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The majority of esophageal squamous dysplasia (ESD) patients progress slowly, while a subset of patients can undergo recurrence rapidly or progress to invasive cancer even after proper treatment. However, the molecular mechanisms underlying these clinical observations are still largely unknown.

Abstract Background Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine.

Background: Osteosarcoma is a leading subtype of bone tumor affecting adolescents and adults. Comparative molecular characterization among different age groups, especially in pediatric, adolescents and adults, is scarce. Methods: We collected samples from 194 osteosarcoma patients, encompassing pediatric, adolescent, and adult cohorts. Genomic analyses were conducted to reveal prevalent mutations and compare molecular features in pediatric, adolescent, and adult patients. Results: Samples from 194 osteosarcoma patients across pediatric to adult ages were analyzed, revealing key mutations such as TP53, FLCN, NCOR1, and others. Children and adolescents showed more gene amplifications and HRD mutations, while adults had a greater Tumor Mutational Burden (TMB). Mutations in those over 15 were mainly in cell cycle and PI3K/mTOR pathways, while under 15s had more in cell cycle and angiogenesis with higher VEGFA, CCND3, TFEB mutations. CNV patterns varied with age: VEGFA and XPO5 amplifications more in under 25s, and CDKN2A/B deletions in over 25s. Genetic alterations in genes like MCL1 and MYC were associated with poor prognosis, with VEGFA mutations also indicating worse outcomes. 58% of patients had actionable mutations, suggesting opportunities for targeted therapies. Age-specific patterns were observed, with Multi-TKI mutations more common in younger patients and CDK4/6 inhibitor mutations in adults, highlighting the need for personalized treatment approaches in osteosarcoma. In a small group of patients with VEGFR amplification, postoperative treatment with multi-kinase inhibitors resulted in a PR in 3 of 13 cases, especially in patients under 15. A significant case involved a 13-year-old with a notable tumor size reduction achieving PR, even with other genetic alterations present in some patients with PD. Conclusion: This study delineates the molecular differences among pediatric, adolescent, and adult osteosarcoma patients at the genomic level, emphasizing the necessity for precision diagnostics and treatment strategies, and may offer novel prognostic biomarkers for patients with osteosarcoma. These findings provide a significant scientific foundation for the development of individualized treatment approaches tailored to patients of different age groups. [ABSTRACT FROM AUTHOR]

Context Patients with differentiated thyroid cancer (DTC) with distant metastasis (DM) are usually not recognized as radioactive iodine (RAI)-refractory DTC in a timely manner. The elucidation of genetic features related to RAI uptake patterns may shed light on the early recognition of RAI-refractory DTC. Objective This work aimed to elucidate the underlying molecular features behind different RAI uptake patterns. Methods A total of 214 patients with DM-DTC were retrospectively included in the analysis. RAI uptake patterns were defined as initially RAI refractory (I-RAIR) and initially RAI avid (I-RAIA) according to the first post-treatment scan, then I-RAIA was further divided into continually RAIA (C-RAIA), partly RAIR (P-RAIR), and gradually RAIR (G-RAIR) according to subsequent scans. The molecular subtype groups— BRAFV600E mutated, RAS mutated, fusions, and others—were classified according to main driver genes status. Results BRAF , TERT promoter, and TP53 mutations are more frequently detected in the I-RAIR pattern while RET fusions and RAS mutations are more frequent in the I-RAIA pattern. A late-hit mutation including TERT , TP53 , or PIK3CA is more common in I-RAIR than that in I-RAIA (50.0% vs 26.9%, P =.001), particularly for those with RAS mutations in the I-RAIR group, always accompanied by TERT promoter. Isolated RET fusions accounts for 10% of I-RAIR. When compared among driver gene groups, BRAFV600E -mutated tumors have a higher rate of the I-RAIR pattern (64.4%) than RAS -mutated (4.5%, P <.001) and fusion-positive (20.7%, P <.001) tumors. In I-RAIA subgroups, BRAFV600E -mutated tumors have lower prevalence of the C-RAIA pattern than those with RAS mutation or fusions. Conclusion Patients with the I-RAIR pattern predominantly featured mutations of the BRAF and/or TERT promoter, of which RAS mutations were usually accompanied by late-hit mutations, while fusions mostly occurred alone. [ABSTRACT FROM AUTHOR]

Background: Natural killer/T cell lymphoma (NKTCL) is a clinically and genetically heterogeneous disease with poor prognosis. Genome sequencing and mutation characterization provides a powerful approach for patient stratification, treatment target discovery, and etiology identification. However, previous studies mostly concentrated on base-level mutations in primary NKTCL, whereas the large-scale genomic alterations in NKTCL and the mutational landscapes in relapsed/refractory NKTCL remain largely unexplored. Methods: Here, we assembled whole-genome sequencing and whole-exome sequencing data from 163 patients with primary or relapsed/refractory NKTCL and compared their somatic mutational landscapes at both nucleotide and structure levels. Results: Our study not only confirmed previously reported common NKTCL mutational targets like STAT3, TP53, and DDX3X but also unveiled several novel high-frequency mutational targets such as PRDM9, DST, and RBMX. In terms of the overall mutational landscape, we observed striking differences between primary and relapsed/refractory NKTCL patient groups, with the latter exhibits higher levels of tumor mutation burden, copy number variants (CNVs), and structural variants (SVs), indicating a strong signal of genomic instability. Complex structural rearrangements such as chromothripsis and focal amplification are also significantly enriched in relapsed/refractory NKTCL patients, exerting a substantial impact on prognosis. Accordingly, we devised a novel molecular subtyping system (i.e., C0–C4) with distinct prognosis by integrating potential driver mutations at both nucleotide and structural levels, which further provides an informative guidance for novel treatments that target these specific driver mutations and genome instability as a whole. Conclusions: The striking differences underlying the mutational landscapes between the primary and relapsed/refractory NKTCL patients highlight the importance of genomic instability in driving the progression of NKTCL. Our newly proposed molecular subtyping system is valuable in assisting patient stratification and novel treatment design towards a better prognosis in the age of precision medicine. [ABSTRACT FROM AUTHOR]

Oral leukoplakia (OLK) is a common type of potentially malignant disorder. Early identification of the malignancy potential leads to a better management of OLK and prediction of development of oral squamous cell carcinoma (OSCC). However, there has been no effective biomarker to assess the risk of malignancy in OLK. Genomic copy number alteration (CNA) is a complex chromosomal structural variation in the genome and has been identified as a potential biomarker in multiple cancers. This study aimed to develop a predictive model for the malignant transformation risk of OLK by copy number analysis. A total of 431 OLK samples with long-term follow-up (median follow-up of 67 mo) from multiple academic centers were analyzed for CNAs. CNA events increased with the severity of hyperplasia, mild dysplasia, moderate dysplasia, and severe dysplasia. More CNA events were present in patients with OLK who later developed OSCC than in those with OLK who did not. By multivariate Cox regression analysis, the OLK of the CNA scorehigh group showed an increased risk of malignant transformation than the CNA scorelow group (P < 0.001). A CNA score model was developed to accurately predict the prognosis (area under the receiver operating characteristic curve [AUC] = 0.879; 95% confidence interval [CI], 0.799–0.959) and was validated using data from 2 external centers (AUC = 0.836, 95% CI, 0.683–0.989; AUC = 0.876, 95% CI, 0.682–1.000), and all of them showed better prediction performances than histopathological grade in assessing the transformation risk of OLK. Furthermore, we performed CNA models among 4 subgroups of OLK with hyperplasia, mild dysplasia, moderate dysplasia, and severe dysplasia and found that CNA score can accurately predict malignant transformation of different subgroups. CNA score may be a useful biomarker to predict malignant transformation of OLK. Subtyping of OLK by the CNA score could contribute to better management of OLK and predicting development of OSCC. [ABSTRACT FROM AUTHOR]

Background: Tertiary lymphoid structure (TLS) is a unique organ that carries out tumor cell elimination at tumor sites. It is continuously stimulated by inflammatory tumor signals and has been found to augment immunotherapy response. However, the detailed mechanisms behind it still need to be defined. Methods: To explore and grasp the whole picture of TLS from a pan-cancer view, we collected nine TLS-related genes from previous studies. We performed a comprehensive analysis of 9637 samples across 33 tumor types accessed from The Cancer Genome Atlas (TCGA) database. EdU, Transwell, and flow cytometry were performed on the feature gene PTGDS in U251 cells. The regulatory role of PTGDS on PD-L1 expression and macrophage polarization was verified. Results: Alteration analysis showed that mutations of TLS-related genes were widespread and relatively high. Clustering analysis based on the expression of these nine genes obtained two distinct clusters, with high EIF1AY and PTGDS in cluster 2 and better overall survival in cluster 1. To distinguish the two clusters, we utilized six machine learning algorithms and filtrated EIF1AY, PTGDS, SKAP1, and RBP5 as the characteristic genes, among which the former two genes were proved to be hazardous. PTGDS was found to regulate PD-L1 expression and also promoted the proliferation and migration of U251 cells. The knockdown of PTGDS could reduce the migration of macrophages and inhibit the polarization of macrophages into M2-phenotype. In addition, we established a TLS score to demonstrate patients’ TLS activity. The low TLS-score group overlapped with cluster 1 and displayed a better prognosis. Besides, the low TLS-score group was related to better immunotherapy responses. The HE staining of histopathological sections confirmed that the low TLS-score group exhibited higher infiltration of immune cells. Conclusion: This study reveals broad molecular, tumorigenic, and immunogenic signatures for further functional and therapeutic studies of tertiary lymphoid structure. The TLS score we established effectively predicted immunotherapy response and patients’ survival. Its future application and combination await more research.

Abstract Background Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer. We performed a systematic review and meta‐analysis to evaluate the prevalence of genomic alterations in NEPC and better understand its molecular features to potentially inform precision medicine. Methods EMBASE, PubMed, and Cochrane Central Register of Controlled Trials databases were searched for eligible studies until March 2022. Study qualities were assessed using the Q‐genie tool. The prevalence of gene mutations and copy number alterations (CNAs) were extracted, and meta‐analysis was performed using R Studio with meta package. Results A total of 14 studies with 449 NEPC patients were included in this meta‐analysis. The most frequently mutated gene in NEPC was TP53 (49.8%), and the prevalence of deleterious mutations in ATM/BRCA was 16.8%. Common CNAs in NEPC included RB1 loss (58.3%), TP53 loss (42.8%), PTEN loss (37.0%), AURKA amplification (28.2%), and MYCN amplification (22.9%). RB1/TP53 alterations and concurrent RB1 and TP53 alterations were remarkably common in NEPC, with a prevalence of 83.8% and 43.9%, respectively. Comparative analyses indicated that the prevalence of (concurrent) RB1/TP53 alterations was significantly higher in de novo NEPC than in treatment‐emergent NEPC (t‐NEPC). Conclusions This study presents the comprehensive prevalence of common genomic alterations and potentially actionable targets in NEPC and reveals the genomic differences between de novo NEPC and t‐NEPC. Our findings highlight the importance of genomic testing in patients for precision medicine and provide insights into future studies exploring different NEPC subtypes.

Genomic alterations (GA) in NF2 tumor-suppressor gene have been associated with aggressive behavior in kidney tumors. We used comprehensive genomic profiling (CGP) to evaluate the frequencies of NF2 GA in histologic subtypes of kidney tumors and co-occurring GA in other genes and biomarkers. Advanced kidney tumors included 1875 clear cell (ccRCC), 405 papillary (pRCC), 108 chromophobe (chRCC), 171 sarcomatoid (sRCC), 61 collecting duct (cdRCC), 49 medullary (mRCC), 134 unclassified (uRCC), 906 urothelial carcinoma of renal pelvis (UC), and 147 Wilms tumors underwent hybrid-capture based CGP to evaluate all classes of GA. 192 (4.9%) of kidney tumors featured NF2 GA which were predominantly structural variant mutations (89%), followed by copy number alterations (9%). Gender and age were similar between NF2 -mutant (NF2 mut) and NF2 -wild type (NF2 wt) cohorts with male preponderance. NF2 GA frequency was highest in cdRCC (30%), sRCC (21%), uRCC (15%), and pRCC (12%) while lowest in ccRCC (3%), UC (3%) Wilms tumor (1%), and chRCC (0%). NF2 mutational status was associated with loss of Ch 22 (P <.001). NF2 mut RCC harbored co-occurring GA including CDKN2A , CDKN2B , SETD2 , and BAP1. VHL , PBRM1 , PTEN , and FGFR3 GA were significantly more frequent in NF2 wt than in NF2 mut tumors. MTOR pathway GAs were uncommon in NF2 mut tumors. No NF2 mutated RCC featured MSI-high or high TMB. sRCC was associated with high PD-L1 expression. PD-L1 SP142 tumoral (P =.04) and immune cells (P =.013) were more frequent in NF2 mut as compared to NF2 wt group. Among histologic subtypes of RCC, cdRCC, sRCC, pRCC, and uRCC are enriched in NF2 GA. Co-occurrent GA in CDKN2A/B , SETD2 , and BAP1 may represent potential therapeutic targets. Higher level of PD-L1 expression in NF2 mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies. [ABSTRACT FROM AUTHOR]

Lymph node metastasis, a crucial factor in the spread of gastric cancer (GC), is strongly associated with a negative prognosis for patients. This study aimed to investigate the association of the mesothelin (MSLN) gene polymorphisms (rs3764247, rs3764246, rs12597489, rs1057147, and rs3765319) with the risk of lymph node metastasis of GC patients in a Chinese Han population. The PCR-LDR genotyping was used to detect the genotypes of MSLN polymorphisms in GC patients with lymph node metastasis (n = 610) or without (n = 356). Our research indicates that certain genetic markers, specifically rs3764247, rs3764246, rs12597489, and rs3765319, do not appear to be linked with an increased risk of lymph node metastasis in GC. However, we did observe that patients with the rs1057147 GA genotype exhibited a higher likelihood of lymph node metastasis in GC when compared to those with the GG genotype (OR = 1.33, 95% CI = 1.01 − 1.76, P = 0.045). Patients with rs1057147 GA + AA genotype were found to have a higher likelihood of lymph node involvement (OR = 1.35, 95% CI = 1.03 − 1.77, P = 0.029) when compared to those with GG genotype in the dominant model. The allelic model revealed that the A allele of rs1057147 exhibited a stronger correlation with lymph node metastasis compared to the G allele (OR = 1.28, 95% CI = 1.02 − 1.60, P = 0.031). In addition, we found that rs1057147 polymorphism revealed a poor prognosis for GC patients with lymph node metastasis. Further stratified analysis revealed that the prognostic effect of rs1057147 was more pronounced in patients with GC who had lymph node metastasis and had a tumor size of 4 cm or greater, as well as more than 2 lymph node metastases. Bioinformatics studies showed that the binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. Our study confirmed the important role of MSLN rs1057147 polymorphism locus in GC lymph node metastases and suggested a potential prognostic factor during GC progression. Key points: • Rs1057147 GA genotype had an increased risk of lymph node metastasis in gastric cancer. • The A allele of rs1057147 had a stronger association with lymph node metastasis than the G allele. • The binding mode of miR-3144-5p or miR-3619-3p to MSLN was altered by the mutation of rs1057147. [ABSTRACT FROM AUTHOR]

The treatment of World Health Organization (WHO) grades 2 and 3 meningiomas remains difficult and controversial. The pathogenesis of high-grade meningiomas was expected to be elucidated to improve treatment strategies. The molecular biology of meningiomas has been clarified in recent years. High-grade meningiomas have been linked to NF2 mutations and 22q deletion. CDKN2A/B homozygous deletion and TERT promoter mutations are independent prognostic factors for WHO grade 3 meningiomas. In addition to 22q loss, 1p, 14p, and 9q loss have been linked to high-grade meningiomas. Meningiomas enriched in copy number alterations may be biologically invasive. Furthermore, several new comprehensive classifications of meningiomas have been proposed based on these molecular biological features, including DNA methylation status. The new classifications may have implications for treatment strategies for refractory aggressive meningiomas because they provide a more accurate prognosis compared to the conventional WHO classification. Although several systemic therapies, including molecular targeted therapies, may be effective in treating refractory aggressive meningiomas, these drugs are being tested. Systemic drug therapy for meningioma is expected to be developed in the future. Thus, this review aims to discuss the distinct genomic alterations observed in WHO grade 2 and 3 meningiomas, as well as their diagnostic and therapeutic implications and systemic drug therapies for high-grade meningiomas.

Backgrounds: The pandemic of overweight and obesity (quantified by body mass index (BMI) ≥ 25) has rapidly raised the patient number of non-alcoholic fatty hepatocellular carcinoma (HCC), and several clinical trials have shown that BMI is associated with the prognosis of HCC. However, whether overweight/ obesity is an independent prognostic factor is arguable, and the role of overweight/obesity-related metabolisms in the progression of HCC is scarcely known. Materials and methods: In the present study, clinical information, mRNA expression profile, and genomic data were downloaded from The Cancer Genome Atlas (TCGA) as a training cohort (TCGA-HCC) for the identification of overweight/obesity-related transcriptome. Machine learning and the Cox regression analysis were conducted for the construction of the overweight/ obesity-associated gene (OAG) signature. The Kaplan-Meier curve, receiver operating characteristic (ROC) curve, and the Cox regression analysis were performed to assess the prognostic value of the OAG signature, which was further validated in two independent retrospective cohorts from the International Cancer Genome Consortium (ICGC) and Gene Expression Omnibus (GEO). Subsequently, functional enrichment, genomic profiling, and tumor microenvironment (TME) evaluation were utilized to characterize biological activities associated with the OAG signature. GSE109211 and GSE104580 were retrieved to evaluate the underlying response of sorafenib and transcatheter arterial chemoembolization (TACE) treatment, respectively. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic response. Results: Overweight/obesity-associated transcriptome was mainly involved in metabolic processes and noticeably and markedly correlated with prognosis and TME of HCC. Afterward, a novel established OAG signature (including 17 genes, namely, GAGE2D, PDE6A, GABRR1, DCAF8L1, DPYSL4, SLC6A3, MMP3, RIBC2, KCNH2, HTRA3, PDX1, ATHL1, PRTG, SHC4, C21orf29, SMIM32, and C1orf133) divided patients into high and low OAG score groups with distinct prognosis (median overall survival (OS): 24.87 vs. 83.51 months, p < 0.0001), and the values of area under ROC curve (AUC) in predicting 1-, 2-, 3-, and 4-year OS were 0.81, 0.80, 0.83, and 0.85, respectively. Moreover, the OAG score was independent of clinical features and also exhibited a good ability for prognosis prediction in the ICGC-LIHC-JP cohort and GSE54236 dataset. Expectedly, the OAG score was also highly correlated with metabolic processes, especially oxidative-related signaling pathways. Furthermore, abundant enrichment of chemokines, receptors, MHC molecules, and other immunomodulators as well as PD-L1/PD-1 expression among patients with high OAG scores indicated that they might have better responses to immunotherapy. However, probably exclusion of T cells from infiltrating tumors resulting in lower infiltration of effective T cells would restrict immunotherapeutic effects. In addition, the OAG score was significantly associated with the response of sorafenib and TACE treatment. Conclusions: Overall, this study comprehensively disclosed the relationship between BMI-guided transcriptome and HCC. Moreover, the OAG signature had the potential clinical applications in the future to promote clinical management and precision medicine of HCC. [ABSTRACT FROM AUTHOR]

Abstract Background HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status. Methods We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results. Results HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271). Conclusion Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors.

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.

Aim: To understand physicians' attitudes and behaviors regarding EGFR testing and retesting strategies in newly diagnosed metastatic non-small cell lung cancer patients. Materials & methods: Oncologists and pathologists completed an online, cross-sectional survey. Results: Most oncologists (73.3%) and pathologists (53.4%) agreed that concurrent testing increases sensitivity for detecting EGFR mutations. Upon tissue insufficiency, oncologists and pathologists reported using liquid biopsy 77.0% and 39.0% of the time, respectively. Tumor accessibility, smoking status, patient willingness and age were key drivers of tissue re-biopsy. Most oncologists reported high confidence in proceeding to first-line therapy based solely on liquid biopsy (60.7-80.0%); fewer pathologists (37.9%) were comfortable with this decision. Conclusion: Variation in physicians' perceptions of testing and retesting highlights the need for greater stakeholder consensus.

Summary: Scoring systems for classifying genomic alterations (GAs) with respect to their potential targeted anticancer therapies (TTs) may be useful for rational and evidence-based decision-making, for example in molecular tumor boards. Therefore, a working group of the European Society for Medical Oncology (ESMO) has developed a comprehensive and reproducible classification score that allows the ranking of GAs and TTs according to their level of evidence and clinical relevance. This score is called the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Another score not explicitly developed for TTs but helpful in grading novel TTs is the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool was designed to objectively quantify the clinical benefit of novel approved therapies. The current review summarizes the status quo of these scores and their applicability for molecular tumor boards. [ABSTRACT FROM AUTHOR]

The allure of potentially dramatic and durable responses to immunotherapy has driven the study of several immune checkpoint inhibitor (ICI) agents in ovarian cancer. However, the results of ICI therapy in ovarian cancer have been rather disappointing. It is important to understand the reasons for the poor efficacy of ICI in ovarian cancer and to look for new targets for immunotherapy. To solve this problem, ovarian cancer-associated datasets were individually collected from The Cancer Genome Atlas (TCGA)International Cancer Genome Consortium (ICGC)Genotype-Tissue Expression (GTEx), and comprehensively performed to expression, prognostic, pathological correlation, genomic and immunologic analyses of reported all immune checkpoints by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Tumor and Immune System Interaction Database (TISIDB), cBio Cancer Genomics Portal (cBioPortal), and Kaplan-Meier Plotter. We concluded that those well-identified immune checkpoints might not be ideal targets for ovarian cancer immunotherapy. Intriguingly, the genomic alteration of X-box binding protein 1 (XBP1), the important mediator of chemotherapy-induced cancer immunogenic cell death, was found to be a potential coregulator of immune checkpoints in ovarian cancer. Importantly, XBP1 was detected to be highly expressed in ovarian cancer compared with normal ovarian tissue, and high XBP1 expression significantly benefits both overall survival (OS) and disease-free survival (DFS) of ovarian cancer patients. More importantly, XBP1 was further observed to be closely related to anti-tumor immunity in ovarian cancer, including multiple T-cell signatures and immunity-killing molecules. In conclusion, upregulating XBP1 rather than targeting immune checkpoints represents a potentially more efficient approach for ovarian cancer therapy. [ABSTRACT FROM AUTHOR]

Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP/CDKN2AMUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co)mutation trends. We found significantly higher proportions of sarcomatoid)positive patients with MTAPMUT or CDKN2AMUT compared with MTAP/CDKN2A wild-type (WT) patients (P < 0.001). Of the 574 RCC samples from the FUSCC cohort and 3,563 RCC samples from 17 independent cohorts, the MTAP/ CDKN2AMUT significantly predicted extremely poor outcomes (P < 0.0001). The Western cohort suggested a concordant relationship between MTAP/ CDKN2AMUT and sarcomatoid differentiation in RCC. Moreover, although MTAP/CDKN2AMUT RCC may be insensitive to targeted therapy, the high degree of tumor heterogeneity and higher PD-L1 and CXCL13 expression characterizations reflected that MTAP/CDKN2A-deficient features could benefit from immunotherapy for patients with RCC. This study utilized RCC samples from large-scale, global, multicenter sequencing cohorts and first proved that MTAP/CDKN2A deficiency significantly correlates with sarcomatoid differentiation in RCC and predicts aggressive progression, poor prognosis, and primary resistance to targeted therapy and potential favorable responses to immune checkpoint blockade. Unlike conventional targeted therapies, emerging drugs such as immunotherapies or synthetic lethal PRMT5 inhibitors may become novel therapeutic options for patients with MTAP/CDKN2AMUT RCC. [ABSTRACT FROM AUTHOR]

Normal protein‐protein interactions (normPPIs) occur with high fidelity to regulate almost every physiological process. In cancer, this highly organised and precisely regulated network is disrupted, hijacked or reprogrammed resulting in oncogenic protein‐protein interactions (oncoPPIs). OncoPPIs, which can result from genomic alterations, are a hallmark of many types of cancers. Recent technological advances in the field of mass spectrometry (MS)‐based interactomics, structural biology and drug discovery have prompted scientists to identify and characterise oncoPPIs. Disruption of oncoPPI interfaces has become a major focus of drug discovery programs and has resulted in the use of PPI‐specific drugs clinically. However, due to several technical hurdles, studies to build a reference oncoPPI map for various cancer types have not been undertaken. Therefore, there is an urgent need for experimental workflows to overcome the existing challenges in studying oncoPPIs in various cancers and to build comprehensive reference maps. Here, we discuss the important hurdles for characterising oncoPPIs and propose a three‐phase multidisciplinary workflow to identify and characterise oncoPPIs. Systematic identification of cancer‐type‐specific oncogenic interactions will spur new opportunities for PPI‐focused drug discovery projects and precision medicine. [ABSTRACT FROM AUTHOR]

Sarcomatoid differentiation is a highly aggressive pathological characteristic of renal cell carcinoma (RCC) and is characterized by susceptibility to progression and extremely poor prognosis. In this study, we included all genomic alteration events that led to a loss of protein function of MTAP and CDKN2A, and enrolled 5,307 RCC patients with genomic sequencing data from Western and Chinese cohorts. Notably, MTAP/CDKN2AMUT occurred in the Chinese population ~2 times more frequently than in the Western cohort and showed significant co-mutation trends. We found significantly higher proportions of sarcomatoid-positive patients with MTAPMUT or CDKN2AMUT compared with MTAP/CDKN2A wild-type (WT) patients (P

Unlike early clear cell renal cell carcinoma (ccRCC), locally advanced and metastatic ccRCC present poor treatment outcomes and prognosis. As immune checkpoint inhibitors have achieved favorable results in the adjuvant treatment of metastatic ccRCC, we aimed to investigate the immunogenomic landscape during ccRCC progression and its potential impact on immunotherapy and prognosis. Using multi-omics and immunotherapy ccRCC datasets, an integrated analysis was performed to identify genomic alterations, immune microenvironment features, and related biological processes during ccRCC progression and evaluate their relevance to immunotherapy response and prognosis. We found that aggressive and metastatic ccRCC had higher proportions of genomic alterations, including SETD2 mutations, Del(14q), Del(9p), and higher immunosuppressive cellular and molecular infiltration levels. Of these, the Del(14q) might mediate immune escape in ccRCC via the VEGFA-VEGFR2 signaling pathway. Furthermore, immune-related pathways associated with ccRCC progression did not affect the immunotherapeutic response to ccRCC. Conversely, cell cycle pathways not only affected ccRCC progression and prognosis, but also were related to ccRCC immunotherapeutic response resistance. Overall, we described the immunogenomic characteristics of ccRCC progression and their correlations with immunotherapeutic response and prognosis, providing new insights into their prediction and the development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the increase of molecular biomarkers to be characterized to tailor therapeutic strategies for non-squamous non-small cell lung carcinoma (NS-NSCLC), it is now more and more challenging to evaluate these biomarkers using sequential analyses. We report here our experience concerning the development of an optimal workflow for genomic alteration assessment as reflex testing in routine clinical practice at diagnosis for NS-NSCLC patients by using an ultra-fast-next generation sequencing (NGS) approach. The analytical validation of the NGS workflow demonstrated 100% concordance with the gold standard methods. Only few cases failed for DNA/RNA NGS results. The mean turnaround time (TAT) was 72 h (ranging from 48 to 96 h). An ultra-fast NGS technique can maximize the management of the sample workflow in thoracic oncology to obtain the molecular biology results in an appropriate TAT, even when only a small amount of nucleic acids is available. The number of genomic alterations required for targeted therapy of non-squamous non-small cell lung cancer (NS-NSCLC) patients has increased and become more complex these last few years. These molecular abnormalities lead to treatment that provides improvement in overall survival for certain patients. However, these treated tumors inexorably develop mechanisms of resistance, some of which can be targeted with new therapies. The characterization of the genomic alterations needs to be performed in a short turnaround time (TAT), as indicated by the international guidelines. The origin of the tissue biopsies used for the analyses is diverse, but their size is progressively decreasing due to the development of less invasive methods. In this respect, the pathologists are facing a number of different challenges requiring them to set up efficient molecular technologies while maintaining a strategy that allows rapid diagnosis. We report here our experience concerning the development of an optimal workflow for genomic alteration assessment as reflex testing in routine clinical practice at diagnosis for NS-NSCLC patients by using an ultra-fast-next generation sequencing approach (Ion Torrent Genexus Sequencer, Thermo Fisher Scientific). We show that the molecular targets currently available to personalized medicine in thoracic oncology can be identified using this system in an appropriate TAT, notably when only a small amount of nucleic acids is available. We discuss the new challenges and the perspectives of using such an ultra-fast NGS in daily practice. [ABSTRACT FROM AUTHOR]

Background: HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status.Methods: We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results.Results: HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271).Conclusion: Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors. [ABSTRACT FROM AUTHOR]

Abstract Background The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. Methods A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. Results Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. Conclusions The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

Unlike early clear cell renal cell carcinoma (ccRCC), locally advanced and metastatic ccRCC present poor treatment outcomes and prognosis. As immune checkpoint inhibitors have achieved favorable results in the adjuvant treatment of metastatic ccRCC, we aimed to investigate the immunogenomic landscape during ccRCC progression and its potential impact on immunotherapy and prognosis. Using multi-omics and immunotherapy ccRCC datasets, an integrated analysis was performed to identify genomic alterations, immune microenvironment features, and related biological processes during ccRCC progression and evaluate their relevance to immunotherapy response and prognosis. We found that aggressive and metastatic ccRCC had higher proportions of genomic alterations, including SETD2 mutations, Del(14q), Del(9p), and higher immunosuppressive cellular and molecular infiltration levels. Of these, the Del(14q) might mediate immune escape in ccRCC via the VEGFA-VEGFR2 signaling pathway. Furthermore, immune-related pathways associated with ccRCC progression did not affect the immunotherapeutic response to ccRCC. Conversely, cell cycle pathways not only affected ccRCC progression and prognosis, but also were related to ccRCC immunotherapeutic response resistance. Overall, we described the immunogenomic characteristics of ccRCC progression and their correlations with immunotherapeutic response and prognosis, providing new insights into their prediction and the development of novel therapeutic strategies.

Immunogenicity, influenced by tumor antigenicity and antigen presenting efficiency, critically determines the effectiveness of immune checkpoint inhibitors. The role of immunogenicity has not been fully elucidated in gliomas. In this study, a large-scale bioinformatics analysis was performed to analyze the prognostic value and predictive value of antigen presentation machinery (APM) signature in gliomas. ssGSEA algorithm was used for development of APM signature and LASSO regression analysis was used for construction of APM signature-based risk score. APM signature and risk score showed favorable performance in stratifying survival and predicting tumorigenic factors of glioma patients. APM signature and risk score were also associated with different genomic features in both training cohort TCGA and validating cohort CGGA. Furthermore, APM signature-based risk score was independently validated in three external cohorts and managed to predict immunotherapy response. A prognostic nomogram was constructed based on risk score. Risk score-derived CALR was found to mediate the invasion and polarization of macrophages based on the coculture of HMC3 and U251 cells. CALR could significantly predict immunotherapy response. In conclusion, APM signature and APM signature-based risk score could help promote the clinical management of gliomas. [ABSTRACT FROM AUTHOR]

Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two subtypes of esophageal cancer with diverse epidemiology and pathogenesis as well as different molecular profiles. This review analyzes the genomic alterations in ESCC and EAC and summarizes the potential therapeutic targets of ESCC and EAC. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Early diagnosis and continuous monitoring are necessary for an efficient management of cervical cancers (CC). Liquid biopsy, such as detecting circulating tumor DNA (ctDNA) from blood, is a simple, non-invasive method for testing and monitoring cancer markers. However, tumor-specific alterations in ctDNA have not been extensively investigated or compared to other circulating biomarkers in the diagnosis and monitoring of the CC. Therfore, Next-generation sequencing (NGS) analysis with blood samples can be a new approach for highly accurate diagnosis and monitoring of the CC. Method Using a bioinformatics approach, we designed a panel of 24 genes associated with CC to detect and characterize patterns of somatic single-nucleotide variations, indels, and copy number variations. Our NGS CC panel covers most of the genes in The Cancer Genome Atlas (TCGA) as well as additional cancer driver and tumor suppressor genes. We profiled the variants in ctDNA from 24 CC patients who were being treated with systemic chemotherapy and local radiotherapy at the Jeonbuk National University Hospital, Korea. Result Eighteen out of 24 genes in our NGS CC panel had mutations across the 24 CC patients, including somatic alterations of mutated genes (ZFHX3–83%, KMT2C-79%, KMT2D-79%, NSD1–67%, ATM-38% and RNF213–27%). We demonstrated that the RNF213 mutation could be used potentially used as a monitoring marker for response to chemo- and radiotherapy. Conclusion We developed our NGS CC panel and demostrated that our NGS panel can be useful for the diagnosis and monitoring of the CC, since the panel detected the common somatic variations in CC patients and we observed how these genetic variations change according to the treatment pattern of the patient.

Abstract Background Glioblastoma is the most malignant tumor of the central nervous system. Several prediction models have been produced to aid in prognosis assessment. Age, a primary decision factor for prognosis, is associated with increased genomic alterations, however the exact link between increased age and poor prognosis is unknown. Objective In this study, we aimed to reveal the underlying cause of poor prognosis in elderly patients. Methods This study included data on 616 primary GBM tumor samples from the CGGA and TCGA databases and 41 nontumor brain tissue samples obtained from GSE53890. Hallmarks and clinicopathological characteristics were evaluated in both tumor and nontumor brain tissues. The association between choice of treatment regimen and age was measured using ANOVA and Student's t test. Results Age was a robust predictor of poor prognosis in glioma. No age‐related hallmarks of cancer were detected, including pathological characteristics or mutations. However, treatment choice was strongly significantly different between old and young patients. Combined chemo‐radiation therapy could benefit old and young GBM patients, however, old patients are currently less likely to choose it. Conclusion The vast divergence in prognosis between young and old GBM patients is largely caused by choice of treatment rather than age‐related tumor genomic characteristics. Postoperative standard radio‐ and chemotherapy provide strong benefits to primary glioblastoma patients of all ages.

Immunogenicity, influenced by tumor antigenicity and antigen presenting efficiency, critically determines the effectiveness of immune checkpoint inhibitors. The role of immunogenicity has not been fully elucidated in gliomas. In this study, a large-scale bioinformatics analysis was performed to analyze the prognostic value and predictive value of antigen presentation machinery (APM) signature in gliomas. ssGSEA algorithm was used for development of APM signature and LASSO regression analysis was used for construction of APM signature-based risk score. APM signature and risk score showed favorable performance in stratifying survival and predicting tumorigenic factors of glioma patients. APM signature and risk score were also associated with different genomic features in both training cohort TCGA and validating cohort CGGA. Furthermore, APM signature-based risk score was independently validated in three external cohorts and managed to predict immunotherapy response. A prognostic nomogram was constructed based on risk score. Risk score-derived CALR was found to mediate the invasion and polarization of macrophages based on the coculture of HMC3 and U251 cells. CALR could significantly predict immunotherapy response. In conclusion, APM signature and APM signature-based risk score could help promote the clinical management of gliomas.

Introduction: Upfront next-generation sequencing (NGS) in patients with metastatic NSCLC has been associated with cost savings and shorter time-to-test results in the United States. Nevertheless, this may not apply in jurisdictions where the prevalence of patients with actionable mutations, cost of health care, and reimbursement models differ. Methods: A decision analytical model was built to compare sequential, panel, exclusionary, and upfront NGS testing in patients with metastatic NSCLC in Hong Kong. In sequential and panel testing, patients were tested for genomic alterations (GAs) with treatment followed by sequential or NGS. In exclusionary testing, EGFR and ALK were tested first, followed by NGS. For each modality, the mutation identified, time to receive testing results, and costs (2020 U.S. dollars) were estimated. Results: Exclusionary testing required the shortest time-to-results (1.6 wk) and was most cost saving. In the scenario where all patients used exclusionary testing, a cost saving of $4.6 million was expected relative to current practice, with 90.7% of actionable and 46.5% of nonactionable GAs detected; when all patients used NGS, it would be $2.9 million more expensive with a 100% GA detection rate. Results were sensitive to testing costs and the proportion of patients that continued testing. Conclusions: Exclusionary testing is the best option in terms of cost and time-to-results in Hong Kong. This finding may be applicable for other Asian countries; however, exclusionary testing does not capture all possible GAs. As more GAs become actionable and the cost of NGS declines, NGS may become a cost-saving option.

RNA binding motif protein 15 (RBM15) is a key regulatory factor involved in N6-methyladenosine (m6A) methylation. It has been reported that RBM15 plays an important role in the progress of laryngeal squamous cell carcinoma (LSCC), promoting LSCC migration and invasion. However, the role of RBM15 in human different cancers remains unknown. This study aims to analyze the prognostic value of RBM15, and to demonstrate the correlation between RBM15 expression and tumor immunity, as well as to provide clues for further mechanism research. The results showed that RBM15 was mutated or copy number varied in 25 types of cancer. RBM15 mRNA was abnormally up-regulated across various cancers. Survival analysis suggested high expression of RBM15 was associated with poor prognosis in many cancer types. Among these, it affected patients’ overall survival (OS) in 10 cancer types, disease-free interval (DFI) in 8 cancer types, progression-free interval (PFI) in 12 cancer types and disease-specific survival (DSS) in 7 cancer types. Importantly, in pancreatic adenocarcinoma (PAAD), overexpression of RBM15 is associated with patients’ OS, DFI, PFI, or DSS. In addition, RBM15 expression was positively correlated with immune infiltrating cells in kidney renal clear cell carcinoma (KIRC), brain lower grade glioma (LGG), and PAAD. Moreover, RBM15 expression showed a strong correlation with immune checkpoint markers in PAAD. Cell counting kit-8 (CCK-8) assay showed that knockdown of RBM15 significantly inhibited the proliferation of pancreatic cancer cells. PPI analysis showed USP10, USP24, SMG1, NRAS were closely connected with RBM15 alterations. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that many biological processes (BP), cellular components (CC), molecular functions (MF), cancer related pathways including “sister chromatid cohesion”, “peptidyl-serine phosphorylation”, “cell division”, “nucleoplasm”, “nucleus”, “protein binding”, “protein serine/threonine kinase activity”, “T cell receptor signaling pathway”, “Cell cycle” were regulated by RBM15 alterations. Taken together, pan-cancer analysis of RBM15 suggested it may be served as a prognostic biomarker and immunotherapeutic target for PAAD.

BackgroundHyperkeratosis of the nipple and areola (HNA) is a rare skin disease with unknown etiology. Some patients are misdiagnosed or never diagnosed, especially during the early stage of this disease. In addition, the mechanism involved in the development of HNA is still unknown, and genomic alterations have not been reported anywhere.Case InformationA 26-year-old female suffered gradual bilateral areola thickening and enlargement, with accompanying intense itching, and was diagnosed with HNA at the First Affiliated Hospital of Chongqing Medical University. No obvious abnormalities were found in laboratory test examinations such as hormone testing for estrogen, progesterone, or prolactin. Typical papillomatous skin with orthokeratotic hyperkeratosis and numerous infiltrating lymphocytes was detected through a histopathological examination. The results from RNA-sequencing showed that the molecular expression between HNA and a normal nipple and areola (NNA) was obviously different. No significant difference was found in the bilateral lesions. In addition, immune-related cell signaling pathways were overactivated in HNA compared to the control HNA.ConclusionThe typical symptoms, clinical features, and histopathological alterations presented in this case lead to a profound understanding of HNA, which can avoid the misdiagnosis and missed diagnosis of this disease at an early stage. The dysfunction of the local immune system, which was demonstrated by pathological examination and genomic analysis, suggests that anti-autoimmune therapy, such as steroid medication, may be an effective treatment for HNA at an early stage.

The immune microenvironment has profound impacts on the initiation and progression of colorectal cancer (CRC). Therefore, the goal of this article is to identify two robust immune subtypes in CRC, further provide novel insights for the underlying mechanisms and clinical management. In this study, two CRC immune subtypes were identified using the consensus clustering of immune-related gene expression profiles in the meta-GEO dataset (n = 1,198), and their reproducibility was further verified in the TCGA-CRC dataset (n = 638). Subsequently, we characterized the immune escape mechanisms, gene alterations, and clinical features of two immune subtypes. Cluster 1 (C1) was defined as the “immune cold subtype” with immune cell depletion and deficiency, while cluster 2 (C2) was designed as the “immune hot subtype”, with abundant immune cell infiltration and matrix activation. We also underlined the potential immune escape mechanisms: lack of MHC molecules and defective tumor antigen presentation capacity in C1, increased immunosuppressive molecules in C2. The prognosis and sensitivity to 5-FU, Cisplatin and immunotherapy differed between two subtypes. According to the two immune subtypes, we developed a prognosis associated risk score (PARS) with the accurate performance for predicting the prognosis. Additionally, two nomograms for overall survival (OS) and disease-free survival (DFS) were further constructed to facilitate clinical management. Overall, our research provides new references and insights for understanding and refining the CRC.

Prostate-specific membrane antigen (PSMA) is frequently overexpressed in nonprostate malignancies. This preclinical study investigated the molecular basis of the application of PMSA-targeting radiopharmaceuticals in breast cancer subtypes. Methods: The somatic copy number status and the transcriptomic and protein expressions of FOLH1 (gene name of PSMA) were analyzed across breast cancer subtypes in 998 patients from The Cancer Genome Atlas dataset. Results: FOLH1 was frequently amplified in basallike breast cancer (BLBC) (32%) compared with luminal and human epidermal growth factor receptor 2-positive subtypes (16% and 17%, respectively; P < 0.01). FOLH1 expression was higher in BLBC ( P < 0.001) and was negatively correlated with estrogen-receptor and progesterone-receptor expressions. Consistently, the PSMA protein level was higher in BLBC ( P < 0.05). Interestingly, FOLH1 expression was associated with relapse-free and distant metastasis-free survival in patients with BLBC. Conclusion: The BLBC subtype exhibited frequent amplification and overexpression of PSMA, supporting the exploration of PSMA-targeting radiopharmaceuticals in this aggressive breast cancer subtype., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Non-small cell lung cancer (NSCLC) is characterized by relatively rapid response to systemic treatments yet inevitable resistance and predisposed to distant metastasis. We thus aimed at performing sequencing analysis to determine genomic events and underlying mechanisms concerning drug resistance in NSCLC. We performed targeted sequencing of 40 medication-relevant genes on plasma samples from 98 NSCLC patients and analyzed impact of genetic alterations on clinical presentation as well as response to systemic treatments. Profiling of multi-omics data from 1024 NSCLC tissues in public datasets was carried out for comparison and validation of identified molecular events implicated in resistance. A genetic association of CYP2D6 deletion with drug resistance was identified through circulating tumor DNA (ctDNA) profiling and response assessment. FCGR3A amplification was potentially involved in resistance to EGFR inhibitors. We further verified our findings in tissue samples and focused on potential resistance mechanisms, which uncovered that depleted CYP2D6 affected a set of genes involved in EMT, oncogenic signaling as well as inflammatory pathways. Tumor microenvironment analysis revealed that NSCLC with CYP2D6 loss manifested increased levels of immunomodulatory gene expressions, PD-L1 expression, relatively high mutational burden and lymphocyte infiltration. DNA methylation alterations were also found to be correlated with mRNA expressions and copy numbers of CYP2D6. Finally, MEK inhibitors were identified by CMap as the prospective therapeutic drugs for CYP2D6 deletion. These analyses identified novel resistance mechanisms to systemic NSCLC treatments and had significant implications for the development of new treatment strategies. [ABSTRACT FROM AUTHOR]

Melanoma represents the deadliest skin cancer. Recent therapeutic developments, including targeted and immune therapies have revolutionized clinical management and improved patient outcome. This progress was achieved by rigorous molecular and functional studies followed by robust clinical trials. The identification of key genomic alterations and gene expression profiles have propelled the understanding of distinct characteristics within melanoma subtypes. The aim of this review is to summarize and highlight the main genetic and epigenetic findings of melanomas and highlight their pathological and therapeutic importance. [ABSTRACT FROM AUTHOR]

BackgroundThe characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated.MethodsGenomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations.ResultsA total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1–4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB, TEX10-NTRK2 fusion, who may benefit from larotrectinib or entrectinib treatment.ConclusionThe genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs.

ObjectiveBladder urothelial carcinoma (BUC) is a common urological malignancy with molecular heterogeneity. However, the genetic feature of Chinese BUC patients is still not well-identified.MethodsWe performed deep sequencing by a large panel (450 genes) on 22 BUC samples and using matched normal bladder tissue as control. Genomic alterations (GAs), pathways and Tumor Mutation Burden (TMB) were investigated.ResultsThe frequencies of GAs (TERT, 54.5%; CREBBP, 27.3%; GATA3, 22.7%; BRAF, 18.2%; TEK, 18.2% and GLI1, 18.2%) were significantly higher in Chinese than Western BUC patients. Other GAs’ frequencies were in accordance with previous study (TP53, 50.0%; KDM6A, 31.8%; KMT2D, 22.7%; etc.). Besides, we detected gene amplification in ERBB2, FRS2, FAS, etc. The gene fusion/rearrangement took place in the chromosome 11, 12, 14, 17, 19, 22, and Y. Other than cell cycle and PI3K-AKT-mTOR, mutated genes were more associated with the transcription factor, chromatin modification signaling pathways. Interestingly, the TMB value was significantly higher in the BUC patients at stages T1–T2 than T3–T4 (P = 0.025).ConclusionDeep genomic sequencing of BUC can provide new clues on the unique GAs of Chinese patients and assist in therapeutic decision.

Genomic alterations constitute crucial elements of colorectal cancer (CRC). However, a comprehensive understanding of CRC genomic alterations from a global perspective is lacking. In this study, a total of 2,778 patients in 15 public datasets were enrolled. Tissues and clinical information of 30 patients were also collected. We successfully identified two distinct mutation signature clusters (MSC) featured by massive mutations and dominant somatic copy number alterations (SCNA), respectively. MSC-1 was associated with defective DNA mismatch repair, exhibiting more frequent mutations such as ATM, BRAF, and SMAD4. The mutational co-occurrences of BRAF-HMCN and DNAH17-MDN1 as well as the methylation silence event of MLH-1 were only found in MSC-1. MSC-2 was linked to the carcinogenic process of age and tobacco chewing habit, exhibiting dominant SCNA such as MYC (8q24.21) and PTEN (10q23.31) deletion as well as CCND3 (6p21.1) and ERBB2 (17q12) amplification. MSC-1 displayed higher immunogenicity and immune infiltration. MSC-2 had better prognosis and significant stromal activation. Based on the two subtypes, we identified and validated the expression relationship of FAM83A and IDO1 as a robust biomarker for prognosis and distant metastasis of CRC in 15 independent cohorts and qRT-PCR data from 30 samples. These results advance precise treatment and clinical management in CRC.

ObjectivesVarious genomic alterations and genomic signatures, including ERBB2 amplification, mutations in PIK3CA, AKT1, and ESR1, and tumor mutational burden (TMB), have become important biomarkers for treatment selection in breast cancer (BC). This study aimed to investigate the mutational features of Chinese early-stage BC patients.MethodsTumors and matched blood samples collected from 589 Chinese patients with early-stage BC were sequenced using a commercial gene panel consisting of 520 cancer-related genes to analyze all types of genomic alterations and estimate the TMB status.ResultsA total of 18 genes were found to be more frequently mutated (P10mutations/Mb were found in 5.7% of our cohort. Although the TMB was similar for various molecular subtypes between our cohort and the BC cohort of The Cancer Genome Atlas (TCGA) study, the TMB were statistically different for HR+/HER-, HR+/HER2+, and triple-negative subtypes between our cohort and African Americans in the TCGA study. As compared to the TCGA BC cohort, our cohort had a much earlier median age of diagnosis (48 vs. 58 years, P

Background: The characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated. Methods: Genomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations. Results: A total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1–4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB, TEX10 - NTRK2 fusion, who may benefit from larotrectinib or entrectinib treatment. Conclusion: The genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs. [ABSTRACT FROM AUTHOR]

Objective: Bladder urothelial carcinoma (BUC) is a common urological malignancy with molecular heterogeneity. However, the genetic feature of Chinese BUC patients is still not well-identified. Methods: We performed deep sequencing by a large panel (450 genes) on 22 BUC samples and using matched normal bladder tissue as control. Genomic alterations (GAs), pathways and Tumor Mutation Burden (TMB) were investigated. Results: The frequencies of GAs (TERT , 54.5%; CREBBP , 27.3%; GATA3 , 22.7%; BRAF , 18.2%; TEK , 18.2% and GLI1 , 18.2%) were significantly higher in Chinese than Western BUC patients. Other GAs' frequencies were in accordance with previous study (TP53 , 50.0%; KDM6A , 31.8%; KMT2D , 22.7%; etc.). Besides, we detected gene amplification in ERBB2, FRS2, FAS , etc. The gene fusion/rearrangement took place in the chromosome 11, 12, 14, 17, 19, 22, and Y. Other than cell cycle and PI3K-AKT-mTOR, mutated genes were more associated with the transcription factor, chromatin modification signaling pathways. Interestingly, the TMB value was significantly higher in the BUC patients at stages T1–T2 than T3–T4 (P = 0.025). Conclusion: Deep genomic sequencing of BUC can provide new clues on the unique GAs of Chinese patients and assist in therapeutic decision. [ABSTRACT FROM AUTHOR]

Objectives: Various genomic alterations and genomic signatures, including ERBB2 amplification, mutations in PIK3CA , AKT1 , and ESR1 , and tumor mutational burden (TMB), have become important biomarkers for treatment selection in breast cancer (BC). This study aimed to investigate the mutational features of Chinese early-stage BC patients. Methods: Tumors and matched blood samples collected from 589 Chinese patients with early-stage BC were sequenced using a commercial gene panel consisting of 520 cancer-related genes to analyze all types of genomic alterations and estimate the TMB status. Results: A total of 18 genes were found to be more frequently mutated (P <0.05) or amplified (P <0.05) in stage T3–4 tumors as compared with T1–2 tumors. A total of 18 genes were found to be differentially mutated (P <0.05) or amplified (P <0.05) in patients with lymph node metastasis than those without lymph node metastasis. Younger patients (≤35 years) were more frequently identified with mutations or gene amplifications in eleven genes (P <0.05). TMB >10mutations/Mb were found in 5.7% of our cohort. Although the TMB was similar for various molecular subtypes between our cohort and the BC cohort of The Cancer Genome Atlas (TCGA) study, the TMB were statistically different for HR+/HER-, HR+/HER2+, and triple-negative subtypes between our cohort and African Americans in the TCGA study. As compared to the TCGA BC cohort, our cohort had a much earlier median age of diagnosis (48 vs. 58 years, P <0.001), and had significantly lower frequency of triple-negative subtype (11.5% vs. 18.4%, P <0.001) and invasive lobular BC (2.4% vs. 19.0%, P <0.001). Further subgroup analyses revealed that mutation rates in various genes including TP53 , ERBB2 , and PIK3CA were distinct for patients who were younger (≤35 years), had triple-negative or invasive lobular BC in our cohort than in the TCGA cohort. Conclusions: This study revealed distinct mutational features of various molecular subtypes of early-stage BC among Chinese patients. Moreover, we provide new insights into the differences in early-stage BC between the East and West. [ABSTRACT FROM AUTHOR]

Genomic alterations constitute crucial elements of colorectal cancer (CRC). However, a comprehensive understanding of CRC genomic alterations from a global perspective is lacking. In this study, a total of 2,778 patients in 15 public datasets were enrolled. Tissues and clinical information of 30 patients were also collected. We successfully identified two distinct mutation signature clusters (MSC) featured by massive mutations and dominant somatic copy number alterations (SCNA), respectively. MSC-1 was associated with defective DNA mismatch repair, exhibiting more frequent mutations such as ATM, BRAF , and SMAD4. The mutational co-occurrences of BRAF - HMCN and DNAH17 - MDN1 as well as the methylation silence event of MLH-1 were only found in MSC-1. MSC-2 was linked to the carcinogenic process of age and tobacco chewing habit, exhibiting dominant SCNA such as MYC (8q24.21) and PTEN (10q23.31) deletion as well as CCND3 (6p21.1) and ERBB2 (17q12) amplification. MSC-1 displayed higher immunogenicity and immune infiltration. MSC-2 had better prognosis and significant stromal activation. Based on the two subtypes, we identified and validated the expression relationship of FAM83A and IDO1 as a robust biomarker for prognosis and distant metastasis of CRC in 15 independent cohorts and qRT-PCR data from 30 samples. These results advance precise treatment and clinical management in CRC. [ABSTRACT FROM AUTHOR]