Age-dependent molecular variations in osteosarcoma: implications for precision oncology across pediatric, adolescent, and adult patients.

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.

Genomic characterization and risk stratification of esophageal squamous dysplasia.

Objectives: 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. Methods: By sequencing the genomic data of 160 clinical samples from 49 tumor-free ESD patients and 88 esophageal squamous cell carcinoma (ESCC) patients, we demonstrated lower somatic mutation and copy number alteration (CNA) burden in ESD compared with ESCC. Results: Cross-species screening and functional assays identified ACSM5 as a novel driver gene for ESD progression. Furthermore, we revealed that miR-4292 promoted ESD progression and could serve as a non-invasive diagnostic marker for ESD. Conclusions: These findings largely expanded our understanding of ESD genetics and tumorigenesis, which possessed promising significance for improving early diagnosis, reducing overtreatment, and identifying high-risk ESD patients.

Frequent Amplification and Overexpression of PSMA in Basallike Breast Cancer from Analysis of The Cancer Genome Atlas.

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.

Full-spectral genome analysis of natural killer/T cell lymphoma highlights impacts of genome instability in driving its progression.

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.

The tertiary lymphoid structure-related signature identified PTGDS in regulating PD-L1 and promoting the proliferation and migration of glioblastoma.

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.

Copy Number Alterations Predict Development of OSCC from Oral Leukoplakia.

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.

Characterizing Genetic Alterations Related to Radioiodine Avidity in Metastatic Thyroid Cancer.

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.

Expanded detection of BAP1 alterations in cancer and tumor type-specific expression score comparison.

BAP1 is a tumor suppressor gene that was originally studied in uveal melanoma (UVM), kidney renal cell clear cell carcinoma (KIRC), and malignant mesothelioma (MESO). Early analyses focused on single-nucleotide variants, but other alteration types such as larger indels and gene-level copy number (CN) loss can also lead to loss of BAP1 expression. We performed integrated multi-omic analyses using data from The Cancer Genome Atlas (TCGA) for 33 cancer types and more than 10,000 individuals. We combined and manually reviewed existing variant calls and new calls derived from a de novo local realignment pipeline across multiple independent variant callers including indel callers, increasing detection of high-quality somatic variant calls by 30% from 91 to 130, including 7 indels ≥40bp. Including CN loss alterations, 1561 samples from 32 cancer types were BAP1-altered, with alterations being predominantly CN-driven. Differential expression and survival analyses revealed both shared and tissue-specific consequences associated with BAP1 alteration. Our findings broadly emphasize the improvements that are gained by using new computational approaches in large cancer-genome studies such as TCGA.

HPV-positive clinically advanced squamous cell carcinoma of the urinary bladder (aBSCC): A comprehensive genomic profiling (CGP) study.

BACKGROUND: Advanced bladder squamous cell carcinoma (aBSCC) is an uncommon form of urinary bladder malignancy when compared with the much higher urothelial carcinoma incidence. We studied the genomic alteration (GA) landscape in a series of aBSCC based on the association with human papilloma virus (HPV) to determine if differences in GA would be observed between the positive and negative groups. METHODS: Using a hybrid capture-based FDA-approved CGP assay, a series of 171 aBSCC were sequenced to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Programmed cell death ligand -1 (PD-L1) expression was determined by IHC (Dako 22C3) with negative expression when PD-L1 was 0, lower expression of positivity set at 1 to 49%, and higher expression set at ≥50% expression. RESULTS: Overall, 11 (6.4%) of the aBSCC were found to harbor HPV sequences (10 HPV16 and 1 HPV 11). HPV+ status was identified slightly more often in women (NS) and in younger patients (P = 0.04); 2 female patients with aBSCC had a prior history of SCC including 1 anal SCC and 1 vaginal SCC. HPV+ aBSCC had fewer GA/tumor (P < 0.0001), more inactivating mutations in RB1 (P = 0.032), and fewer inactivating GA in CDKN2A (P < 0.0001), CDKN2B (P = 0.05), TERT promoter (P = 0.0004) and TP53 (P < 0.0001). GA in genes associated with urothelial carcinoma including FGFR2 and FGFR3 were similar in both HPV+ and HPV- aBSCC groups. MTAP loss (homozygous deletion) which has emerged as a biomarker for PRMT5 inhibitor-based clinical trials was not identified in any of the 11 HPV+ aBSCC cases, which was significantly lower than the 28% positive frequency of MTAP loss in the HPV- aBSCC group (P < 0.0001). MTOR and PIK3CA pathway GA were not significantly different in the 2 groups. Putative biomarkers associated with immunotherapy (IO) response, including MSI and TMB status, were also similar in the 2 groups. PD-L1 expression data was available for a subset of both HPV+ and HPV- cases and showed high frequencies of positive staining which was not different in the 2 groups. CONCLUSIONS: HPV+ aBSCC tends to occur more often in younger patients. As reported in other HPV-associated squamous cell carcinomas, HPV+ aBSCC demonstrates significantly reduced frequencies of inactivating mutations in cell cycle regulatory genes with similar GA in MTOR and PIK3CA pathways. The implication of HPV in the pathogenesis of bladder cancer remains unknown but warrants further exploration and clinical validation.

Genomic Variations in Esophageal Squamous Cell Carcinoma and Esophageal Adenocarcinoma.

Objectives Using a comprehensive dataset derived from the American Association for Cancer Research (AACR) Project Genomics, Evidence, Neoplasia, Information, and Exchange (GENIE), we sought to demonstrate the genetic characteristics of esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC). Methodology Data were extracted from cBioPortal for cancer genomics (genie.cbioportal.org). Patients with EAC and squamous cell carcinoma were selected. To compare categorical variables, either the chi-square or Kruskal-Wallis test was used. The Benjamini-Hochberg method was applied to correct P-values, and consequently, false discovery rate-adjusted q-values were computed. When the q-value was <0.05, the P-value < 0.05 was accepted as statistically significant. Results In this study, 1,381 patients with EAC and 312 patients with ESCC were analyzed. Gene alterations were different between the two groups. In EAC, genetic alterations were detected in ERBB2, KRAS, SMAD4, and TACC3 genes, whereas ESCC exhibited alterations in CCDN1, NFE2L2, FGF19, FGF3, FGF4, NOTCH1, and CDKN2B genes. Conclusions Notably, this study showed distinct differences in gene alterations between ESCC and EAC, thereby enhancing our understanding of the genetic landscape of these tumors. Further research is required to elucidate the functional implications of these genetic variations to develop targeted therapies that can improve the prognosis of patients with esophageal cancer.

Variant allele frequency changes in TP53 predict pembrolizumab response in patients with metastatic urothelial carcinoma.

Prognoses for patients with metastatic urothelial carcinoma (mUC) have improved with pembrolizumab treatment, an immune checkpoint inhibitor, but clinical benefits are limited to a subset of patients. Therefore, a non-invasive biomarker to predict pembrolizumab response is required. The present study retrospectively examined genomic alterations in 25 plasma circulating tumor DNA (ctDNA) samples using targeted sequencing of 77 genes from 16 patients with mUC during pembrolizumab treatment. A total of 11 (68.8%) patients demonstrated ≥2 genomic alterations, including TP53 mutations (as defined by ctDNA-positive status). The proportion of responders to pembrolizumab in the ctDNA-positive group was higher compared with that in the ctDNA-negative group (72.7 vs. 20.0%). Furthermore, among all detected genomic alterations, variant allele frequency decreases in TP53 during pembrolizumab treatment were mainly associated with therapeutic response. Collectively, these data suggest that profiling of ctDNA in plasma, particularly TP53, may be useful for predicting and monitoring therapeutic responses to pembrolizumab in patients with mUC.

Targeted deep sequencing reveals the genetic heterogeneity in well-differentiated pancreatic neuroendocrine tumors with liver metastasis.

Background: Pancreatic neuroendocrine tumor is a rare and heterogeneous entity, and approximately half of the patients harbored liver metastasis when initially diagnosed, whose prognosis is dismal. High-throughput sequencing has largely uncovered the genomic features of pancreatic neuroendocrine tumor, but the genetic alterations in the metastatic cases remain relatively unclear, which we aimed to study. Methods: Pathologically confirmed well-differentiated pancreatic neuroendocrine tumor samples resected in our hospital from 2000 to 2019 were collected. We performed deep sequencing on the exome of 341 tumor-related genes, and compared the differences of genetic alterations between the metastatic and the non-metastatic cases, as well as between the primary and the paired liver metastatic tumors. Results: Sequencing data of 79 samples from 29 pancreatic neuroendocrine tumor patients were included into analysis. A total of 2,471 somatic variants were identified, 75.5% of which were considered as low-abundance. NOTCH1 was the most frequently mutated gene, altered in 26 (53.1%) pancreatic neuroendocrine tumor samples from 18 (62.1%) patients. Compared with the non-metastatic pancreatic neuroendocrine tumors, the metastatic cases were discovered with more single nucleotide variants and copy number variations, indicating the increased genomic instability. In addition, among the paired metastatic cases, the primary and the metastatic lesions shared limited mutated genes. Conclusions: Through the targeted deep sequencing, we identified the intratumor, intraindividual, and interindividual heterogeneity in the pancreatic neuroendocrine tumor patients, particularly in the metastatic cases, bringing potential challenges for the current biopsy strategies in guiding clinical treatments.

Tumor Genomic Profile Is Associated With Arterial Thromboembolism Risk in Patients With Solid Cancer.

Background: Patients with cancer have an increased risk for arterial thromboembolism (ATE). Scant data exist about the impact of cancer-specific genomic alterations on the risk for ATE. Objectives: The aim of this study was to determine whether individual solid tumor somatic genomic alterations influence the incidence of ATE. Methods: A retrospective cohort study was conducted using tumor genetic alteration data from adults with solid cancers who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets testing between 2014 and 2016. The primary outcome, ATE, was defined as myocardial infarction, coronary revascularization, ischemic stroke, peripheral arterial occlusion, or limb revascularization and identified through systematic electronic medical record assessments. Patients were followed from date of tissue-matched blood control accession to first ATE event or death, for up to 1 year. Cause-specific Cox proportional hazards regression was used to determine HRs of ATE for individual genes adjusted for pertinent clinical covariates. Results: Among 11,871 eligible patients, 74% had metastatic disease, and there were 160 ATE events. A significantly increased risk for ATE independent of tumor type was noted for the KRAS oncogene (HR: 1.98; 95% CI: 1.34-2.94; multiplicity-adjusted P = 0.015) and the STK11 tumor suppressor gene (HR: 2.51; 95% CI: 1.44-4.38; multiplicity-adjusted P = 0.015). Conclusions: In a large genomic tumor-profiling registry of patients with solid cancers, alterations in KRAS and STK11 were associated with an increased risk for ATE independent of cancer type. Further investigation is needed to elucidate the mechanism by which these mutations contribute to ATE in this high-risk population.

Polymorphism rs1057147 located in mesothelin gene predicts lymph node metastasis in patients with gastric cancer.

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.

Genomic alterations in neuroendocrine prostate cancer: A systematic review and meta-analysis.

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.

Comprehensive Genomic Profiling of NF2-Mutated Kidney Tumors Reveals Potential Targets for Therapy.

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 (NF2mut) and NF2-wild type (NF2wt) 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). NF2mut RCC harbored co-occurring GA including CDKN2A, CDKN2B, SETD2, and BAP1. VHL, PBRM1, PTEN, and FGFR3 GA were significantly more frequent in NF2wt than in NF2mut tumors. MTOR pathway GAs were uncommon in NF2mut 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 NF2mut as compared to NF2wt 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 NF2mut cohort suggests that these tumors might be sensitive to immune checkpoint inhibitor therapies.

TPD52 is a Potential Prognostic Biomarker and Correlated with Immune Infiltration: A Pan-cancer Analysis.

BACKGROUND: Some tumors have a poor prognosis regarding TPD52 (tumor protein D52). This study aims to explore TPD52's role in the cancer process from a pan-cancer perspective. METHODS: A pan-cancer analysis was conducted to investigate how TPD52 may be involved in cancer as well as its association with prognosis. RESULTS: A variety of human cancers express TPD52 abnormally and correlate with clinical stage. There was a significant association between low expression of TPD52 and poor survival in BRCA, KIRP, LAML, LIHC, UCEC, and UVM. TPD52 alterations were most frequently amplified in pan-cancer. The co-occurrence of 10 genes alterations was found in the TPD52 altered group. There was a significant association between TPD52 expression and MSI in four cancer types and TMB in twelve cancer types. There was a significant correlation between TPD52 expression and immunerelated cell infiltration. A significant correlation was found between TPD52 expression in many tumor types and 8 immune checkpoint genes. There were signaling pathways involved in pan-cancer caused by TPD52, including endocytosis, Fc gamma Rmediated phagocytosis, and so on. TPD52 may be involved in chemotherapy and chemoresistance. CONCLUSION: The TPD52 gene may be important for human cancer treatment.

Combined use of pathological and genomic alteration analyses for the diagnosis of gray zone lymphoma.

Histiocytic sarcoma (HS) is a rare malignancy showing morphologic and immunophenotypic features of histiocytes. HS has morphologic overlap with many other diseases, including various kinds of lymphomas. Gray zone lymphoma (GZL) is a rare B-cell lymphoma subtype characterized by overlapping features between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The histologic overlap with other diverse diseases of HS and the pathological diversity of GZL make it difficult to render a diagnosis. A 44-year-old woman who was initially diagnosed with HS was diagnosed with GZL after reexamination, including a genetic alteration test. After 6 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine, she achieved a complete response. Genomic alteration assessment may be useful for the accurate diagnosis of malignant lymphomas, which are difficult to diagnose, such as GZL.

Multifaceted investigation underlies diverse mechanisms contributing to the downregulation of Hedgehog pathway-associated genes INTU and IFT88 in lung adenocarcinoma and uterine corpus endometrial carcinoma.

Hedgehog (Hh) signaling primarily functions in the control of mammalian embryonic development but also has roles in cancer. The Hh activation depends on ciliogenesis, a cellular process that describes outgrowth of the primary cilium from cell membrane. Ciliogenesis initiation requires a set of proteins known as planar cell polarity (PCP) effectors. Inturned (INTU) is a PCP effector that reportedly functions synergistically with Hh signaling in basal cell carcinoma, suggesting that INTU has an oncogenic role. In this study, we carried out a pan-cancer investigation on the prognostic significance of INTU in different types of cancer. We demonstrated that INTU downregulation correlated with reduced survival probabilities in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC) patients. Similar expression patterns and prognostic values were identified for intraflagellar transport 88 (IFT88), another Hh pathway-associated gene. We elucidated multiple mechanisms at transcriptional, post-transcriptional and translational levels that involved transcription factor 4 and non-coding RNAs-associated regulatory networks contributing to the reduction of INTU and IFT88 levels in LUAD and UCEC samples. Taken together, this study demonstrates the prognostic significance of the Hh-related genes INTU and IFT88 in LUAD and UCEC and further delineates multifaceted mechanisms leading to INTU and IFT88 downregulation in tumor samples.

Genomic alteration of MTAP/CDKN2A predicts sarcomatoid differentiation and poor prognosis and modulates response to immune checkpoint blockade in renal cell carcinoma.

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.