The Cancer Genome Atlas Program Research Articles

The increasing incidence of uterine serous cancers in the elderly and Black women: what molecular markers can guide novel treatment approaches for these patients?

<h3>Objectives:</h3> To evaluate rare histologic subtypes of uterine cancer in women older than 70 years of age using four large national databases. <h3>Methods:</h3> Incidence rates were estimated in elderly women diagnosed at age 70+ years old with uterine cancer between 2001 and 2016 from the United States Cancer Statistics (USCS) program after correcting for hysterectomy and pregnancy prevalence from the Behavioral Risk Factor Surveillance System. SEER*Stat and Joinpoint regression were used to calculate the incidence rate (per 100,000) and average annual percent change (AAPC). Data from National Cancer Institute Genomic Data Commons Data Portal including The Cancer Genome Atlas Program (TCGA) were obtained to evaluate genomic features that vary between racial groups. <h3>Results:</h3> There were 206,600 women in the USCS registry with uterine cancer diagnosed at 70+ years old between 2001 and 2016. The incidence of endometrioid endometrial carcinoma increased modestly whereas the incidence of uterine carcinosarcoma remained relatively flat over the 15 year study period. In contrast, the incidence of serous carcinomas rose significantly in each of the elderly age groups: 70-74, 75-79, and 80+ (with an annual percent increase of 5.7%, 5.1% and 4.3%, respectively; P<0.001). Black women diagnosed between 70 and 74 years old had the highest incidence of serous histology (61/100,000), with an annual increase of 7.3% between 2001 and 2016 (P<0.001). Based on current projections, the incidence of serous uterine cancer in Black women between 70 and 74 years will surpass that in endometrioid histology by the year 2030 (Fig. 1). We then evaluated the molecular markers related to targetable novel therapies in Black vs White elderly patients. There were 284 eligible uterine cancer patients diagnosed at >70 year old and 57% of the tumors from Black patients (n=42) expressed TP53 vs 44% from White patients (n=153, P=0.12). In contrast, expression between Black and White women was consistent for HER2 (10% vs 7%; P=0.62), PTEN (33% vs 46%; p=0.13), POLE (7% vs 9%; P=0.68), <i>BRCA1</i> (3% vs 5%; P=0.64), and <i>BRCA2</i> (7% vs 8%; P=0.77), respectively. <h3>Conclusions:</h3> There is a significant increase in serous uterine cancer in elderly black patients at an annual rate of 7% that is projected to surpass endometrioid adenocarcinoma within 10 years. Further research must be conducted into potential treatments such as targetable therapies to provide clinical benefit for these patients with overall poorer prognosis.

The increasing incidence of uterine cancers in younger women

<h3>Objectives:</h3> To evaluate the incidence and genetic profiling trends in uterine cancer for women younger than 50 years of age in the United States. <h3>Methods:</h3> Incidence rates were estimated from the United States Cancer Statistics (USCS) program for uterine cancers diagnosed at < 50 years old between 2001 and 2016 after correcting for hysterectomy and pregnancy prevalence from the Behavioral Risk Factor Surveillance System. SEER*Stat and Joinpoint regression were used to calculate the incidence rate (per 100,000) and average annual percent change (AAPC). Data from National Cancer Institute Genomic Data Commons Data Portal including The Cancer Genome Atlas Program (TCGA) were obtained to compare genomic profiles by age. <h3>Results:</h3> There were 93,693 eligible women diagnosed <50 years old with uterine cancer between 2001 to 2016. The highest incidence was reported for women between the ages of 45 and 49 years old (33.84/100,000) compared with the younger cohorts (<45 years old). In addition, uterine cancer incidence per 100,000 increased between 2001 and 2016 for each age group<45 years of age including those 30-34 years old (3.8 to 5.8), 35-39 years old (7.7 to 11.4) and 40-44 years old (15.8 to 19.9, all p<0.001). The highest annual increase in uterine cancer diagnosed in the 30-34 year old age group was 4.4% for Hispanic women compared with 3.5% for Black women and 1.5% for White women. We then evaluated a panel of targetable molecular markers in young women diagnosed with uterine cancer at <50 years old (n=96) relative to older women diagnosed ≥50 years old (n=1,005). Tumors from younger women were more likely to express <i>BRCA1</i> (11% vs. 4%; P=0.004), <i>BRCA2</i> (14% vs. 8%; P=0.06), CDK12 (9% vs 4%; P=0.02), POLE (15% vs 8%; P=0.02), and less likely to express TP53 (14% vs 27%; P=0.005). <h3>Conclusions:</h3> The incidence of uterine cancer in young women is increasing in the United States, especially for Black and Hispanic women. Tumors from younger patients may have molecular markers associated with targetable agents and may portend better prognosis.

The increasing incidence of uterine serous cancers in the elderly and Black women: what molecular markers can guide novel treatment approaches for these patients?

<h3>Objectives:</h3> To evaluate rare histologic subtypes of uterine cancer in women older than 70 years of age using four large national databases. <h3>Methods:</h3> Incidence rates were estimated in elderly women diagnosed at age 70+ years old with uterine cancer between 2001 and 2016 from the United States Cancer Statistics (USCS) program after correcting for hysterectomy and pregnancy prevalence from the Behavioral Risk Factor Surveillance System. SEER*Stat and Joinpoint regression were used to calculate the incidence rate (per 100,000) and average annual percent change (AAPC). Data from National Cancer Institute Genomic Data Commons Data Portal including The Cancer Genome Atlas Program (TCGA) were obtained to evaluate genomic features that vary between racial groups. <h3>Results:</h3> There were 206,600 women in the USCS registry with uterine cancer diagnosed at 70+ years old between 2001 and 2016. The incidence of endometrioid endometrial carcinoma increased modestly whereas the incidence of uterine carcinosarcoma remained relatively flat over the 15 year study period. In contrast, the incidence of serous carcinomas rose significantly in each of the elderly age groups: 70-74, 75-79, and 80+ (with an annual percent increase of 5.7%, 5.1% and 4.3%, respectively; P<0.001). Black women diagnosed between 70 and 74 years old had the highest incidence of serous histology (61/100,000), with an annual increase of 7.3% between 2001 and 2016 (P<0.001). Based on current projections, the incidence of serous uterine cancer in Black women between 70 and 74 years will surpass that in endometrioid histology by the year 2030 (Fig. 1). We then evaluated the molecular markers related to targetable novel therapies in Black vs White elderly patients. There were 284 eligible uterine cancer patients diagnosed at >70 year old and 57% of the tumors from Black patients (n=42) expressed TP53 vs 44% from White patients (n=153, P=0.12). In contrast, expression between Black and White women was consistent for HER2 (10% vs 7%; P=0.62), PTEN (33% vs 46%; p=0.13), POLE (7% vs 9%; P=0.68), <i>BRCA1</i> (3% vs 5%; P=0.64), and <i>BRCA2</i> (7% vs 8%; P=0.77), respectively. <h3>Conclusions:</h3> There is a significant increase in serous uterine cancer in elderly BlackBlack patients at an annual rate of 7% that is projected to surpass endometrioid adenocarcinoma within 10 years. Further research must be conducted into potential treatments such as targetable therapies to provide clinical benefit for these patients with overall poorer prognosis.

Construction and Validation of a Novel Eight-Gene Risk Signature to Predict the Progression and Prognosis of Bladder Cancer.

The progression from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) increases the risk of death. It is therefore important to find new relevant molecular models that will allow for effective prediction of the progression and prognosis of bladder cancer (BC). Using RNA-Sequence data of 49 BC patients in Shanghai tenth people’s hospital (STPH) and weighted gene co-expression network analysis methods, a co-expression network of genes was developed and three key modules associated with malignant progression were selected. Based on the genes in three key modules, an eight-gene risk signature was established using univariate Cox regression and the Least absolute shrinkage and selection operator Cox model in The Cancer Genome Atlas Program (TCGA) and validated in validation sets. Subsequently, a nomogram based on the risk signature was constructed for prognostic prediction. The mRNA and protein expression levels of eight genes in cell lines and tissues were further investigated. The novel eight-gene risk signature was closely related to the malignant clinical features of BC and could predict the prognosis of patients in the training dataset (TCGA) and four validation sets (GSE32894, GSE13507, IMvigor210 trial, and STPH). The nomogram showed good prognostic prediction and calibration. The mRNA and protein expression levels of the eight genes were differentially expressed in cell lines and tissues. In our study, we established a novel eight-gene risk signature that could predict the progression and prognoses of BC patients.

Whole-genome sequencing of phenotypically distinct inflammatory breast cancers reveals similar genomic alterations to non-inflammatory breast cancers

BackgroundInflammatory breast cancer (IBC) has a highly invasive and metastatic phenotype. However, little is known about its genetic drivers. To address this, we report the largest cohort of whole-genome sequencing (WGS) of IBC cases.MethodsWe performed WGS of 20 IBC samples and paired normal blood DNA to identify genomic alterations. For comparison, we used 23 matched non-IBC samples from the Cancer Genome Atlas Program (TCGA). We also validated our findings using WGS data from the International Cancer Genome Consortium (ICGC) and the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We examined a wide selection of genomic features to search for differences between IBC and conventional breast cancer. These include (i) somatic and germline single-nucleotide variants (SNVs), in both coding and non-coding regions; (ii) the mutational signature and the clonal architecture derived from these SNVs; (iii) copy number and structural variants (CNVs and SVs); and (iv) non-human sequence in the tumors (i.e., exogenous sequences of bacterial origin).ResultsOverall, IBC has similar genomic characteristics to non-IBC, including specific alterations, overall mutational load and signature, and tumor heterogeneity. In particular, we observed similar mutation frequencies between IBC and non-IBC, for each gene and most cancer-related pathways. Moreover, we found no exogenous sequences of infectious agents specific to IBC samples. Even though we could not find any strongly statistically distinguishing genomic features between the two groups, we did find some suggestive differences in IBC: (i) The MAST2 gene was more frequently mutated (20% IBC vs. 0% non-IBC). (ii) The TGF β pathway was more frequently disrupted by germline SNVs (50% vs. 13%). (iii) Different copy number profiles were observed in several genomic regions harboring cancer genes. (iv) Complex SVs were more frequent. (v) The clonal architecture was simpler, suggesting more homogenous tumor-evolutionary lineages.ConclusionsWhole-genome sequencing of IBC manifests a similar genomic architecture to non-IBC. We found no unique genomic alterations shared in just IBCs; however, subtle genomic differences were observed including germline alterations in TGFβ pathway genes and somatic mutations in the MAST2 kinase that could represent potential therapeutic targets.

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer.

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management.

Inhibition of DKC1 induces telomere-related senescence and apoptosis in lung adenocarcinoma

BackgroundLung cancer is one of the most widely spread cancers in the world and half of the non-small cell lung cancers are lung adenocarcinoma (LUAD). Although there were several drugs been approved for LUAD therapy, a large portion of LUAD still cannot be effectively treated due to lack of available therapeutic targets. Here, we investigated the oncogenic roles of DKC1 in LUAD and its potential mechanism and explored the possibility of targeting DKC1 for LUAD therapy.MethodsThe Gene Expression Omnibus (GEO) and The Cancer Genome Atlas Program (TCGA) databases were used to examine the DKC1 transcript levels. Gene expression with clinical information from tissue microarray of LUAD were analyzed for associations between DKC1 expression and LUAD prognosis. In addition, loss- and gain-of-function assays were used for oncogenic function of DKC1 both in vitro and in vivo.ResultsDKC1 is overexpressed in LUAD compared with adjacent normal tissues. High expression of DKC1 predicts the poor overall survival. DKC1 knockdown in LUAD cell lines induced G1 phase arrest and inhibited cell proliferation. Ectopic expression of DKC1 could rescue the growth of LUAD cell lines. In addition, the abundance of DKC1 is positively correlated with telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) levels in LUAD. DKC1 downregulation resulted in decreased TERC expression, reduced telomerase activity and shorten telomere, and thus eventually led to cell senescence and apoptosis.ConclusionsOur results show that high DKC1 expression indicates poor prognosis of LUAD and DKC1 downregulation could induce telomere-related cell senescence and apoptosis. This study suggests that DKC1 could serve as a candidate diagnostic biomarker and therapeutic target for LUAD.

Exploration of the Associations of lncRNA Expression Patterns with Tumor Mutation Burden and Prognosis in Colon Cancer

BackgroundTumor mutation burden (TMB) is emerging as a new biomarker to monitor the response of cancer patients to immunotherapy. Long non-coding RNAs (lncRNAs) are critical in regulating gene expression and play a significant role in cancer-associated immune responses. However, the association between lncRNA expression patterns and TMB levels and survival outcomes remains unknown in colon cancer.MethodsIn colon cancer patients from The Cancer Genome Atlas Program (TCGA), a multi-lncRNAs based classifier for predicting TMB levels was established using the least absolute shrinkage and selection operator (LASSO) method. The association between classifier index and immune-related characteristics of patients was also investigated. Quantitative polymerase chain reaction (qPCR) was used to verify the expression levels of these lncRNAs in normal and CRC cell lines.ResultsThe multi-lncRNAs based classifier had ability to predict TMB level of patients with accuracy (AUC= 0.70), and the general applicability of this classifier was proved in the validation set (AUC= 0.71) and the pooled set (AUC= 0.70). The classifier index was related to three immune checkpoints (PD1, PD-L1, and CTLA-4), the infiltration level of immune cells, and immune response-related score (IFN-γ score, gene expression profiles (GEP) score, cytolytic activity (CYT) score and MHC score). A nomogram, which integrates classifier and some common clinical information, was able to predict the overall survival of colon cancer patients accurately.ConclusionLncRNA expression patterns are associated with TMB, which may serve as a classifier to predict the TMB in colon cancer patients. The nomogram could potentially evaluate survival outcomes and provide a reference to better manage colon cancer patients.

PTGS2 Over-Expression: A Colorectal Carcinoma Initiator not an Invasive Factor.

Cyclooxygenase-2 (COX-2) main product is Prostaglandin E2 (PGE2) which cause mitogenesis and inflammation. COX-2 is the product of prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression. COX-2 dysregulation can cause angiogenesis, differentiation, and promotion of cancer and its suppression related to control of the tumor's size, number, and cell shape. This study focused on the association of COX-2 expression with colorectal carcinoma (CRC) among Iranian patients on mRNA level and in the Cancer Genome Atlas Program (TCGA) colon and rectum RNAseq dataset, and its relation with pathological features. PTGS2 expression was assayed by quantitative-PCR method from 90 tissue samples collected from 45 participants. The control samples come from the non-tumor area of the same patients. The data analyzed based on ΔΔCq. The PTGS2-RNAseq data extracted and analyzed by UCSC Xena browser, and its association assessed the occurrence of CRC and invasive-features. PTGS2 showed very significant over-expression in tumor tissues (p< 0.0001) with an N-fold expression of 2.25. But, there was not any significant association between PTGS2 and CRC invasive-pathological features such as Lymphatic, vascular and perineural invasion, the Grades of cancer, and Pathologic-M in both parts of this study. The increase in PTGS2 is related to the occurrence of CRC among patient samples. But in both part of this study, PTGS2 is not an invasive factor, and it does not affect the cell differentiation of tumors and metastasis. Based on the high N-fold for patient samples, it can be a strong candidate as a CRC initiator biomarker.

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation.

Tumor repopulation during cycles of radiotherapy limits the radio-response in ensuing cycles and causes failure of treatment. It is thus of vital importance to unveil the mechanisms underlying tumor repopulating cells. Increasing evidence suggests that a subpopulation of drug-tolerant persister cancer cells (DTPs) could survive the cytotoxic treatment and resume to propagate. Whether these persister cells contribute to development of radio-resistance remains elusive. Based on the genetic profiling of DTPs by integrating datasets from Gene Expression Omnibus database, this study aimed to provide novel insights into tumor-repopulation mediated radio-resistance and identify predictive biomarkers for radio-response in clinic. A prognostic risk index, grounded on four persister genes (LYNX1, SYNPO, GADD45B, and PDLIM1), was constructed in non-small-cell lung cancer patients from The Cancer Genome Atlas Program (TCGA) using stepwise Cox regression analysis. Weighted gene co-expression network analysis further confirmed the interaction among persister-gene based risk score, radio-response and overall survival time. In addition, the predictive role of risk index was validated in vitro and in other types of TCGA patients. Gene set enrichment analysis was performed to decipher the possible biological signaling, which indicated that two forces behind persister cells, stress response and survival adaptation, might fuel the tumor repopulation after radiation. Targeting these persister cells may represent a new prognostic and therapeutic approach to enhance radio-response and prevent radio-resistance induced by tumor repopulation.

Long Non-Coding RNA LINC00662 Regulated Proliferation and Migration by Targeting miR-34a-5p/LMAN2L Axis in Glioma.

BackgroundNumerous studies suggest that long non-coding RNAs (lncRNAs) participate in the biological process of diverse malignancies, including glioma. Although many differentially expressed lncRNAs have been identified in glioma, to our best knowledge, the role of LINC00662 and its potential underlying mechanism in glioma progression remains unclear. This study aimed to explore the function and regulatory network of LINC00662 in glioma.MethodsExpressions of LINC00662, miR-34a-5p and lectin mannose-binding 2-like (LMAN2L) in glioma tissues were analyzed using The Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases. Colony formation, Celltiter-Glo and BrdU (5-bromo-2ʹ-deoxyuridine) incorporation assays were used to detect cell proliferation in vitro. Xenograft mouse models were established to determine cell proliferation in vivo. Transwell and wound healing assay was used to detect cell migration. In addition, epithelial–mesenchymal transition (EMT) markers were detected by Western blot. Annexin V and 7-AAD were used to stain apoptotic cells. Interactions between miR-34a-5p and LINC00662 or the 3′-UTR of LMAN2L were predicted and determined by bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation (RIP) assays.ResultsHigh LINC00662 level predicted poor overall survival of glioma patients. Functional studies revealed that suppression of LINC00662 remarkably inhibited cell proliferation, clonogenicity and EMT pathway. Mechanistically, LINC00662 sponged miR-34a-5p to regulate LMAN2L expression. Furthermore, miR-34a-5p inhibitor reversed the anti-proliferation and anti-migration effect of LINC00662 knockdown, which could be rescued by downregulation of LMAN2L in glioma cells.ConclusionOur study was the first to report that LINC00662 acted as a competing endogenous RNA (ceRNA) to regulate glioma progression by targeting miR-34a-5p/LMAN2L axis, providing a new therapeutic target for glioma.

Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment.

The syndecan (Sdc) family is comprised of four members of cell surface molecules (Sdc-1 to 4) with different biological functions. Syndecan-3 (Sdc-3) is known to be mainly expressed in the brain and nervous tissue and plays a key role in development, cell adhesion, and migration. Recent studies point to important roles for Sdc-3 in inflammatory disease, but the patterns of expression and significance of Sdc-3 in cancer remains unexplored. Here we show that Sdc-3 expression is upregulated on several cancer types, especially in solid tumors that are known to be hypoxic. The Cancer Genome Atlas program (TCGA) data demonstrated that Sdc-3 expression in the tumor microenvironment positively correlates with a hypoxia gene signature. To confirm a potential cause-effect, we performed experiments with tumor cell lines showing increased expression upon in vitro exposure to 1% oxygen or dimethyloxalylglycine, an inhibitor of prolyl hydroxylases, indicating that Sdc-3 expression is promoted by hypoxia inducible factors (HIFs). HIF-1α was responsible for this upregulation as confirmed by CRISPR-engineered tumor cells. Using single-cell RNA sequencing data of melanoma patients, we show that Sdc-3 is expressed on tumor associated macrophages, cancer cells, and endothelial cells. Syndecan-3 expression positively correlated with a macrophage gene signature across several TCGA cancer types. In vitro experiments demonstrated that hypoxia (1% oxygen) or treatment with IFN-γ stimulate Sdc-3 expression on RAW-264.7 derived macrophages, linking Sdc-3 expression to a proinflammatory response. Syndecan-3 expression correlates with a better patient overall survival in hypoxic melanoma tumors.

Favorable Immune Microenvironment in Patients with EGFR and MAPK Co-Mutations.

PurposeAlthough EGFR-mutated patients generally do not benefit from checkpoint inhibitors (ICIs), some patients in the KEYNOTE-001 study consistently benefited from this treatment. This study investigated immune microenvironment characteristics to identify the subgroup of patients that may benefit from ICIs.Materials and MethodsUsing data from The Cancer Genome Atlas Program (TCGA) and Cancer Proteome Atlas, TMB and protein level of PD-L1 were explored in the patients with EGFR mutations and wild-type patients. Different patterns of EGFR mutations (according to EGFR co-mutation with different downstream pathway genesets) were used to group EGFR mutation population. Estimated infiltration analyses were used to explore changes in the immune microenvironment.ResultsThis study analyzed somatic mutation data from 1287 patients from five cohorts (TCGA, Broad, The Tumour Sequencing Project, Memorial Sloan Kettering Cancer Center, Catalogue Of Somatic Mutations In Cancer database). The probability of EGFR mutation was approximately 14.30% (184/1287) and the co-mutation rate was 11.41% (21/184) in patients with EGFR mutations. Glycosaminoglycan-related pathways were significantly upregulated in the EGFR mutant group. EGFR-mutated patients had lower TMB and PD-L1 protein levels than those in wild-type patients. Increase immature DCs infiltration and decreased NK CD56dim, T gamma delta, cytotoxic, and Th2 cell infiltration were the main immune changes in EGFR-mutated patients. Patients with EGFR-MAPK co-mutations had higher levels of TMB and PD-L1 protein expression. Meanwhile, the co-mutated patients had a similar immune microenvironment as that in wild-type patients.ConclusionIn this study, we defined a subgroup of patients with EGFR-MAPK co-mutations. These co-mutated patients may benefit from ICI treatment.

Identification of Novel Tumor-Microenvironment-Regulating Factor That Facilitates Tumor Immune Infiltration in Colon Cancer

Colon cancer is one of the most common malignancies causing death worldwide. It is well known that the cells of the tumor microenvironment contribute to the progression and prognosis of colon cancer. However, the gene alterations and potential remodeling mechanisms in the tumor microenvironment of colon cancer remain largely unknown. In this study, immune scores from the ESTIMATE algorithm were used to discriminate between patients with high or low immune-cell infiltration. There were 42 immune differentially expressed genes (DEGs) of prognostic value identified in this study. Among them, KCNJ5 is a key factor in promoting M2 macrophage recruitment and tumor immune infiltration in colon cancer. These findings may provide novel insights for decoding the complicated interplay between cancer cells and the tumor microenvironment as well as for developing new avenues for therapeutic intervention in colon cancer.

Tumor Infiltrating Lymphocytes Signature as a New Pan-Cancer Predictive Biomarker of Anti PD-1/PD-L1 Efficacy.

Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors.

Yottixel - An Image Search Engine for Large Archives of Histopathology Whole Slide Images.

With the emergence of digital pathology, searching for similar images in large archives has gained considerable attention. Image retrieval can provide pathologists with unprecedented access to the evidence embodied in already diagnosed and treated cases from the past. This paper proposes a search engine specialized for digital pathology, called Yottixel, a portmanteau for "one yotta pixel," alluding to the big-data nature of histopathology images. The most impressive characteristic of Yottixel is its ability to represent whole slide images (WSIs) in a compact manner. Yottixel can perform millions of searches in real-time with a high search accuracy and low storage profile. Yottixel uses an intelligent indexing algorithm capable of representing WSIs with a mosaic of patches which are then converted into barcodes, called "Bunch of Barcodes" (BoB), the most prominent performance enabler of Yottixel. The performance of the prototype platform is qualitatively tested using 300 WSIs from the University of Pittsburgh Medical Center (UPMC) and 2,020 WSIs from The Cancer Genome Atlas Program (TCGA) provided by the National Cancer Institute. Both datasets amount to more than 4,000,000 patches of 1000×1000 pixels. We report three sets of experiments that show that Yottixel can accurately retrieve organs and malignancies, and its semantic ordering shows good agreement with the subjective evaluation of human observers.

A signature of 14 immune-related gene pairs predicts overall survival in gastric cancer.

Increasing evidence demonstrates that immune signature plays an important role in the prognosis of gastric cancer (GC). We aimed to develop and validate a robust immune-related gene pair (IRGP) signature for predicting the prognosis of GC patients. RNA-Seq data and corresponding clinical information of GC cohort were downloaded from the TCGA (The Cancer Genome Atlas Program) data portal. GSE84437 and GSE15459 microarray datasets were included as independent external cohorts. Least absolute shrinkage and selection operator (LASSO) regression analysis was used to build the best prognostic signature. All patients were classified into the high immune-risk and low immune-risk groups via the optimal cut-off of the signature scores determined by time-dependent receiver-operating characteristic (ROC) curve analysis. The prognostic role of the signature was measured by a log-rank test and a Cox proportional hazard regression model. 14 immune gene pairs consisting of 25 unique genes were identified to construct the immune prognostic signature. High immune-risk groups showed poor prognosis in the TCGA datasets and GSE84437 datasets as well as in the GSE15459 datasets (all P < 0.001). The 14-IRGP signature was an independent prognostic factor of GC after adjusting for other clinical factors (P < 0.05). Functional analysis revealed that DNA integrity checkpoint, DNA replication, T-cell receptor signaling pathway, and B-cell receptor signaling pathway were enriched in the low immune-risk groups. B cells naive and Monocytes were significantly higher in the high-risk group, and B-cell memory and T-cell CD4 memory activated were significantly higher in the low-risk group. The prognostic signature based on IRGP reflected infiltration by several types of immune cells. The novel proposed clinical-immune signature is a promising biomarker for prediction overall survival in patients with GC and providing new insights into the treatment strategies.

The prognostic significance of fibroblast activation protein-α in human lung adenocarcinoma.

BackgroundFibroblast activation protein (FAP) is a type II cell surface-bound integral serine protease, which is an important biomarker of cancer-associated fibroblasts. FAP-α performs several biological activities, including remolding extracellular matrix and acting as an immunosuppressor in the tumor microenvironment. However, the proliferation role of FAP-α in human lung adenocarcinoma has not been fully elucidated.MethodsThe expression of FAP-α in 94-paired human lung adenocarcinoma tissues was identified by immunohistochemistry test. The effect of FAP on cell proliferation was examined by CCK-8 assay. RNA-sequencing and bioinformatics analysis were utilized to investigate the underlying mechanism. Western blot analysis, quantitative polymerase chain reaction (qPCR), and nude mice experiments, were also conducted for further validation.ResultsThe proliferation rates of human fibroblast strains FAP-HFF and FAP-BJ, and human lung adenocarcinoma cell line FAP-SPC-A-1 were higher than those of controls. The nude mice experiment also showed that FAP could promote the proliferation of SPC-A-1 cell line in vivo. qPCR and Western blot analysis indicated that CCNB1 was upregulated by the overexpression of FAP in the lung adenocarcinoma cell line. The expression of FAP-α was higher in both the cytoplasm and stroma of lung adenocarcinoma than in adjacent normal tissues. Survival analysis indicated that patients with higher expression of FAP-α in tumor stroma had a poor prognosis (P=0.019). The Cancer Genome Atlas Program (TCGA) data also showed that the expression of FAP within tumor tissues was higher (in both cytoplasm and stroma) compared with that in normal tissues (P<0.05).ConclusionsOur study indicates that FAP-α could facilitate the proliferation of lung adenocarcinoma cells and can be a prognostic marker in human lung adenocarcinoma.

Long noncoding RNA TRPM2-AS acts as a microRNA sponge of miR-612 to promote gastric cancer progression and radioresistance

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tumorigenesis and are frequently dysregulated in cancers. Here, we identify a critical lncRNA TRPM2-AS which is aberrantly expressed in gastric cancer (GC) tissues by screening The Cancer Genome Atlas Program(TCGA) database of GC cohort, and its upregulation is clinically associated with advanced pathologic stages and poor prognosis in GC patients. Silencing TRPM2-AS inhibits the proliferation, metastasis and radioresistance of GC cell whereas ectopic expression of TRPM2-AS significantly improves the progression of GC cell in multiple experiments. Mechanistically, TRPM2-AS serves as a microRNA sponge or a competitive endogenous RNA (ceRNA) for tumor suppressive microRNA miR-612 and consequently modulates the derepression of IGF2BP1 and FOXM1. Moreover, induced upregulation of IGF2BP1 subsequently increases the expression of c-Myc and promotes GC cell progression. Meanwhile, TRPM2-AS promotes the radioreistance of GC cell through enhancing the expression of FOXM1 as well. Thus, our findings support a new regulatory axis between TRPM2-AS, miR-612, IGF2BP1, or FOXM1 which serve as crucial effectors in GC tumorigenesis and malignant development, suggesting a promising therapeutic and diagnostic direction for GC.

A comprehensive genome-wide profiling comparison between HBV and HCV infected hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, especially in East Asia. Even with the progress in therapy, 5-year survival rates remain unsatisfied. Chronic infection with the hepatitis B virus (HBV) or hepatitis C virus (HCV) has been epidemiologically associated with HCC and is the major etiology in the East Asian population. The detailed mechanism, especially the changes of DNA methylation and gene expression between the two types of virus-related HCC, and their contributions to the HCC development, metastasis, and recurrence remain largely unknown.MethodsIn this integrated analysis, we characterized genome-scale profiles of HBV and HCV infected HCC by comparing their gene expression pattern, methylation profiles, and copy number variations from the publicly accessible data of The Cancer Genome Atlas Program (TCGA).ResultsThe HLA-A, STAT1, and OAS2 genes were highly enriched and up-regulated discovered in the HCV-infected HCC. Hypomethylation but not copy number variations might be the major factor for the up-regulation of these immune-related genes in HCV-infected HCC.ConclusionsThe results indicated the different epigenetic changes of HBV/HCV related hepatocarcinogenesis. The top up-regulated genes in HCV group were significantly clustered in the immune-related and defense response pathways. These findings will help us to understand the pathogenesis of HBV/HCV associated hepatocellular carcinoma.