Drugging the undruggable proteins in cancer: A systems biology approach.
In recent years, the research community has, with comprehensive systems biology approaches and related technologies, gained insight into the vast complexity of numerous cancers. These approaches allow an in-depth exploration that cannot be achieved solely using conventional low-throughput methods, which do not closely mimic the natural cellular environment. In this review, we discuss recent integrative multiple omics approaches for understanding and modulating previously identified 'undruggable' targets such as members of the RAS family, MYC, TP53, and various E3 ligases and deubiquitinases. We describe how these technologies have revolutionized drug discovery by overcoming an array of biological and technological challenges and how, in the future, they will be pivotal in assessing cancer states in individual patients, allowing for the prediction and application of personalized disease treatments.
Publication Date: 2021-08-25
Journal: Current opinion in chemical biology
Investigating the Mechanism of
Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, which accounts for approximately 10% of all diagnosed cancers and cancer deaths worldwide per year.
We adopted active constituent prescreening, target predicting, protein-protein interaction (PPI) analysis, Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, differentially expressed gene analysis, and molecular docking to establish a system pharmacology database of SBH against CRC.
A total of 64 active constituents of SBH were obtained and 377 targets were predicted, and the result indicated that quercetin, luteolin, wogonin, and apigenin were the main active constituents of SBH. Glucocorticoid receptor (NR3C1), pPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3CA), cellular tumor antigen p53 (TP53), transcription factor AP-1 (JUN), mitogen-activated protein kinase 1 (MAPK1), Myc protooncogene protein (MYC), cyclin-dependent kinase 1 (CDK1), and broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) were the major targets of SBH in the treatment of CRC. GO analysis illustrated that the core biological process regulated by SBH was the regulation of the cell cycle. Thirty pathways were presented and 8 pathways related to CRC were involved. Molecular docking presented the binding details of 3 key targets with 6 active constituents.
The mechanisms of SBH against CRC depend on the synergistic effect of multiple active constituents, multiple targets, and multiple pathways.
Publication Date: 2021-08-13
Journal: Evidence-based complementary and alternative medicine : eCAM
Identification of four gastric cancer subtypes based on genetic analysis of cholesterogenic and glycolytic pathways.
Warburg phenomenon refers to the development of unique metabolic patterns during the growth of tumor cells. This study stratified gastric cancer into prognostic metabolic subgroups according to changes in gene expressions related to glycolysis and cholesterol synthesis. The RNA-seq expression data, single nucleotide variants (SNV), short insertions and deletions (InDel) mutation data, copy number variation (CNV) data and clinical follow-up information data of gastric cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. ConsensusClusterPlus was used to stratify the metabolic subtypes of gastric cancer. Four metabolic subtypes (Cholesterogenic, Glycolytic, Mixed and Quiescent) of gastric cancer were identified, and patients with cholesterogenic tumors had the longest disease-specific survival (DSS). Genome-wide analysis showed that aberrant amplification of TP53 and MYC in gastric cancer was associated with abnormal cholesterol anabolic metabolism. The mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) differed among the four subtypes. Tumors in the glycolytic group showed a higher PDCD1. A genomic signature based on tumor metabolism of different cancer types was established. This study showed that genes related to glucose and lipid metabolism play an important role in gastric cancer and facilitate a personalized treatment of gastric cancer.
Publication Date: 2021-08-05
The genomic landscape of 85 advanced neuroendocrine neoplasms reveals subtype-heterogeneity and potential therapeutic targets.
Metastatic and locally-advanced neuroendocrine neoplasms (aNEN) form clinically and genetically heterogeneous malignancies, characterized by distinct prognoses based upon primary tumor localization, functionality, grade, proliferation index and diverse outcomes to treatment. Here, we report the mutational landscape of 85 whole-genome sequenced aNEN. This landscape reveals distinct genomic subpopulations of aNEN based on primary localization and differentiation grade; we observe relatively high tumor mutational burdens (TMB) in neuroendocrine carcinoma (average 5.45 somatic mutations per megabase) with TP53, KRAS, RB1, CSMD3, APC, CSMD1, LRATD2, TRRAP and MYC as major drivers versus an overall low TMB in neuroendocrine tumors (1.09). Furthermore, we observe distinct drivers which are enriched in somatic aberrations in pancreatic (MEN1, ATRX, DAXX, DMD and CREBBP) and midgut-derived neuroendocrine tumors (CDKN1B). Finally, 49% of aNEN patients reveal potential therapeutic targets based upon actionable (and responsive) somatic aberrations within their genome; potentially directing improvements in aNEN treatment strategies.
Publication Date: 2021-07-31
Journal: Nature communications
The Mechanism of Xiaoyao San in the Treatment of Ovarian Cancer by Network Pharmacology and the Effect of Stigmasterol on the PI3K/Akt Pathway.
This study was aimed at exploring the regulatory mechanism of Xiaoyao San (XYS) and its main compound, Stigmasterol, in the biological network and signaling pathway of ovarian cancer (OC) through network pharmacology-based analyses and experimental validation.
The active compounds and targets of XYS were studied by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The GeneCards and OMIM databases were used to screen common targets of XYS in the treatment of OC. Combined with the STRING database and Cytoscape 3.6.0, the core compounds and targets of XYS were obtained. GO and KEGG pathway enrichment analyses of core target genes were carried out by using the Metascape and DAVID databases. Molecular docking has been achieved by using the AutoDock Vina program to discuss the interaction of the core targets and compounds of XYS in the treatment of OC. The effect of Stigmasterol on proliferation and migration were assessed by CCK8 and wound healing assay. Western blot and qRT-PCR were used to analyze the protein and mRNA expressions of PI3K, Akt, and PTEN after treatment of Stigmasterol.
A total of 113 common targets of XYS for the treatment of OC were obtained from 975 targets related to OC and 239 targets of XYS's effect. The main compounds of XYS include Quercetin, Naringenin, Isorhamnetin, and Stigmasterol, which mainly regulate the targets such as TP53, Akt1, and MYC and PI3K/Akt, p53, and cell cycle signal pathways. At the same time, molecular docking showed that Stigmasterol and Akt1 had good docking conformation. Stigmasterol inhibited OC cell proliferation and migration in vitro and reduced the protein and mRNA expressions of the PI3K/Akt signaling pathway.
Stigmasterol as the one of the main compounds of XYS suppresses OC cell activities through the PI3K-Akt signaling pathway.
Publication Date: 2021-07-27
Journal: Disease markers
Study on HOXBs of Clear Cell Renal Cell Carcinoma and Detection of New Molecular Target.
Our study examined the transcriptional and survival data of HOXBs in patients with clear cell renal cell carcinoma (ccRCC) from the ONCOMINE database, Human Protein Atlas, and STRING website. We discovered that the expression levels of HOXB3/5/6/8/9 were significantly lower in ccRCC than in normal nephritic tissues. In ccRCC, patients with a high expression of HOXB2/5/6/7/8/9 mRNA have a higher overall survival (OS) than patients with low expression. Further analysis by the GSCALite website revealed that the methylation of HOXB3/5/6/8 in ccRCC was significantly negatively correlated to gene expression, while HOXB5/9 was positively correlated to the CCT036477 drug target. As DNA abnormal methylation is one of the mechanisms of tumorigenesis, we hypothesized that HOXB5/6/8/9 are potential therapeutic targets for patients with ccRCC. We analyzed the function of enrichment data of HOXBs in patients with ccRCC from the Kyoto Encyclopedia of Genes and Genomes pathway enrichment and the PANTHER pathway. The results of the analysis show that the function of HOXBs might be associated with the Wnt pathway and that HOXB5/6/8/9 was coexpressed with multiple Wnt pathway classical genes and proteins, such as MYC, CTNNB, Cyclin D1 (CCND1), and tumor protein P53 (TP53), which further confirms that HOXBs inhibit the growth of renal carcinoma cells through the Wnt signaling pathway. In conclusion, our analysis of the family of HOXBs and their molecular mechanism may provide a theoretical basis for further research.
Publication Date: 2021-07-27
Journal: Journal of oncology
EBV-positive HIV-associated diffuse large B cell lymphomas are characterized by JAK/STAT (STAT3) pathway mutations and unique clinicopathologic features.
Even in the era of highly active combination antiretroviral therapy (cART), patients with HIV have a disproportionate risk of developing aggressive lymphomas that are frequently Epstein-Barr virus (EBV)-related. Here, we investigate HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) and compare EBV-positive and EBV-negative cases. HIV-DLBCL were identified from two academic medical centres and characterised by immunohistochemistry, EBV status, fluorescence in situ hybridisation, cell of origin determination by gene expression profiling, and targeted deep sequencing using a custom mutation panel of 334 genes. We also applied the Lymphgen tool to determine the genetic subtype of each case. Thirty HIV-DLBCL were identified, with a median patient age of 46 years and male predominance (5:1). Thirteen cases (48%) were EBV-positive and 14 (52%) EBV-negative. Nine of the 16 tested cases (56%) had MYC rearrangement, three (19%) had BCL6 (two of which were double hit MYC/BCL6) and none had BCL2 rearrangements. Using the Lymphgen tool, half of the cases (15) were classified as other. All HIV-DLBCL showed mutational abnormalities, the most frequent being TP53 (37%), MYC (30%), STAT3 (27%), HIST1H1E (23%), EP300 (20%), TET2 (20%), SOCS1 (17%) and SGK1 (17%). EBV-negative cases were mostly of germinal centre B-cell (GCB) origin (62%), showed more frequent mutations per case (a median of 13·5/case) and significant enrichment of TP53 (57% vs. 15%; P = 0·046), SGK1 (36% vs. 0%; P = 0·04), EP300 (43% vs. 0%; P = 0·02) and histone-modifying gene (e.g. HIST1H1E, HIST1H1D, 79% vs. 31%; P = 0·02) mutations. EBV-positive cases were mostly of non-GCB origin (70%), with fewer mutations per case (median 8/case; P = 0·007), and these tumours were enriched for STAT3 mutations (P = 0·10). EBV-positive cases had a higher frequency of MYC mutations but the difference was not significant (36% vs. 15%; P = 0·38). EBV-association was more frequent in HIV-DLBCLs, arising in patients with lower CD4 counts at diagnosis (median 46·5 vs. 101, P = 0·018). In the era of cART, approximately half of HIV-DLBCL are EBV-related. HIV-DLBCL are enriched for MYC rearrangements, MYC mutations and generally lack BCL2 rearrangements, regardless of EBV status. Among HIV-DLBCL, tumours that are EBV-negative and EBV-positive appear to have important differences, the latter arising in context of lower CD4 count, showing frequent non-GCB origin, lower mutation burden and recurrent STAT3 mutations.
Publication Date: 2021-07-18
Journal: British journal of haematology
Progress in molecular feature of smoldering mantle cell lymphoma.
Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid tumors. However, it sometimes displays indolent behavior in patients and might not necessitate treatment at diagnosis; this has been described as "smoldering MCL" (SMCL). There are significant differences in the diagnosis, prognosis, molecular mechanisms and treatments of indolent MCL and classical MCL. In this review, we discuss the progress in understanding the molecular mechanism of indolent MCL to provide insights into the genomic nature of this entity. Reported findings of molecular features of indolent MCL include a low Ki-67 index, CD200 positivity, a low frequency of mutations in TP53, a lack of SOX11, normal arrangement and expression of MYC, IGHV mutations, differences from classical MCL by L-MCL16 assays and MCL35 assays, an unmutated P16 status, few defects in ATM, no NOTCH1/2 mutation, Amp 11q gene mutation, no chr9 deletion, microRNA upregulation/downregulation, and low expression of several genes that have been valued in recent years (SPEN, SMARCA4, RANBP2, KMT2C, NSD2, CARD11, FBXW7, BIRC3, KMT2D, CELSR3, TRAF2, MAP3K14, HNRNPH1, Del 9p and/or Del 9q, SP140 and PCDH10). Based on the above molecular characteristics, we may distinguish indolent MCL from classical MCL. If so, indolent MCL will not be overtreated, whereas the treatment of classical MCL will not be delayed.
Publication Date: 2021-07-15
Journal: Experimental hematology & oncology
Genomic Analysis Revealed Mutational Traits Associated with Clinical Outcomes in Osteosarcoma.
The limited understanding of correlation between genomic features and biological behaviors has impeded the therapeutic breakthrough in osteosarcoma (OS). This study aimed to reveal the correlation of mutational and evolutionary traits with clinical outcomes.
We applied a case-based targeted and whole exome sequencing of eleven matched primary, recurrent and metastatic samples from three OS patients characterized by different clinical behaviors in local recurrence or systematic progression pattern.
Extensive OS-associated driver genes were detected including TP53, RB1, NF1, PTEN, SPEN, CDKN2A. Oncogenic signaling pathways including cell cycle, TP53, MYC, Notch, WNT, RTK-RAS and PI3K were determined. MYC amplification was observed in the patient with shortest disease-free interval. Linear, branched or mixed evolutionary models were constructed in the three OS cases. A branched evolution with limited root mutation was detected in patient with shorter survival interval. ADAM17 mutation and HEY1 amplification were identified in OS happening dedifferentiation. Signatures 21 associated with microsatellite instability (MSI) was identified in OS patient with extra-pulmonary metastases.
OS was characterized by complex genomic alterations. MYC aberration, limited root mutations, and a branched evolutionary model were observed in OS patient with relatively aggressive course. Extra-pulmonary metastases of OS might attribute to distinct mutational process pertaining to MSI. Further research in a larger number of people is needed to confirm these findings.
Publication Date: 2021-07-09
Journal: Cancer management and research
Dynamics of circulating tumor DNA during postoperative radiotherapy in patients with residual triple-negative breast cancer following neoadjuvant chemotherapy: a prospective observational study.
This study was performed to evaluate circulating tumor DNA (ctDNA) kinetics during postoperative radiotherapy (PORT) in patients with residual triple-negative breast cancer (TNBC) at surgery following neoadjuvant chemotherapy (NAC).
Stage II/III patients with post-NAC residual TNBC who required PORT were prospectively included in this study between March 2019 and July 2020. For 11 TNBC patients, next-generation sequencing targeting 38 genes was conducted in 55 samples, including tumor tissue, three plasma samples, and leukocytes from each patient. The plasma samples were collected at three-time points; pre-PORT (T0), after 3 weeks of PORT (T1), and 1 month after PORT (T2). Serial changes in ctDNA variant allele frequency (VAF) were analyzed.
Somatic variants were found in the tumor specimens in 9 out of 11 (81.8%) patients. Mutated genes included TP53 (n = 7); PIK3CA (n = 2); and AKT1, APC, CSMD3, MYC, PTEN, and RB1 (n = 1). These tumor mutations were not found in plasma samples. Plasma ctDNA variants were detected in three (27.3%) patients at T0. Mutations in EGFR (n = 1), CTNNB1 (n = 1), and MAP2K (n = 1) was identified with ctDNA analysis. In two (18.2%) patients, the ctDNA VAF decreased through T1 and T2 while increasing at T2 in one (9.1%) patient. After a median follow-up of 22 months, no patient showed cancer recurrence.
Among patients with post-NAC residual TNBC, more than a quarter exhibited a detectable amount of ctDNA after curative surgery. The ctDNA VAF changed variably during the course of PORT. Therefore, ctDNA kinetics can serve as a biomarker for optimizing adjuvant treatment.
Publication Date: 2021-06-22
Journal: Breast cancer research and treatment
Formation of autotriploid Carassius auratus and its fertility-related genes analysis.
Formation of triploid organism is useful in genetics and breeding. In this study, autotriploid Carassius auratus (3nRR, 3n = 150) was generated from Carassius auratus red var. (RCC, 2n = 100) (♀) and autotetraploid Carassius auratus (4nRR, 4n = 200) (♂). The female 3nRR produced haploid, diploid and triploid eggs, whereas the male 3nRR was infertile. The aim of the present study was to explore fertility of potential candidate genes of 3nRR.
Gonadal transcriptome profiling of four groups (3 females RCC (FRCC), 3 males 4nRR (M4nRR), 3 males 3nRR (M3nRR) and 3 females 3nRR (F3nRR)) was performed using RNA-SEq. A total of 78.90 Gb of clean short reads and 24,262 differentially expressed transcripts (DETs), including 20,155 in F3nRR vs. FRCC and 4,107 in M3nRR vs. M4nRR were identified. A total of 106 enriched pathways were identified through KEGG enrichment analysis. Out of the enriched pathways, 44 and 62 signalling pathways were identified in F3nRR vs. FRCC and M3nRR vs. M4nRR, respectively. A total of 80 and 25 potential candidate genes for fertility-related in F3nRR and M3nRR were identified, respectively, through GO, KEGG analyses and the published literature. Moreover, protein-protein interaction (PPI) network construction of these fertility-associated genes were performed. Analysis of the PPI networks showed that 6 hub genes (MYC, SOX2, BMP4, GATA4, PTEN and BMP2) were involved in female fertility of F3nRR, and 2 hub genes (TP53 and FGF2) were involved in male sterility of M3nRR.
Establishment of autotriploid fish offers an ideal model to study reproductive traits of triploid fish. RNA-Seq data revealed 6 genes, namely, MYC, SOX2, BMP4, GATA4, PTEN and BMP2, involved in the female fertility of the F3nRR. Moreover, 2 genes, namely, TP53 and FGF2, were related to the male sterility of the M3nRR. These findings provide information on reproduction and breeding in triploid fish.
Publication Date: 2021-06-11
Journal: BMC genomics
The pancreatic cancer genome revisited.
Pancreatic cancer is a genetic disease, and the recurrent genetic alterations characteristic of pancreatic cancer indicate the cellular processes that are targeted for malignant transformation. In addition to somatic alterations in the most common driver genes (KRAS, CDKN2A, TP53 and SMAD4), large-scale studies have revealed major roles for genetic alterations of the SWI/SNF and COMPASS complexes, copy number alterations in GATA6 and MYC that partially define phenotypes of pancreatic cancer, and the role(s) of polyploidy and chromothripsis as factors contributing to pancreatic cancer biology and progression. Germline variants that increase the risk of pancreatic cancer continue to be discovered along with a greater appreciation of the features of pancreatic cancers with mismatch repair deficiencies and homologous recombination deficiencies that confer sensitivity to therapeutic targeting. Wild-type KRAS pancreatic cancers, some of which are driven by alternative oncogenic events affecting NRG1 or NTRK1 - for which targeted therapies exist - further underscore that pancreatic cancer is formally entering the era of precision medicine. Given the vast developments within this field, here we review the wide-ranging and most current information related to pancreatic cancer genomics with the goal of integrating this information into a unifying description of the life history of pancreatic cancer.
Publication Date: 2021-06-06
Journal: Nature reviews. Gastroenterology & hepatology
NGS-based liquid biopsy profiling identifies mechanisms of resistance to ALK inhibitors: a step toward personalized NSCLC treatment.
Despite impressive and durable responses, nonsmall cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors (ALK-Is) ultimately progress due to development of resistance. Here, we have evaluated the clinical utility of circulating tumor DNA (ctDNA) profiling by next-generation sequencing (NGS) upon disease progression. We collected 26 plasma and two cerebrospinal fluid samples from 24 advanced ALK-positive NSCLC patients at disease progression to an ALK-I. These samples were analyzed by NGS and digital PCR. A tool to retrieve variants at the ALK locus was developed (VALK tool). We identified at least one resistance mutation in the ALK locus in ten (38.5%) plasma samples; the G1269A and G1202R mutations were the most prevalent among patients progressing to first- and second-generation ALK-Is, respectively. Overall, 61 somatic mutations were detected in 14 genes: TP53, ALK, PIK3CA, SMAD4, MAP2K1 (MEK1), FGFR2, FGFR3, BRAF, EGFR, IDH2, MYC, MET, CCND3, and CCND1. Specifically, a deletion in exon 19 in EGFR, a non-V600 BRAF mutation (G466V), and the F129L mutation in MAP2K1 were identified in four patients who showed no objective survival benefit from ALK-Is. Potential ALK-I-resistance mutations were also found in PIK3CA and IDH2. Finally, a c-MYC gain, along with a loss of CCND1 and FGFR3, was detected in a patient progressing on a first-line treatment with crizotinib. We conclude that NGS analysis of liquid biopsies upon disease progression identified different putative ALK-I-resistance mutations in most cases and could be a valuable approach for therapy decision making.
Publication Date: 2021-06-01
Journal: Molecular oncology
Molecular characterization of ctDNA from Chinese patients with advanced gastric adenocarcinoma reveals actionable alterations for targeted and immune therapy.
Circulating tumor DNA (ctDNA) is considered an ideal sample type for genotyping patients with advanced unresectable cancer to inform treatment decision. It may better capture tumor heterogeneity, especially in gastric adenocarcinoma (GAC). However, there exists little evidence regarding genomic profiling of Chinese advanced GAC patients from ctDNA. Blood samples were obtained from 200 advanced GAC patients. Next-generation sequencing (NGS) was performed on ctDNA using a validated 150-gene panel. Blood tumor mutation burden (bTMB) was calculated according to the NGS results. Blood microsatellite instability (bMSI) status was determined by targeted sequencing of 100 microsatellite loci. One hundred sixty-nine (84.5%) patients carried at least one genomic alteration and 138 (69%) patients had at least one deleterious or likely deleterious alteration (del-alteration). The clonal fraction of del-alterations was higher than that of non-del-alterations (80.1% vs 54.5%, P < 0.0001). The most frequently altered genes were TP53 (38%), LRP1B (20%), MYC (13.5%), ERBB2 (12.5%), and KRAS (11.5%). The alterations were most enriched in the TP53/cell cycle (52%) and the RTK-Ras-MAPK pathway (51.5%). The median bTMB was two (range 0 to 42). Eight patients were identified to be high bMSI, with higher median bTMB than the blood microsatellite stable (bMSS) patients (15 vs 2, P = 0.0062). Patients harboring del-alterations of the DDR pathway had significantly higher percentages of high bTMB and bMSI-H patients than the wild-type subgroup (61.1% vs 6.5%, P < 0.0001; 33.3% vs 1.7%, P = 0.0002). A total of 45.5% cases harbored at least one potentially actionable alteration and one patient achieved complete response after receiving matched targeted therapy. Our study uncovered the molecular characterization of Chinese patients with advanced GAC from ctDNA, including genomic alteration, bTMB, and bMSI status. The findings suggested that targeted NGS-based ctDNA analysis may help inform the clinical decision in advanced GAC. KEY MESSAGES: We report the molecular profiling of the largest Chinese advance stage GACs cohort using a CLIA-certified ctDNA assay. Potentially actionable genomic alterations were identified in 45.5% of patients, suggesting clinical utility for ctDNA NGS in advance stage GACs. There was evidence of clinical benefit in one GAC patient with MET amplification treated with MET inhibitor.
Publication Date: 2021-06-01
Journal: Journal of molecular medicine (Berlin, Germany)
Taking Aim at the Undruggable.
The term "undruggable" is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into "druggable" targets. Thus, "difficult to drug" or "yet to be drugged" are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmacologically targeting these intractable proteins is now a key challenge of modern drug development, requiring innovation and the development of new technologies. In this article, we discuss some of the recent technologic and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe recent successes in drugging the undruggable
Publication Date: 2021-05-15
Journal: American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
[Comprehensive Genomic Analysis for Small Cell Lung Cancer].
Small cell lung cancer(SCLC)is one of the histological types of lung cancer showing the worst prognosis, and is often diagnosed as an inoperable advanced stage disease. Recently, several comprehensive genomic analyses for SCLC have shown that inactivating mutations of tumor suppressor genes such as TP53 and RB1 and MYC family gene amplifications are involved in the development and progression of SCLC. However, actionable gene alterations for targeted therapies have not yet been identified, and there has been no significant advance in the development of targeted therapies for SCLC. In a nationwide lung cancer genome screening project in Japan, LC‒SCRUM‒Japan, a large‒scale genomic analysis was prospectively performed for Japanese SCLC patients, and based on this genomic analysis, a clinical study to evaluate the efficacy of a targeted therapy for PI3K/AKT/mTOR pathway gene‒altered SCLC(EAGLE‒PAT trial)was conducted. In this article, we describe the results of the genomic analysis in LC‒SCRUM‒Japan and the EAGLE‒PAT trial, and also provide the overview of genetic alterations reported in SCLC and the current and future development of targeted therapies for SCLC.
Publication Date: 2021-05-13
Journal: Gan to kagaku ryoho. Cancer & chemotherapy
MAP-kinase and JAK-STAT pathways dysregulation in plasmablastic lymphoma.
Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology and plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma (BL), plasma cell myeloma (PCM) and some variants of diffuse large B-cell lymphoma (DLBCL) may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated thirty-four PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, EBVnegative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors related to EBV infection.
Publication Date: 2021-05-07
Uterine serous carcinoma.
Serous endometrial cancer represents a relative rare entity accounting for about 10% of all diagnosed endometrial cancer, but it is responsible for 40% of endometrial cancer-related deaths. Patients with serous endometrial cancer are often diagnosed at earlier disease stage, but remain at higher risk of recurrence and poorer prognosis when compared stage-for-stage with endometrioid subtype endometrial cancer. Serous endometrial cancers are characterized by marked nuclear atypia and abnormal p53 staining in immunohistochemistry. The mainstay of treatment for newly diagnosed serous endometrial cancer includes a multi-modal therapy with surgery, chemotherapy and/or radiotherapy. Unfortunately, despite these efforts, survival outcomes still remain poor. Recently, The Cancer Genome Atlas (TCGA) Research Network classified all endometrial cancer types into four categories, of which, serous endometrial cancer mostly is found within the "copy number high" group. This group is characterized by the increased cell cycle deregulation (e.g., CCNE1, MYC, PPP2R1A, PIKCA, ERBB2 and CDKN2A) and TP53 mutations (90%). To date, the combination of pembrolizumab and lenvatinib is an effective treatment modality in second-line therapy, with a response rate of 50% in advanced/recurrent serous endometrial cancer. Owing to the unfavorable outcomes of serous endometrial cancer, clinical trials are a priority. At present, ongoing studies are testing novel combinations of various targeted and immunotherapeutic agents in newly diagnosed and advanced/recurrent endometrial cancer - an important strategy for serous endometrial cancer, whereby tumors are usually p53+ and pMMR, making response to PD-1 inhibitor monotherapy unlikely. Here, the rare tumor working group (including members from the European Society of Gynecologic Oncology (ESGO), Gynecologic Cancer Intergroup (GCIG), and Japanese Gynecologic Oncology Group (JGOG)), performed a narrative review reporting on the current landscape of serous endometrial cancer and focusing on standard and emerging therapeutic options for patients affected by this difficult disease.
Publication Date: 2021-05-04
Journal: Gynecologic oncology
Elevated APOBEC mutational signatures implicate chronic injury in etiology of an aggressive head-and-neck squamous cell carcinoma: a case report.
Aggressive squamous cell carcinomas (SCCs) present frequently in the context of chronic skin injury occurring in patients with the congenital blistering disease recessive dystrophic epidermolysis bullosa. Recently, these cancers were shown to harbor mutation signatures associated with endogenous deaminases of the active polynucleotide cytosine deaminase family, collectively termed APOBEC, and clock-like COSMIC [Catalogue of Somatic Mutations in Cancer] signatures, which are associated with normal aging and might result from cumulative DNA replication errors. We present a case of a nasal septal SCC arising in the context of recurrent injury, but also modest past tobacco use. Our genetic analysis of this tumor reveals unusually high APOBEC and clock-like but low tobacco-related COSMIC signatures, suggesting that chronic injury may have played a primary role in somatic mutation. This case report demonstrates how signature-based analyses may implicate key roles for certain mutagenic forces in individual malignancies such as head-and-neck SCC, with multiple etiological origins.
We report the case of a 43-year-old male former smoker who presented with congestion and swelling following a traumatic nasal fracture. During surgery, the mucosa surrounding the right nasal valve appeared abnormal, and biopsies revealed invasive keratinizing SCC. Frozen section biopsies revealed multiple areas to be positive for SCC. Gene sequencing showed loss of PTEN (exons 2-8), CDKN2A/B and TP53 (exons 8-9), MYC amplification, and BLM S338*. Exome sequencing data also revealed that 36% of mutations matched an APOBEC mutational signature (COSMIC signatures 2 and 13) and 53% of mutations matched the clock-like mutation signature (COSMIC signature 5). These proportions place this tumor in the 90th percentile bearing each signature, independently, in a reference data set combining cutaneous and The Cancer Genome Atlas (TCGA) head and neck SCC data. In contrast, few mutations harbored a tobacco-related COSMIC signature 4, representing about the 10th percentile in our reference SCC data set. The patient was treated with partial rhinectomy with local flap reconstruction, bilateral neck dissection, and adjuvant radiation therapy; the patient remains disease-free to date.
Based on comparative mutational signature analysis, we propose that the history of tobacco use and traumatic injury may have collaborated in activating APOBEC enzymes and the clock-like mutational process, ultimately leading to cancer formation. Clinical awareness of the relationship between epithelial injury and tumorigenesis should enhance earlier detection of this particularly aggressive type of cancer.
Publication Date: 2021-05-01
Journal: Journal of medical case reports
The Clinical Implications of Tumor Mutational Burden in Osteosarcoma.
Osteosarcoma (OTS) is aggressive bone malignancy without well-recognized prognosis biomarker. Tumor mutational burden (TMB) has been proved as effective biomarker in predicting clinical outcomes in several cancer types. However, its prognostic value in OTS remains unknown. In this study, we aim to evaluate the implication of TMB in OTS patients.
To depict the landscape of somatic mutations in OTS, we performed Whole-Exome Sequencing (WES) on 31 OTS tissue samples and corresponding White Blood Cells (WBCs) as matched control. TMB was calculated as the total number of somatic alterations in coding regions normalized to the per sequenced genomic megabase (~30.4Mb in WES). The prognostic values of TMB were evaluated by Kaplan-Meier methods and Cox regression models.
The median age was 16.0 years at diagnosis, and 54.8% of patients were male. The most common genetic alterations were mainly involved in cell cycle and DNA damage response and repair, including H3F3A, TP53, MYC, and CDKN2A/B. The median progression-free survival (PFS) was 775.5 days in TMB-High (defined as third quartile of TMB value, <2.565) versus 351 days in TMB-Low (<2.565). All patients with TMB-High are PFS-Long (>400 days), while 36.4% of all patients with TMB-Low were PFS-Long (
TMB-High can be used as prognostic marker for OTS. Our findings demonstrate that TMB may be helpful in combination with traditionally clinicopathologic risk factors to optimize risk stratification and guide treatment decisions.
Publication Date: 2021-04-27
Journal: Frontiers in oncology