EC patients in China. Formalin-Fixed Paraffin Embedded (FFPE) tissue of 233 EC patients were retrospectively collected from Qilu Hospital, China. Genomic DNA was extracted and subjected to an all-in-one simplified NGS panel covering POLE, TP53 as well as MSI for subtyping. The information for ProMisE classification were also collected. With the median follow-up was 66 (range 7-122) months, overall survival (OS) and disease-specific survival (DSS) were also been analyzed across the subtypes. Base on NGS panel classification, the fractions of POLE, MSI, CNH and CNL group were 8.15%, 18.88%, 11.59% and 61.37%, respectively. 61patients with ProMisE classification available, the fractions of the former subtypes were11.48%, 36.07%, 14.75%, and 37.70% respectively. The OS and DSS was (P=0.046 for OS, P=0.024 for DSS) significantly in the four subtypes based on NGS testing in 131 followed patients. There was no significant difference in OS (P = 0.91) and DSS (P = 0.95) across the four subtypes by ProMisE in 50 followed patients (Table).Table: 558PSurvival analysis results based on the two classifiersNGS-based classifier（N=131）POLEMSICNHCNLP8 years -OS rate100%80.00%50.00%92.26%0.0468 years -DSS rate100%88.89%66.67%100%0.024ProMisE classifier (N=50)8 years -OS rate83.33%89.47%100%80.00%0.918 years -DSS rate100%94.73%100%92.31%0.95 Open table in a new tab The NGS-based strategy was confirmed to effectively classify four prognostically significant subgroups in endometrial cancer patients. Further analysis showed that the clinicopathological features of each molecular subtype were significantly different. All the results confirmed the feasibility of molecular subtyping of EC in clinical practice by a simplified NGS approach.

Contrast-Enhanced CT Texture Analysis in Colon Cancer: Correlation with Genetic Markers.

Background: The purpose of the study was to determine whether contrast-enhanced CT texture features relate to, and can predict, the presence of specific genetic mutations involved in CRC carcinogenesis. Materials and methods: This retrospective study analyzed the pre-operative CT in the venous phase of patients with CRC, who underwent testing for mutations in the KRAS, NRAS, BRAF, and MSI genes. Using a specific software based on CT images of each patient, for each slice including the tumor a region of interest was manually drawn along the margin, obtaining the volume of interest. A total of 56 texture parameters were extracted that were compared between the wild-type gene group and the mutated gene group. A p-value of <0.05 was considered statistically significant. Results: The study included 47 patients with stage III-IV CRC. Statistically significant differences between the MSS group and the MSI group were found in four parameters: GLRLM RLNU (area under the curve (AUC) 0.72, sensitivity (SE) 77.8%, specificity (SP) 65.8%), GLZLM SZHGE (AUC 0.79, SE 88.9%, SP 65.8%), GLZLM GLNU (AUC 0.74, SE 88.9%, SP 60.5%), and GLZLM ZLNU (AUC 0.77, SE 88.9%, SP 65.8%). Conclusions: The findings support the potential role of the CT texture analysis in detecting MSI in CRC based on pre-treatment CT scans.

Prognostic significance of myocardial salvage assessed by cardiac magnetic resonance in reperfused ST-segment elevation myocardial infarction.

AimsMyocardial salvage index (MSI) is attracting increasing attention for predicting prognosis in acute myocardial infarction (AMI); however, the evaluation of MSI is mainly based on contrast agent-dependent cardiac magnetic resonance (CMR) scanning sequences. This study aims to investigate the prognostic value of MSI in reperfused ST-segment elevation myocardial infarction (STEMI) through the contrast agent-free CMR technique.Methods and resultsNighty-two patients with acute STEMI, who underwent CMR after primary percutaneous coronary intervention (PPCI), were finally enrolled. Patients were subcategorized into two groups according to median MSI. T1 and T2 mapping were conducted for measuring infarct size (IS) and area at risk (AAR). IS was significantly larger in < median MSI group than ≥ median MSI group (P < 0.001). AAR between the two groups showed no obvious differences (P = 0.108). Left ventricular ejection fraction (LVEF) was lower in < median MSI group than ≥ median MSI group (P = 0.014). There was an obvious inverse correlation between MSI and reperfusion time (R = –0.440, P < 0.001) and a strong inverse correlation between MSI and IS (R = –0.716, P = 0.011). As for the relationship LVEF, MSI showed positive but weak correlation (R = 0.2265, P < 0.001). Over a median follow-up period of 263 (227–238) days, prevalence of MACEs was significantly higher in the < median MSI group [HR: 0.15 (0.04–0.62); Log-rank P = 0.008]. The univariate Cox regression analysis revealed that LVEF, IS, and MSI were significant predictors for major adverse cardiovascular events (MACEs) (all P < 0.05). In the stepwise multivariate Cox regression analysis, LVEF and MSI were identified as independent parameters for predicting MACEs (both P < 0.05). In the receiver-operating characteristic analysis, LVEF, IS, and MSI showed prognostic value in predicting MACEs with AUCs of 0.809, 0.779, and 0.896, respectively, all (P < 0.05). A combination of MSI with LVEF showed the strongest prognostic value of MACEs (AUC: 0.901, sensitivity: 77.78%, specificity: 98.80%, P < 0.001). Delong’s test showed that the combination of LVEF with MSI had an incremental value than LVEF itself in predicting MACEs (P = 0.026).ConclusionContrast agent-free CMR technique provides a reliable evaluation of MSI, which contributes to assessing the efficacy of reperfusion therapy and predicting the occurrence of MACEs.

Microsatellite instability is associated with worse overall survival in resectable colorectal liver metastases

BackgroundMicrosatellite instability (MSI) has been associated with improved overall survival (OS) in locoregional colorectal cancer; however, the effects on colorectal liver metastases (CRLM) have not been studied. MethodsThe National Cancer Database (NCDB) was queried for patients with CRLM that underwent metastasectomy. Patients with microsatellite stable tumors (MSS) (n = 2,316, 84.4%) were compared those with MSI (n = 427, 15.6%). ResultsBaseline characteristics, including sex, race, and underlying comorbidities, were similar between groups. MSS patients had lower rates of high-risk pathologic features and higher rates of receiving multi-agent chemotherapy. On Kaplan-Meier analysis, median OS in the MSS group was improved compared with the MSI group (41.1 mo vs. 33.2 mo, p < 0.01). On multivariate analysis MSI status remained associated with worse OS (HR: 1.21 95% CI: 1.01–1.46, p = 0.04). ConclusionsThis national analysis of CRLM validates MSI status as a biomarker to guide clinical decision-making due to the associated poor prognosis.

Homologous recombination deficiency is linked to shorter survival expectancy in late-stage colorectal cancer.

e15576 Background: Colorectal cancer patients with high-level microsatellite instability (MSI-H) benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers to predict their prognosis. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients’ overall survival. Methods: We used whole-exome sequencing (WES) to analyze 99 colorectal cancer samples. The patients were further classified into different groups based on their microsatellite status (MS), homologous recombination deficiency (HRD) score, as well as other clinical characteristics, which might associate with clinical outcomes. Afterward, survival analysis and stratification analysis were performed to explore the significant prognosis and predictive indicators in each group. Additionally, we assessed somatic genomic lesions, copy number aberrations, and mutational pathway, and analyzed the differential genetic patterns in distinct clinical benefit groups. Results: The multivariate Cox regression analysis proved that HRD score was associated with significant OS (HR 0.19, 95% CI 0.12-0.94, p = 0.002), suggesting HRD are prognostic factors for late stage CRC. Therefore, the patients were classified into two subgroups according to the value of the HRD scores (HRD-high vs HRD-low). For comparison, the prominent difference was observed in the somatic mutations and copy number alterations (SCNAs). Our results showed TP53 (78%) , APC (50%) and KRAS (41%) as the most frequently cancer-related mutations in CRC, consistent with previous studies. In patients with MSS group, the SMAD4 mutation was occurred frequently (p &lt; 0.01), as well as a distinctive pattern of chromosomal amplification in HRD-high group patients. However, in patients with MSI group, none significant mutations were observed in HRD-high and HRD-low groups. Conclusions: We integrated HRD statue as prognosis and predictive factors for late stage CRC as determined using WES sequencing. Moreover, we also provide a comprehensive differential genetic pattern in stratification of CRC patients, as well as underscore an importance of combining strategy for molecular diagnosis of CRC.

Shock index and modified shock index are predictors of long-term mortality not only in STEMI but also in NSTEMI patients

Background Shock index (SI) and modified shock index (mSI) are useful instruments for early risk stratification in acute myocardial infarction (AMI) patients. They are strong predictors for short-term mortality. Nevertheless, the association between SI or mSI and long-term mortality in AMI patients has not yet been sufficiently examined. Material and methods For this study, a total of 10,174 patients with AMI was included. All cases were prospectively recorded by the population-based Augsburg Myocardial Infarction Registry from 2000 until 2017. Endpoint was all-cause mortality with a median observational time of 6.5 years [IQR: 3.5–7.4]. Using ROC analysis and calculating Youden-Index, the sample was dichotomized into a low and a high SI and mSI group, respectively. Moreover, multivariable adjusted COX regression models were calculated. All analyses were performed for the total sample as well as for STEMI and NSTEMI cases separately. Results Optimal cut-off values were 0.580 for SI and 0.852 for mSI (total sample). AUC values were 0.6382 (95% CI: 0.6223–0.6549) for SI and 0.6552 (95% CI: 0.6397–0.6713) for mSI. Fully adjusted COX regression models revealed significantly higher long-term mortality for patients with high SI and high mSI compared to patients with low indices (high SI HR: 1.42 [1.32–1.52], high mSI HR: 1.46 [1.36–1.57]). Furthermore, the predictive ability was slightly better for mSI compared to SI and more reliable in NSTEMI cases compared to STEMI cases (for SI and mSI). Conclusion High SI and mSI are useful tools for early risk stratification including long-term outcome especially in NSTEMI cases, which can help physicians to make decision on therapy. NSTEMI patients with high SI and mSI might especially benefit from immediate invasive therapy. Key messages Shock index and modified shock index are predictors of long-term mortality after acute myocardial infarction. Both indices predict long-term mortality not only for STEMI cases, but even more so for NSTEMI cases.

Predictive Value of Metabolic Parameters Derived From 18F-FDG PET/CT for Microsatellite Instability in Patients With Colorectal Carcinoma.

BackgroundMicrosatellite instability (MSI) is one of the important factors that determine the effectiveness of immunotherapy in colorectal cancer (CRC) and serves as a prognostic biomarker for its clinical outcomes.PurposeTo investigate whether the metabolic parameters derived from18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) can predict MSI status in patients with CRC.Materials and MethodsA retrospective analysis was performed on CRC patients who underwent 18F-FDG PET/CT examination before surgery between January 2015 and April 2021. The metabolic 18F-FDG PET/CT parameters of the primary CRC lesion were calculated and recorded with different thresholds, including the maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean), as well as the metabolic tumor volume (MTV) and the total lesion glycolysis (TLG). The status of MSI was determined by immunohistochemical assessment. The difference of quantitative parameters between MSI and microsatellite stability (MSS) groups was assessed, and the receiver operating characteristic (ROC) analyses with area under ROC curves (AUC) was used to evaluate the predictive performance of metabolic parameters.ResultsA total of 44 patients (24 men and 20 women; mean ± standard deviation age: 71.1 ± 14.2 years) were included. There were 14 patients in the MSI group while there were 30 in the MSS group. MTV30%, MTV40%, MTV50%, and MTV60%, as well as TLG50% and TLG60% showed significant difference between two groups (all p-values <0.05), among which MTV50% demonstrated the highest performance in the prediction of MSI, with an AUC of 0.805 [95% confidence interval (CI): 0.657–0.909], a sensitivity of 92.9% (95% CI: 0.661–0.998), and a specificity of 66.7% (95% CI: 0.472–0.827). Patients’ age and MTV50% were significant predictive indicators of MSI in multivariate logistic regression.ConclusionThe metabolic parameters derived from18F-FDG PET/CT were able to preoperatively predict the MSI status in CRC, with MTV50% demonstrating the highest predictive performance. PET/CT imaging could serve as a noninvasive tool in the guidance of immunotherapy and individualized treatment in CRC patients.

Abstract 2523: Novel genomic characterization in late stage colorectal cancer

Abstract Introduction: Colorectal cancer patients with high-level microsatellite instability benefit more from immune checkpoint inhibitor therapy, but they only account for around 15% of all colorectal cancer patients. The remaining patients are still lack of effective therapeutic biomarkers. For patients in late stage without optimal treatment, it is essential to find novel biomarkers which can be used to select appropriate therapies and therefore improve patients' overall survival. Methods: We used whole-exome sequencing to analyze 114 colorectal cancer samples. The samples included 86 primary late stage tumors and 28 metastatic tumors from liver, lung and other organs. The primary samples were further divided into different groups based on their tumor location (sideness) and microsatellite status (MS) since these indications are of great significance in clinical presentation and treatment. We then assessed somatic genomic lesions, copy number variations, germline gene alterations and mutational signatures in the above three pairs of comparisons respectively (primary vs. metastatic, right- vs. left-sided, MS instable vs. stable). Results: There were significant differences between the analyzed pairs. For the primary and metastatic samples, the most prominent difference was the copy number variation which happened in 25 genes in the metastatic samples and only one gene in the primary samples (gain of IL12) (p = 0.036). For the right- and left-sided comparison, SNP/Indel mutations were the most prominent. They happened more frequently in the right-sided than the left-sided tumors and those are rare genes in colorectal cancer, including BCL11A (p = 0.018), DICER1 (p = 0.038), NR4A3 (p = 0.004), NIN (p = 0.008) and FBXW7 (p = 0.019). For the MSI-MSS comparison, tumor mutation burden (TMB) stands out high in the MSI group compared to the MSS group (p &amp;lt; 0.0001). In addition, dozens of significantly mutated genes were observed in the MSI samples (p &amp;lt; 0.0001), such as KMT2B, ACVR2A, KMT2D, ASXL1, TCF7L2 and etc. However, TP53 occurred mainly in the MSS patients (p = 0.0007). Conclusion: Our study enables a deeper understanding of the genomic characterization of colorectal cancer from an integrated view. Copy number variations, gene mutations, and TMB were found to be the most significant differences between the comparison groups of primary vs. metastatic samples, left vs. right sided samples, and MSI vs. MSS samples respectively. Genomic differences between metastatic and primary samples may be potential therapeutic targets for metastatic colorectal cancer. Citation Format: Jianxia Li, Qianchao Wu, Jianwei Zhang, Huabin Hu, Yue Cai, Jiayu Lin, Jun Liu, Yanhong Deng. Novel genomic characterization in late stage colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2523.

Clinicopathologic characteristics of distinct molecular subtypes of endometrial carcinoma in Chinese population.

e17568 Background: Stratifying endometrial carcinoma (EC) based on molecular profiling is of importance. While, spectrum of molecular subtypes of EC in Chinese population needs to be elucidated. Conventional approaches involve methodologies including Sanger sequencing as well as immunohistochemistry which is highly dependent on experience of pathologists. This study is of first time to display clinical and pathological characters of molecular subtypes of EC which were defined by a simplified NGS panel in Chinese population. Methods: Paraffin-embedded tissues of 135 consented EC patients were retrospectively collected from Qilu Hospital, Shandong Province, China. Genomic DNA was extracted and subjected to a simplified panel covering POLE, TP53 as well as 55 MSI loci for massive parallel sequencing. Mutations annotated as Tier I, II were applied for subtyping. MSI was defined as instability in 22 or more microsatellite loci. Subtypes were stratified as POLE, MSI, TP53-wt or TP53-mut group. Correlations of clinicopathological characters as well as prognosis were further conducted. Results: Histology of collected samples were mostly Endometrioid EC (EEC, 93.33%). Most of samples were at stage I (80%). The fractions of POLE (n=10), MSI (n=29), TP53-wt (n=84) and TP53-mut (n=12) group were 7.41%, 21.48%, 62.22%, and 8.89%, respectively. POLE group was associated with earlier stage (Stage I, 90%), EEC (80%) and less lympho-vascular space invasion (LVSI) (10%). TP53-mutant subtype was correlated to later stage (Stage II-IV, 41.67%), higher grade (G2+G3, 83.33%), serous histology (25%) and higher rate of LVSI (25%). The median follow-up was 74 (1.5-122) months. The 8-year overall (OS) and disease-specific survival (DSS) rate were 100% in POLE group, while only 58.3% and 75% in TP53 mutant cases (P&lt;0.001 for OS, P=0.01 for DSS). Conclusions: Molecular subtypes of EC significantly correlated with clinicopathologic characters, especially with patients’ prognosis. This simplified NGS-panel could accurately delineate different EC subgroups.[Table: see text]

In Vitro Comparison between Metal Sleeve-Free and Metal Sleeve-Incorporated 3D-Printed Computer-Assisted Implant Surgical Guides.

The present study aims to compare the accuracy of metal sleeve-free 3D-printed computer-assisted implant surgical guides (MSF group) (n = 10) with metal sleeve-incorporated 3D-printed computer-assisted implant surgical guides (MSI group) (n = 10). Implants of diameter 4.0 mm and 5.0 mm were placed in the left second premolars and bilateral first molars, respectively, using a fully guided system. Closed-form sleeves were used in teeth on the left and open-form sleeves on the right. The weight differences of the surgical guides before and after implant placement, and angular deviations before and after implant placement were measured. Weight differences were compared with Student’s t-tests and angular deviations with Mann–Whitney tests. Cross-sectional views of the insert parts were observed with a scanning electron microscope. Preoperative and postoperative weight differences between the two groups were not statistically significant (p = 0.821). In terms of angular deviations, those along the mesiodistal direction for the left second premolars were significantly lower in the MSF group (p = 0.006). However, those along the mesiodistal direction for the bilateral molars and those along the buccolingual direction for all teeth were not significantly different (p > 0.05). 3D-printed implant surgical guides without metal sleeve inserts enable accurate implant placement without exhausting the guide holes, rendering them feasible for fully guided implant placement.

Abstract 5293: A molecular classification of gastric cancer in Chilean patients

Abstract Objective: Incidence and mortality rates of gastric cancer (GC) are characterized by their geographical heterogeneity. In Chile, GC is the leading cause of cancer death. To date, GC patients' response to standard therapies remains limited. A molecular classification of GCs may deliver better stratifications. Herein, we obtained clinical data, protein expression and genetic profiles in a cohort of Chilean patients and present a molecular classification that correlated with overall survival (OS) rates. Methods: A total of 71 patients were included. Clinical data were obtained from medical records; protein expression was analyzed by a Tissue MicroArray. We also performed Next Generation Sequencing to assess p53 status (WT or Mut). Supervised clustering was used to generate a molecular classification. Kaplan-Meier method was used to calculate OS. Hazard ratio was calculated by Cox regression. Results: We defined 5 GC subgroups: Epstein-Barr virus+ (EBV, n=9; 13%), Microsatellite Instable (MSI, n=9; 13%), E-cadherin loss (EMT-like, n=12; 17%). The remaining patients (those MSS-/EBV-/not EMT-like) were classified either as p53 WT (n=21; 30%) or p53 Mutated (n=20; 28%). According to subgroups, 5-year survival rates were: MSI=77,8%; EBV=43.2%; p53WT=43.5%; p53Mut=25% and EMT-like=16.7%. Hazard ratios for p53Mut and EMT-like were 5.1 (IC 95%: 1.16-22.41; p=0.031) and 6.81 (IC 95%: 1.48-31.24; p=0.014), respectively against the MSI group used as reference. This association is maintained in a multivariate model using age, gender and stage. Conclusions: Our study defined 5 GC subgroups. These are associated to OS rates. EMT-like and p53Mut subgroups displayed poorer survival. Future studies should explore actionable targets in these subsets in order to improve their survival. Citation Format: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido. A molecular classification of gastric cancer in Chilean patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5293.

Abstract 47: Mutation in homologous recombination as a prognostic factor independent of TCGA molecular subtypes in endometrial cancer

Abstract Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 529 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 62 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.47; 95% CI, 0.28-0.79; P &amp;lt;0.05), progression-free survival (PFS) (HR, 0.50; 95% CI, 0.35-0.72; P &amp;lt;0.05) and overall survival (OS) (HR, 0.48; 95% CI, 0.31-0.73; P &amp;lt;0.05) in endometrial cancers. HR mutation was related with clinical characteristics including FIGO stage (P&amp;lt;0.05), tumor grade (P&amp;lt;0.05) and histological types (P&amp;lt;0.05). HR mutation was enriched in MSI (hypermutated) group (49%) and copy-number low group (19.6%). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, the association between HR mutation and PFS was still significant (HR, 0.22; 95% CI, 0.05-0.88; P = 0.03), which indicating the HR mutation is an independent prognostic factor for PFS. Gene set enrichment analysis suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. Conclusion: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications Citation Format: Luyang Zhao, Yibo Dai, Yuanjing Hu, Zhiqi Wang, Chengcheng Li, Guoqiang Wang, Jianliu Wang. Mutation in homologous recombination as a prognostic factor independent of TCGA molecular subtypes in endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 47.

Multisite Injection of Bioengineered Hepatic Units from Collagen Hydrogel and Neonatal Liver Cells in Parenchyma Improves Liver Cirrhosis.

Intrahepatic transplantation of hepatocytes/progenitor cells remodels or repopulates livers resulting in improved hepatic function, which represents a promising treatment option for liver diseases, but poor engraftment of transplanted liver cells in livers has been the major obstacle for exerting therapeutic efficacy on liver diseases. We herein demonstrated great potential of multisite injection of bioengineered hepatic units generating from collagen hydrogel and neonatal liver cells (MSI) in promoting engraftment, survival of liver cells, and the therapeutic potential of liver diseases in livers. The MSI allowed transplantation of large number of liver cells into parenchyma in one time. Superiorly, the MSI promoted the engraftment and survival of liver cells, and generated large, dispersively distributed tissue masses whose sizes were positively correlated with the number of injection sites in livers. Consistently, the MSI improved liver cirrhosis as evidenced by the reduction of collagen matrix deposit, improved liver architecture, and hepatic function in the MSI group compared to that of the nontreated control. These data indicate that the MSI represents a novel, improved bioengineered strategy that can exert therapeutic efficacy on liver diseases.

F145. Characterization of surround inhibition and SICI in the motor cortex by TMS-EEG

Short-latency cortical inhibition (or SICI) is mediated by GABA-A inhibition and can be investigated with paired pulses TMS. Motor surround inhibition (mSI) is supportive for the execution of selective finger movements. When TMS is delivered at movement onset, the motor evoked potential (MEP) recorded from a “surround” muscle that does not act as a synergist is reduced. TMS evokes cortical potentials that can be recorded by EEG (TEP). Past studies suggested that cortical GABA-A mediated inhibition may modulate TEP components of up to 45 ms latency, while component at 100 ms may be a marker of GABA-B inhibition. In this TMS-EEG exploratory study, we investigated the cortical correlates of SICI and mSI in healthy subjects. We enrolled 17 right handed healthy volunteers (HVs). EMG was recorded from the first dorsal interosseous (FDI) and from the abductor digiti minimi (ADM). EEG was recorded from a 32 channel cap. TMS was delivered on the ADM hotspot, using S50 as the intensity for the TS and 80% of the resting motor threshold (RMT) as the CS. HVs were asked to press with the index finger. Three randomized conditions were tested (100 trials each): single pulse at rest (SP); SP at movement onset (index finger flexion 3 s after a tone) (Mov); paired pulses at rest (ISI: 2 ms) (PP). ADM MEPs were measured to calculate SICI (PP/SP) and mSI (Mov/SP). HVs were divided in a mSI and in a NO_mSI group using a cut-off value of 0.8. Average TEPs were calculated for each condition and for 5 predetermined regions of interest (ROI) on the scalp. Peak-to-peak amplitudes of P30, N45, P60, N100 and P180 were measured in each condition-ROI. Mixed design repeated-measures ANOVA was used for statistical analysis with factors Group, Condition, Component, and ROI EMG analysis showed that all but one subject showed SICI. 10 HVs showed mSI, 7 HVs were classified as NO_mSI. TEPs on the sensorimotor cortex showed that SICI was associated with a reduction in the excitatory components P30 and P60, and an increase in the inhibitory component N45. When all HVs were considered, movement onset was associated with a widespread N100 and P180 reduction, and a P30 reduction of the non-stimulated sensorimotor cortex. Movement-induced TEP modulation was different in people with and without mSI. Only in people with mSI, movement onset was associated with a P30 and P60 reduction and N45 increase of the stimulated sensorimotor cortex At the level of sensorimotor cortex, SICI and mSI are associated with a similar modulation of cortical excitability that occurs in the first 60 ms after TMS. Such modulation is likely to be mediated by a GABA-A inhibition. N100 reduction at movement onset is likely related to a facilitatory state associated with a reduction in the GABA-B tone. Our findings can be used to develop new hypotheses to study the pathophysiological mechanisms underlying SICI and mSI abnormalities in patients with Parkinson disease and dystonia.