The landscape of POLE variants in colorectal and endometrial tumors: Correlation with microsatellite instability (MSI) and tumor mutation burden (TMB).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13538-e13538
Author(s):  
Sanjeevani Arora ◽  
Joanne Xiu ◽  
Davendra Sohal ◽  
Emil Lou ◽  
Richard M. Goldberg ◽  
...  
Keyword(s):  
Life Sciences ◽  
Mutation Rates ◽  
Chi Square ◽  
Tumor Mutation Burden ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Polymerase Epsilon ◽  
Very High

e13538 Background: Polymerase epsilon (POLE) is a major replicative DNA polymerase. Somatic POLE pathogenic variants (PV) are prevalent in endometrial cancer (EC) and in germline predispose to colorectal cancer (CRC), EC, and possibly other cancers (CA). PVs in the exonuclease domain (ExoD) [amino acid (AA) 268-471] lead to CAs with exceptionally high TMB. PV and uncertain variants (VUS) outside ExoD are sometimes concurrent with an ExoD PV and/or MSI. We hypothesized that the presence of non-ExoD variants may further increase POLE-associated mutation rate and tumor mutational burden. Methods: We retrospectively examined 1870 CRC and 4481 EC genomic profiles conducted by Caris Life Sciences (6/2016-6/2019). All patients had a 592-targeted gene somatic panel. Profiles with a POLE variant (PV or VUS) were analyzed. Median TMB (TMB, in mutations/megabase) was dichotomized to low/intermed ( < 17) vs high (>17). Tumors were grouped by: single ExoD PV, ExoD PV plus another variant (PV or VUS), or no ExoD PV. Known CRC/EC ExoD PV drivers were identified (Campbell et al, Cell 2017): D275G, P286R, S297F/Y, F367C/L/V, V411L, L424F, P436R/S/Y, M444K/L, A456P, S459F/Y, S461L/P, A465V. Kruskal-Wallis and chi-square tests were used. Results: Overall 4.5% CRC (80/1870) and 6.5% EC (303/4481) samples had POLE variants (Table). High TMB was seen in 56.3% CRC and 53.3% EC. In both CRC/ECs, TMB was higher in tumors with an ExoD PV and a 2nd variant compared to those with a solitary ExoD PV or no ExoD PV (both p < 0.001). MSI was more prevalent in CRC and EC with high TMB but no ExoD PV vs those with either high TMB and an ExoD PV, or low/intermed TMB and no ExoD PV (both p < 0.001). In both CRC/ECs, several ExoD PV associated with very high TMB when non-ExoD regions of POLE contained recurrent variant clusters: AA 1906 (TMB 225); AA 1826-7 (TMB 243); AA 1380-2 (TMB 229). Conclusions: In CRC/ECs, POLE ExoD PV and MSI appear to drive TMB in distinct and largely non-overlapping ways. Non-ExoD POLE variants may synergize with ExoD PVs to further increase mutation rates. [Table: see text]

scholarly journals DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244558
Author(s):  
McKayla J. Riggs ◽  
Nan Lin ◽  
Chi Wang ◽  
Dava W. Piecoro ◽  
Rachel W. Miller ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Microsatellite Instability ◽  
Information Exchange ◽  
P Value ◽  
Tumor Mutation Burden ◽  
Prognostic Features ◽  
Oncology Research ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden

Objective DACH1 is a transcriptional repressor and tumor suppressor gene frequently mutated in melanoma, bladder, and prostate cancer. Loss of DACH1 expression is associated with poor prognostic features and reduced overall survival in uterine cancer. In this study, we utilized the Oncology Research Information Exchange Network (ORIEN) Avatar database to determine the frequency of DACH1 mutations in patients with endometrial cancer in our Kentucky population. Methods We obtained clinical and genomic data for 65 patients with endometrial cancer from the Markey Cancer Center (MCC). We examined the clinical attributes of the cancers by DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Kentucky women with endometrial cancer had an increased frequency of DACH1 mutations (12/65 patients, 18.5%) compared to The Cancer Genome Atlas (TCGA) endometrial cancer population (25/586 patients, 3.8%) with p-value = 1.04E-05. DACH1 mutations were associated with increased tumor mutation count in both TCGA (median 65 vs. 8972, p-value = 7.35E-09) and our Kentucky population (490 vs. 2160, p-value = 6.0E-04). DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (24 vs. 6.02, p-value = 4.29E-05). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, and PMS2. DACH1 mutations were not associated with an increase in microsatellite instability at MCC (MSI-H) (p-value = 0.1342). Conclusions DACH1 mutations are prevalent in Kentucky patients with endometrial cancer. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 may be a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.

scholarly journals Prolonged Response to Anti–PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden

2019 ◽  
Vol 17 (6) ◽  
pp. 644-648 ◽  
Author(s):  
Olumide Gbolahan ◽  
Neda Hashemi-Sadraei ◽  
Bert O’Neil
Keyword(s):  
Overall Survival ◽  
Clinical Symptoms ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Tumor Genome ◽  
Prolonged Response

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

PD-L1 expression landscape and its relationship with tumor mutation burden in Chinese cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15267-e15267
Author(s):  
Haihua Yang ◽  
Longgang Cui ◽  
Yuzi Zhang ◽  
Zhengyi Zhao ◽  
Yuezong Bai ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Expression Profiles ◽  
Chinese Patients ◽  
Cancer Type ◽  
Tissue Samples ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Tumor Mutational Burden ◽  
Chinese Cancer Patients

e15267 Background: Little is known about the pan-cancer PD-L1 expression landscape in Chinese patients although PD-L1 expression has been approved by FDA as a diagnosis for anti-PD-(L)1 therapy in several types of cancer. We did a cross-sectional analysis to assess the PD-L1 expression landscape in Chinese patients and its relationship with Tumor mutation burden (TMB). Methods: Tissue samples were collected from more than 8,000 consecutive cases in China between January, 2017, and August, 2019 and were analyzed by 3D Medicines, a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The method for NGS sequencing and tumor mutational burden (TMB) measurement were described previously. Clinical data and PD-L1 expression profiles were obtained from 8,063 patients whose tissue samples assed quality control. IHC staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay (Dako North America, Carpentaria, CA, U.S.) or Ventana PD-L1 SP263 assay (Ventana Medical Systems, Tucson, AZ, U.S.). PD-L1 expression was determined using Tumor Proportion Score (TPS), the percentage of viable tumor cells stained. Results: PD-L1 expression was examined for 8,063 tissue samples collected from more than 18 different types of solid tumors. There were 4,866 (60%) male and 3,197 (40%) female patients. Their median age was 59 (IQR range, 50-66) years. Given the significance of different cut-points of PD-L1 expression in predicting clinical outcomes, expression levels of PD-L1 were arranged into the following intervals: < 1%, 1%-5%, 5%-50% and ≥50% for each cancer type. Small cell lung cancer (SCLC) had the lowest and Squamous Carcinoma of Head and Neck (HNSC) had the highest levels of PD-L1 expression. Spearman correlation analysis indicated no correlation between PD-L1 and tumor mutational burden (TMB) for Chinese cancer patients (R = 0.1, P < 0.01), which is in line with the previous reports that PD-L1 and TMB were two independent predictors in immunotherapy. Conclusions: The landscape of PD-L1 expression among Chinese cancer population in this study will further assist the utilization of PD-L1 as a predictive biomarker in clinical practice.

Real-world patterns on tumor mutation burden testing in a pan-tumor population

2021 ◽  
Author(s):  
Santosh Gautam ◽  
Sumesh Kachroo ◽  
Richard W DeClue ◽  
Maxine D Fisher ◽  
Anirban Basu
Keyword(s):  
Real World ◽  
Clinical Characteristics ◽  
Tumor Mutation Burden ◽  
Mutational Burden ◽  
Mutation Burden ◽  
Black Patients ◽  
Study Results ◽  
Tumor Mutational Burden ◽  
Anticancer Treatment ◽  
World Information

Background: There is limited real-world information on use of tumor mutational burden (TMB) testing and characteristics of patients receiving it. Materials & methods: Patients ≥18 years old and diagnosed with advanced solid tumors between 1 January 2015 and 31 January 2019 with TMB testing (TMB cohort) and without it (non-TMB) were included in this retrospective, observational study. Results: The TMB cohort (n = 202) was younger than non-TMB (n = 212) (mean age 62.1 vs 65.6 at diagnosis; p = 0.005). There were more Black patients in the TMB cohort (21.3 vs 11.8% in non-TMB; p = 0.004). Clinical characteristics were comparable between the two cohorts; however, systemic anticancer treatment was higher among TMB cohort (91.6 vs 77.8% in non-TMB). Conclusion: Notable differences were observed between patients receiving TMB test and those not receiving it.

CMS subtypes characterized by high TMB shows immunosuppressive microenvironment that implies resistance to immunotherapy.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 610-610
Author(s):  
Christopher Szeto ◽  
Chad Garner ◽  
Kevin Kazmierczak ◽  
Charles Joseph Vaske ◽  
Stephen Charles Benz ◽  
...  
Keyword(s):  
Wnt Pathway ◽  
Molecular Subtypes ◽  
Pathogenic Variants ◽  
Mutational Burden ◽  
Mutational Status ◽  
Pathway Activation ◽  
Tumor Mutational Burden ◽  
Significant Enrichment ◽  
Immunosuppressive Microenvironment ◽  
Lower Expression

610 Background: Tumor mutational burden (TMB) is emerging as an important biomarker for immune checkpoint therapy (ICT) response. Yet even in the context of high TMB, ICT are likely ineffective in an immuno-suppressed microenvironment. Here we demonstrate that a well-characterized subtype of CRC, CMS2, associated with Wnt pathway activation, is immunosuppressive despite high TMB. Methods: Tumor/normal-paired DNAseq (WGS or WES) and deep RNAseq (∼200x106reads per tumor) was performed on 464 GI tumors from a commercial database. Samples were classified as high TMB if they had > 200 non-synonymous exonic mutations as previously established (Rizvi et al, 2015). Each sample was assigned to one of the colorectal Consensus Molecular subtypes (CMS) based on RNA classification. A curated panel of 109 genes that discriminate between 22 immune subsets was identified. For each of these immune signatures, a database containing 1880 unselected tumors was used to define a distribution of expression. The study samples were then scored for their deviances within such distributions. Significant enrichment was analyzed between immune subsets, CMS types, TMB status, and somatic mutational status. Results: Compared to other subtypes, CMS1 & CMS2 were significantly high-TMB (adj. p < 3.8E-4 & p < 4.7E-3 respectively). Perplexingly, CMS2 had significantly lower expression of 11 well-established checkpoint and TME markers including LAG3 and PDL1 (adj. p 1.5E-2 & 2.9E-9 respectively), while CMS1 (MSI-enriched) expresses selected TME markers more than other subtypes (PDL1 adj. p < 4.0E-6 & LAG3 adj. p < 1.0E-6). As expected, CMS2 tumors were significantly enriched for likely pathogenic variants in the Wnt-associated gene APC (adj. p < 1.3E-8). Immune-deconvolution indicated substantial exclusion of Tem cells from CMS2 tumors, in line with Wnt/b-catenin blockade of TcmàTem maturation for immunoreactivity. Conclusions: The most common subtype of CRC, CMS2 (~37%), is highly immunosuppressive despite high TMB. ICT is only effective in an immunologically active microenvironment. TMB alone as a biomarker likely is insufficient to indicate the effectiveness of immunotherapy.

Characteristics of colorectal cancer (CRC) patients with BRCA1 and BRCA2 mutations.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 606-606 ◽  
Author(s):  
Madiha Naseem ◽  
Joanne Xiu ◽  
Mohamed E. Salem ◽  
Richard M. Goldberg ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Brca1 And Brca2 ◽  
Chi Square ◽  
Statistical Correlations ◽  
Pathogenic Variants ◽  
Tumor Mutational Burden ◽  
Brca2 Mutations ◽  
Brca1 And Brca2 Mutations ◽  
Next Generation Sequencing Ngs

606 Background: Between 3-5% of CRC patients have BRCA1/2 pathogenic mutations. This study aims to identify associations between BRCA1 and BRCA2 mutations and clinical characteristics in CRC. Methods: A total of 6396 CRC tumor samples were tested with Next-Generation Sequencing (NGS) on a 592-gene panel, pathogenic or presumed pathogenic variants were counted as mutations (mt). Microsatellite instability (MSI) and tumor mutational burden (TMB) were tested by NGS. Statistical correlations were investigated using ANOVA, Chi-square and t-test. Results: Among tumors sampled, 53% derived from male patients and median age was 60 years. BRCA1 mt were detected in 1.1% (n = 72) of tumors, while BRCA2 in 2.8% (n = 179). BRCA1 mt were more frequent in women (W;65%) than men (M;35%) (p = 0.0019) while no relationship with sex was seen for BRCA2 mt (42% F vs. 58% M). No significant associations with age were noticed. Majority of pathogenic mt in BRCA1 (52%; n = 34) and BRCA2 (62%; n = 103) occurred in MSI-High (MSI-H) cases. MSI-H pts had more frameshift mt in both BRCA1/2 than MSS pts. MSS cases had lower rates of BRCA1 and 2 pathogenic mt (44% and 37%, respectively). Right-sided tumors were significantly associated with BRCA1 (p = 0.0056) and BRCA2 (p < 0.0001) mt in MSI-H cases only. BRCA1/2 mt were associated with higher TMB in all CRCs, including MSI-H and MSS cases (p < 0.001). POLE mt (n = 31) were associated with higher BRCA1/2 mt rates (9.6%, 55% respectively). Among MSS cases with POLE wild-type status, BRCA1 (p = 0.0269) and BRCA2 (p = 0.0151) mt were associated with high TMB and combining both BRCA1/2 mutations led to an even higher TMB (3.6%; p = 0.001). Conclusions: This is the first study to show that BRCA1/2 mutations are more frequent in MSI-H, and independently associated with higher TMB, pathogenic POLE mutations, and right-sided tumors in MSI-H CRCs. Given their relationship with TMB, the presence of BRCA1/2 mutations may be potential predictive biomarkers for checkpoint or PARP inhibitors in CRC, a finding that should be prospectively evaluated.

740 Biomarkers diverging between tumor mutation burden and microsatellite instability

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A786-A787
Author(s):  
Jason Ding ◽  
Nihir Patel
Keyword(s):  
Dna Repair ◽  
Microsatellite Instability ◽  
Dna Repair Genes ◽  
Loss Of Function ◽  
Tumor Mutation Burden ◽  
Dna Polymerase Epsilon ◽  
Mutation Burden ◽  
Polymerase Epsilon ◽  
Repair Genes

BackgroundDNA repair is a critical process to maintain DNA integrity. It is conducted by distinct pathways of genes, many of whose alterations are thought to result in genomic instability and hypermutability, ultimately contributing to tumorigenesis. Tumor Mutation Burden (TMB) and Microsatellite Instability (MSI) are considered as efficacy biomarkers for immunotherapy.1 2 However, there has been little characterization of the association between DNA repair genes and TMB/MSI in cancer. This study aims to further understand DNA repair genes and evaluate the contribution of their alteration to TMB and MSI.MethodsWe systematically analyzed 282 DNA repair genes involved in 20 DNA repair pathways. These genes were evaluated for mutations based on 274 sequenced colorectal tumor samples from the TCGA database. The functional impacts of these mutations were analyzed, and only damaging mutations were used for the subsequent analysis. The most frequently mutated genes were identified. The association between the damaging mutations and TMB/MSI status was calculated for each gene, and the significant genes were subject to further pathway enrichment analysis. We also compared the gene expression between TMB high and low as well as between MSI-H and MSI-L/MSS for each gene based on their RNAseq data. The potential associations with TMB/MSI high phenotypes were evaluated.Results94 genes were identified to be significantly mutated in TMB high, including all of the 26 genes that were significant in MSI-H . The genes are enriched in multiple pathways, including Fanconi anemia, Base excision repair, and Mismatch repair. At the expression level, 28 genes are significantly downregulated in TMB high samples, while 35 genes in MSI-H, suggesting that the inactivation of these genes might be mediated by epigenetic abnormalities (figure 1). 10 genes, including POLE, were identified that are significantly mutated in TMB high samples as compared to MSI-H samples (table 1). Loss of function of these genes may result in an ultra-mutated phenotype. Contradicting the notion that POLE mutation is predominantly associated with MSS tumors and are mutually exclusive with the complete loss of MMR,4–6 we found about half of POLE-mutant samples (8/16) were MSI high, five of which had MMR mutations (figure 2).Abstract 740 Figure 1Venn diagram of significant genes associated with MSI-H and TMB-high, identified using expression changes and loss of function mutations.Abstract 740 Table 1Genes significantly mutated in TMB-high compared to MSI-H.Abstract 740 Figure 2MLH1 expressed significantly lower in MSI-H samplesConclusionsThe study investigated the association of DNA repair genes with TMB and MSI. We compared genes significantly altered in TMB high and MSI-H samples and identified genes pointing to a potential mechanism that induces ultra-mutation in a subset of cancer patients with intact MMR, which can serve as potential biomarkers for immunotherapy efficacy linked with high TMB.ReferencesChan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 2019; 30(1):44–56.Chang L, Chang M, Chang HM, Chang F. Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy. Appl Immunohistochem Mol Morphol 2018;26(2):e15–e21.Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337.Albertson TM, Ogawa M, Bugni JM, et al. DNA polymerase epsilon and delta proofreading suppress discrete mutator and cancer phenotypes in mice. Proc Natl Acad Sci U S A 2009;106:17101-17104.Church DN, Briggs SE, Palles C, et al. DNA polymerase epsilon and delta exonuclease domain mutations in endometrial cancer. Hum Mol Genet 2013;22:2820–2828.Valle L, Hernandez-Illan E, Bellido F, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Genet 2014;23:3506–3512.

scholarly journals Exploration of Key Genes Combining with Immune Infiltration Level and Tumor Mutational Burden in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Jing Chen ◽  
shuzhen wu ◽  
sijia ge ◽  
ran Ji ◽  
Yuyan Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Poor Prognosis ◽  
R Package ◽  
Immune Microenvironment ◽  
Chi Square ◽  
Term Survival ◽  
Immune Infiltration ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
And Function

Abstract Background: Hepatocellular carcinoma (HCC) is still a lethal malignancy because of its heterogenicity and aggressive behavior, with unsatisfactory early diagnosis and poor prognosis. Recently, few somatic mutations have been reported to associated with HCC carcinogenesis and function in predicting HCC progression. Interactions of tumor cells with surrounding immune microenvironment in HCC participate in orchestrating the onset and development. Herein, our aim is to investigate the associations of tumor mutational burden (TMB) with immune microenvironment in HCC. Then we will seek for differential expression genes (DEGs) in terms of immune and TMB scores and discuss whether their latent functions affect HCC prognosis and progression.Methods: The expression, clinical and mutational data were downloaded from TCGA database, then calculated the immune infiltration of these HCC samples by R package “ssGSEA”, “CIBERSORT” and “ESTIMATE”. Then the samples were clarified to 2 groups according to the immune levels. TMB was also calculated and differential expressional genes (DEGs) in the low and high TMB group were intersected and the different immune level groups. Then the cox analyses and prognostic model were performed and tested by R package “glmnet”. Then the selected genes BCL10 and TRAF3 were tested their expression by qrt-PCR and IHC and tested their clinical correlation by chi-square analyses and their biological processes enriched by GSEA, and their immune infiltration by “ssGSEA” individualy. Last, pearson algorithm was employed to judge the relevance of BCL10 and TRAF3.Results: Upregulated degrees of immune infiltration correlated with TMB, they synergistically predicted poor prognosis in HCC. DEGs enriched in immune-related pathways could serve as an indicator of therapeutic effect of HCC immunotherapy. Among these DEGs, BCL10 and TRAF3 were highly expressed in HCC tissues, especially in TP53 mutation group. BCL10 and TRAF3 corporately exhibited immunological function, thereby affecting HCC progression and prognosis.Conclusions: We identified that BCL10 and TRAF3 exhibited good prognostic value in predicting the clinical outcome of HCC patients, which may influence TMB and tumor microenvironment (TME) and help us moving towards immune-based therapies with HCC patients, ultimately improving their long-term survival.

Correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC: A retrospective analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20019-e20019
Author(s):  
Yao Yu ◽  
Rongbo Lin ◽  
Ning He ◽  
Yadong Yang ◽  
Ge Jin ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Density ◽  
Driver Genes ◽  
Chi Square ◽  
Metastatic Nsclc ◽  
Tumor Infiltrating Lymphocyte ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Chi Square Test

e20019 Background: To investigate the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in tumor tissue of patients with NSCLC. Methods: 79 patients with confirmed NSCLC admitted from January 2018 to January 2019 were included. Tumor DNA was isolated from FFPE samples or fresh tissue samples. Mutation profiles were obtained by targeted deep sequencing of 620 selected genes. Tumor mutational burden (TMB) was defined as the number of non-synonymous mutations per 1Mbp and divided into tertiles. PD-L1 expression, CD8+ T cell and tumor infiltrating lymphocyte density were evaluated by immunohistochemical analysis. The correlation coefficient of TMB, tumor microenvironment and alterations of driver genes was calculated by chi-square test. Results: Median TMB of these patients is 6.915 Muts/Mbp (4.22-9.44 Muts/Mbp). Prevalence of PD-L1 expression is 28.0% (n = 7/25) at a tumor proportion score cutoff of at least 5% evaluated by Dako 28-8 PharmDx Assay kit and prevalence of CD8+ T cell density is 95.8% (n = 23/24). TP53 mutations are the most common alteration (n = 49/79, 62.0%), followed by EGFR alterations (n = 31/79, 39.2%), CDKN2A alterations (n = 11/79, 13.9%), KRAS mutations (n = 10/79, 12.7%), STK11 mutations (n = 5/79, 6.3%), ALK fusions (n = 4/79, 5.1%) and POLE mutations (n = 4/79, 5.1%). According to results of chi-square test, squamous cell carcinoma has higher TMB (p= 0.023) than adenocarcinoma. Metastatic NSCLC has higher PD-L1 expression (p= 0.049) than non-metastatic NSCLC. Furthermore, EGFR alterations are associated with lower TMB (p=0.020) and POLE mutations are associated with higher TMB (p= 0.015). There are no correlations among CD8+ T cell density, tumor infiltrating lymphocyte density and other variants. Conclusions: Our study highlights the correlation of tumor mutational burden, tumor microenvironment and alterations of driver genes in patients with NSCLC. This result may be the reference of anti-PD-1 therapy.

Molecular characterization of appendiceal goblet cell carcinoid.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 231-231
Author(s):  
Hiroyuki Arai ◽  
Yasmine Baca ◽  
Curtis Johnston ◽  
Richard M. Goldberg ◽  
Philip Agop Philip ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Goblet Cell ◽  
Mutation Rates ◽  
Molecular Characteristics ◽  
Goblet Cell Carcinoid ◽  
Chi Square ◽  
Pathologic Features ◽  
Significant Difference ◽  
Tumor Mutational Burden ◽  
Chi Square Test

231 Background: Goblet cell carcinoid (GCC) is a distinct subtype of appendiceal neoplasm that exhibits unique clinical and pathologic features. There are a few reports focusing on the molecular differences between GCC and other appendiceal tumors such as adenocarcinoma and neuroendocrine tumor (NET). Methods: A total of 495 appendiceal tumor samples (53 GCCs, 428 adenocarcinomas and 14 NETs) were tested with Next-Generation Sequencing (NGS) on a 592-gene panel and immunohistochemistry (IHC). Microsatellite instability (MSI) / mismatch repair (MMR) status was tested with a combination of NGS, IHC and fragment analysis. Tumor mutational burden (TMB) was evaluated by NGS, and PD-L1 were tested by IHC (SP142). Molecular characteristics of GCCs are compared with those of adenocarcinomas and NETs, using Chi-square test. Results: The top five genes with most frequent mutation rate in GCCs were TP53 (24.0%), ARID1A (15.4%), SMAD4 (9.4%), KRAS (7.5%) and CHEK2 (4.0%). Compared to adenocarcinomas, GCCs showed significantly lower mutation rates in KRAS (7.5% vs 60.4%), GNAS (3.8% vs 34.4%), APC (1.9% vs 11.7%), while significantly higher mutation rates in CDH1 (3.8% vs 0.7%), CHEK2 (4.0% vs 0.3%), CDC73 (2.0% vs 0.0%), ERCC2 (2.0% vs 0.0%) and FGFR2 (1.9% vs 0.0%). Compared to NETs, GCCs showed significantly lower mutation rate in KRAS (7.5% vs 28.6%), APC (1.9% vs 28.6%), BRCA2 (0.0% vs 7.1%) and FANCA (0.0% vs 7.1%), with all p < 0.05. In GCCs, MSI-H/dMMR, TML-high (> 17mut/Mb) and PD-L1 expression were seen in 0.0%, 0.0% and 2.0%, respectively. No significant difference was observed in these immune-related markers’ frequency, compared to adenocarcinomas and NETs. Conclusions: GCCs had considerably distinct mutational profile compared to appendiceal adenocarcinomas and NETs. Understanding these molecular characteristics may be critical for a development of effective treatment strategy in GCC.

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