Publications by authors named "Katherine A Hoadley"

113 Publications

UNMASC: tumor-only variant calling with unmatched normal controls.

NAR Cancer 2021 Dec 6;3(4):zcab040. Epub 2021 Oct 6.

Center for Cancer Research, University of Tennessee Health Science Center, 19 South Manassas, Memphis, TN 38163, USA.

Despite years of progress, mutation detection in cancer samples continues to require significant manual review as a final step. Expert review is particularly challenging in cases where tumors are sequenced without matched normal control DNA. Attempts have been made to call somatic point mutations without a matched normal sample by removing well-known germline variants, utilizing unmatched normal controls, and constructing decision rules to classify sequencing errors and private germline variants. With budgetary constraints related to computational and sequencing costs, finding the appropriate number of controls is a crucial step to identifying somatic variants. Our approach utilizes public databases for canonical somatic variants as well as germline variants and leverages information gathered about nearby positions in the normal controls. Drawing from our cohort of targeted capture panel sequencing of tumor and normal samples with varying tumortypes and demographics, these served as a benchmark for our tumor-only variant calling pipeline to observe the relationship between our ability to correctly classify variants against a number of unmatched normals. With our benchmarked samples, approximately ten normal controls were needed to maintain 94% sensitivity, 99% specificity and 76% positive predictive value, far outperforming comparable methods. Our approach, called UNMASC, also serves as a supplement to traditional tumor with matched normal variant calling workflows and can potentially extend to other concerns arising from analyzing next generation sequencing data.
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http://dx.doi.org/10.1093/narcan/zcab040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494212PMC
December 2021

Genomic characterization of rare molecular subclasses of hepatocellular carcinoma.

Commun Biol 2021 10 4;4(1):1150. Epub 2021 Oct 4.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy.
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http://dx.doi.org/10.1038/s42003-021-02674-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490450PMC
October 2021

Hepatocyte growth factor pathway expression in breast cancer by race and subtype.

Breast Cancer Res 2021 08 3;23(1):80. Epub 2021 Aug 3.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, 253 Rosenau Hall, CB #7435, 135 Dauer Drive, Chapel Hill, NC, USA.

Background: African American women have the highest risk of breast cancer mortality compared to other racial groups. Differences in tumor characteristics have been implicated as a possible cause; however, the tumor microenvironment may also contribute to this disparity in mortality. Hepatocyte growth factor (HGF) is a stroma-derived marker of the tumor microenvironment that may affect tumor progression differentially by race.

Objective: To examine whether an HGF gene expression signature is differentially expressed by race and tumor characteristics.

Methods: Invasive breast tumors from 1957 patients were assessed for a 38-gene RNA-based HGF gene expression signature. Participants were black (n = 1033) and non-black (n = 924) women from the population-based Carolina Breast Cancer Study (1993-2013). Generalized linear models were used to estimate the relative frequency differences (RFD) in HGF status by race, clinical, and demographic factors.

Results: Thirty-two percent of tumors were positive for the HGF signature. Black women were more likely [42% vs. 21%; RFD = + 19.93% (95% CI 16.00, 23.87)] to have HGF-positive tumors compared to non-black women. Triple-negative patients had a higher frequency of HGF positivity [82% vs. 13% in non-triple-negative; RFD = + 65.85% (95% CI 61.71, 69.98)], and HGF positivity was a defining feature of basal-like subtype [92% vs. 8% in non-basal; RFD = + 81.84% (95% CI 78.84, 84.83)]. HGF positivity was associated with younger age, stage, higher grade, and high genomic risk of recurrence (ROR-PT) score.

Conclusion: HGF expression is a defining feature of basal-like tumors, and its association with black race and young women suggests it may be a candidate pathway for understanding breast cancer disparities.
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http://dx.doi.org/10.1186/s13058-021-01460-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336233PMC
August 2021

Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guérin Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Clin Cancer Res 2021 Aug 11;27(16):4599-4609. Epub 2021 Jun 11.

Department of Surgery (Urology Service), Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Improved risk stratification and predictive biomarkers of treatment response are needed for non-muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC.

Experimental Design: Gene expression in NMIBC samples was profiled by NanoString nCounter, an RNA quantification platform, from two independent cohorts ( = 28, = 50); targeted panel sequencing was performed in a subgroup ( = 50). Gene signatures were externally validated using two RNA sequencing datasets of NMIBC tumors ( = 438, = 73). Established molecular subtype classifiers and novel gene expression signatures were assessed for associations with clinicopathologic characteristics, somatic tumor mutations, and treatment outcomes.

Results: Molecular subtypes distinguished between low-grade Ta tumors with FGFR3 mutations and overexpression (UROMOL-class 1) and tumors with more aggressive clinicopathologic characteristics (UROMOL-classes 2 and 3), which were significantly enriched with TERT promoter mutations. However, UROMOL subclasses were not associated with recurrence after bacillus Calmette-Guérin (BCG) immunotherapy in two independent cohorts. In contrast, a novel expression signature of an inflamed tumor microenvironment (TME) was associated with improved recurrence-free survival after BCG. Expression of immune checkpoint genes (PD-L1/PD-1/CTLA-4) was associated with an inflamed TME, but not with higher recurrence rates after BCG. FGFR3 mutations and overexpression were both associated with low immune signatures.

Conclusions: Assessment of the immune TME, rather than molecular subtypes, is a promising predictive biomarker of BCG response. Modulating the TME in an immunologically "cold" tumor warrants further investigation. Integrated transcriptomic and exome sequencing should improve treatment selection in NMIBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416390PMC
August 2021

Integrative modeling identifies genetic ancestry-associated molecular correlates in human cancer.

STAR Protoc 2021 Jun 19;2(2):100483. Epub 2021 Apr 19.

Center for Computational and Genomic Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Cellular and molecular aberrations contribute to the disparity of human cancer incidence and etiology between ancestry groups. Multiomics profiling in The Cancer Genome Atlas (TCGA) allows for querying of the molecular underpinnings of ancestry-specific discrepancies in human cancer. Here, we provide a protocol for integrative associative analysis of ancestry with molecular correlates, including somatic mutations, DNA methylation, mRNA transcription, miRNA transcription, and pathway activity, using TCGA data. This protocol can be generalized to analyze other cancer cohorts and human diseases. For complete details on the use and execution of this protocol, please refer to Carrot-Zhang et al. (2020).
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http://dx.doi.org/10.1016/j.xpro.2021.100483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082263PMC
June 2021

Protein-based immune profiles of basal-like vs. luminal breast cancers.

Lab Invest 2021 06 23;101(6):785-793. Epub 2021 Feb 23.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.

Tumor-infiltrating lymphocytes play an important, but incompletely understood role in chemotherapy response and prognosis. In breast cancer, there appear to be distinct immune responses by subtype, but most studies have used limited numbers of protein markers or bulk sequencing of RNA to characterize immune response, in which spatial organization cannot be assessed. To identify immune phenotypes of Basal-like vs. Luminal breast cancer we used the GeoMx® (NanoString) platform to perform digital spatial profiling of immune-related proteins in tumor whole sections and tissue microarrays (TMA). Visualization of CD45, CD68, or pan-Cytokeratin by immunofluorescence was used to select regions of interest in formalin-fixed paraffin embedded tissue sections. Forty-four antibodies representing stromal markers and multiple immune cell types were applied to quantify the tumor microenvironment. In whole tumor slides, immune hot spots (CD45+) had increased expression of many immune markers, suggesting a diverse and robust immune response. In epithelium-enriched areas, immune signals were also detectable and varied by subtype, with regulatory T-cell (T) markers (CD4, CD25, and FOXP3) being higher in Basal-like vs. Luminal breast cancer. Extending these findings to TMAs with more patients (n = 75), we confirmed subtype-specific immune profiles, including enrichment of T markers in Basal-likes. This work demonstrated that immune responses can be detected in epithelium-rich tissue, and that TMAs are a viable approach for obtaining important immunoprofiling data. In addition, we found that immune marker expression is associated with breast cancer subtype, suggesting possible prognostic, or targetable differences.
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http://dx.doi.org/10.1038/s41374-020-00506-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140991PMC
June 2021

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

Cell Rep 2021 02;34(5):108707

Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.
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http://dx.doi.org/10.1016/j.celrep.2021.108707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009291PMC
February 2021

Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.

JNCI Cancer Spectr 2021 Feb 23;5(1):pkaa072. Epub 2020 Sep 23.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Background: Black women have higher hormone receptor positive (HR+) breast cancer mortality than White women. Early recurrence rates differ by race, but little is known about genomic predictors of early recurrence among HR+ women.

Methods: Using data from the Carolina Breast Cancer Study (phase III, 2008-2013), we estimated associations between race and recurrence among nonmetastatic HR+/HER2-negative tumors, overall and by PAM50 Risk of Recurrence score, PAM50 intrinsic subtype, and tumor grade using survival curves and Cox models standardized for age and stage. Relative frequency differences (RFD) were estimated using multivariable linear regression. To assess intervention opportunities, we evaluated treatment patterns by race among patients with high-risk disease.

Results: Black women had higher recurrence risk relative to White women (crude hazard ratio = 1.81, 95% confidence interval [CI] = 1.34 to 2.46), which remained elevated after standardizing for clinical covariates (hazard ratio = 1.42, 95% CI = 1.05 to 1.93). Racial disparities were most pronounced among those with high PAM50 Risk of Recurrence score (5-year standardized recurrence risk = 18.9%, 95% CI = 8.6% to 29.1% in Black women vs 12.5%, 95% CI = 2.0% to 23.0% in White women) and high grade (5-year standardized recurrence risk = 16.6%, 95% CI = 11.7% to 21.5% in Black women vs 12.0%, 95% CI = 7.3% to 16.7% in White women). However, Black women with high-grade tumors were statistically significantly less likely to initiate endocrine therapy (RFD = -8.3%, 95% CI = -15.9% to -0.6%) and experienced treatment delay more often than White women (RFD = +9.0%, 95% CI = 0.3% to 17.8%).

Conclusions: Differences in recurrence by race appear greatest among women with aggressive tumors and may be influenced by treatment differences. Efforts to identify causes of variation in cancer treatment are critical to reducing outcome disparities.
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http://dx.doi.org/10.1093/jncics/pkaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791616PMC
February 2021

SCISSOR: a framework for identifying structural changes in RNA transcripts.

Nat Commun 2021 01 12;12(1):286. Epub 2021 Jan 12.

Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.

High-throughput sequencing protocols such as RNA-seq have made it possible to interrogate the sequence, structure and abundance of RNA transcripts at higher resolution than previous microarray and other molecular techniques. While many computational tools have been proposed for identifying mRNA variation through differential splicing/alternative exon usage, challenges in its analysis remain. Here, we propose a framework for unbiased and robust discovery of aberrant RNA transcript structures using short read sequencing data based on shape changes in an RNA-seq coverage profile. Shape changes in selecting sample outliers in RNA-seq, SCISSOR, is a series of procedures for transforming and normalizing base-level RNA sequencing coverage data in a transcript independent manner, followed by a statistical framework for its analysis ( https://github.com/hyochoi/SCISSOR ). The resulting high dimensional object is amenable to unsupervised screening of structural alterations across RNA-seq cohorts with nearly no assumption on the mutational mechanisms underlying abnormalities. This enables SCISSOR to independently recapture known variants such as splice site mutations in tumor suppressor genes as well as novel variants that are previously unrecognized or difficult to identify by any existing methods including recurrent alternate transcription start sites and recurrent complex deletions in 3' UTRs.
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http://dx.doi.org/10.1038/s41467-020-20593-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804101PMC
January 2021

In silico APC/C substrate discovery reveals cell cycle-dependent degradation of UHRF1 and other chromatin regulators.

PLoS Biol 2020 12 11;18(12):e3000975. Epub 2020 Dec 11.

Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

The anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase and critical regulator of cell cycle progression. Despite its vital role, it has remained challenging to globally map APC/C substrates. By combining orthogonal features of known substrates, we predicted APC/C substrates in silico. This analysis identified many known substrates and suggested numerous candidates. Unexpectedly, chromatin regulatory proteins are enriched among putative substrates, and we show experimentally that several chromatin proteins bind APC/C, oscillate during the cell cycle, and are degraded following APC/C activation, consistent with being direct APC/C substrates. Additional analysis revealed detailed mechanisms of ubiquitylation for UHRF1, a key chromatin regulator involved in histone ubiquitylation and DNA methylation maintenance. Disrupting UHRF1 degradation at mitotic exit accelerates G1-phase cell cycle progression and perturbs global DNA methylation patterning in the genome. We conclude that APC/C coordinates crosstalk between cell cycle and chromatin regulatory proteins. This has potential consequences in normal cell physiology, where the chromatin environment changes depending on proliferative state, as well as in disease.
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http://dx.doi.org/10.1371/journal.pbio.3000975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758050PMC
December 2020

Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment.

Cancer Cell 2021 01 19;39(1):38-53.e7. Epub 2020 Nov 19.

Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.
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http://dx.doi.org/10.1016/j.ccell.2020.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478080PMC
January 2021

Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.

J Clin Oncol 2020 12 23;38(35):4184-4193. Epub 2020 Oct 23.

Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, NC.

Purpose: CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.

Patients And Methods: Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.

Results: One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.

Conclusion: In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687PMC
December 2020

An approach for normalization and quality control for NanoString RNA expression data.

Brief Bioinform 2021 05;22(3)

University of North Carolina at Chapel Hill.

The NanoString RNA counting assay for formalin-fixed paraffin embedded samples is unique in its sensitivity, technical reproducibility and robustness for analysis of clinical and archival samples. While commercial normalization methods are provided by NanoString, they are not optimal for all settings, particularly when samples exhibit strong technical or biological variation or where housekeeping genes have variable performance across the cohort. Here, we develop and evaluate a more comprehensive normalization procedure for NanoString data with steps for quality control, selection of housekeeping targets, normalization and iterative data visualization and biological validation. The approach was evaluated using a large cohort ($N=\kern0.5em 1649$) from the Carolina Breast Cancer Study, two cohorts of moderate sample size ($N=359$ and$130$) and a small published dataset ($N=12$). The iterative process developed here eliminates technical variation (e.g. from different study phases or sites) more reliably than the three other methods, including NanoString's commercial package, without diminishing biological variation, especially in long-term longitudinal multiphase or multisite cohorts. We also find that probe sets validated for nCounter, such as the PAM50 gene signature, are impervious to batch issues. This work emphasizes that systematic quality control, normalization and visualization of NanoString nCounter data are an imperative component of study design that influences results in downstream analyses.
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http://dx.doi.org/10.1093/bib/bbaa163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138885PMC
May 2021

Comprehensive Analysis of Genetic Ancestry and Its Molecular Correlates in Cancer.

Cancer Cell 2020 05;37(5):639-654.e6

The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address:

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-associated differences spanned all molecular features and hundreds of genes. Biologically significant differences were usually tissue specific but not specific to cancer. However, admixture and pathway analyses suggested some of these differences are causally related to cancer. Specific findings included increased FBXW7 mutations in patients of African origin, decreased VHL and PBRM1 mutations in renal cancer patients of African origin, and decreased immune activity in bladder cancer patients of East Asian origin.
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http://dx.doi.org/10.1016/j.ccell.2020.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328015PMC
May 2020

A Pan-Cancer and Polygenic Bayesian Hierarchical Model for the Effect of Somatic Mutations on Survival.

Cancer Inform 2020 17;19:1176935120907399. Epub 2020 Feb 17.

Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

We built a novel Bayesian hierarchical survival model based on the somatic mutation profile of patients across 50 genes and 27 cancer types. The pan-cancer quality allows for the model to "borrow" information across cancer types, motivated by the assumption that similar mutation profiles may have similar (but not necessarily identical) effects on survival across different tissues of origin or tumor types. The effect of a mutation at each gene was allowed to vary by cancer type, whereas the mean effect of each gene was shared across cancers. Within this framework, we considered 4 parametric survival models (normal, log-normal, exponential, and Weibull), and we compared their performance via a cross-validation approach in which we fit each model on training data and estimate the log-posterior predictive likelihood on test data. The log-normal model gave the best fit, and we investigated the partial effect of each gene on survival via a forward selection procedure. Through this we determined that mutations at and were together the most useful for predicting patient survival. We validated the model via simulation to ensure that our algorithm for posterior computation gave nominal coverage rates. The code used for this analysis can be found at https://github.com/sarahsamorodnitsky/Pan-Cancer-Survival-Modeling.git, and the results are summarized at http://ericfrazerlock.com/surv_figs/SurvivalDisplay.html.
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http://dx.doi.org/10.1177/1176935120907399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029540PMC
February 2020

Genomic basis for RNA alterations in cancer.

Nature 2020 02 5;578(7793):129-136. Epub 2020 Feb 5.

BGI-Shenzhen, Shenzhen, China.

Transcript alterations often result from somatic changes in cancer genomes. Various forms of RNA alterations have been described in cancer, including overexpression, altered splicing and gene fusions; however, it is difficult to attribute these to underlying genomic changes owing to heterogeneity among patients and tumour types, and the relatively small cohorts of patients for whom samples have been analysed by both transcriptome and whole-genome sequencing. Here we present, to our knowledge, the most comprehensive catalogue of cancer-associated gene alterations to date, obtained by characterizing tumour transcriptomes from 1,188 donors of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Using matched whole-genome sequencing data, we associated several categories of RNA alterations with germline and somatic DNA alterations, and identified probable genetic mechanisms. Somatic copy-number alterations were the major drivers of variations in total gene and allele-specific expression. We identified 649 associations of somatic single-nucleotide variants with gene expression in cis, of which 68.4% involved associations with flanking non-coding regions of the gene. We found 1,900 splicing alterations associated with somatic mutations, including the formation of exons within introns in proximity to Alu elements. In addition, 82% of gene fusions were associated with structural variants, including 75 of a new class, termed 'bridged' fusions, in which a third genomic location bridges two genes. We observed transcriptomic alteration signatures that differ between cancer types and have associations with variations in DNA mutational signatures. This compendium of RNA alterations in the genomic context provides a rich resource for identifying genes and mechanisms that are functionally implicated in cancer.
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http://dx.doi.org/10.1038/s41586-020-1970-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054216PMC
February 2020

Virus expression detection reveals RNA-sequencing contamination in TCGA.

BMC Genomics 2020 Jan 28;21(1):79. Epub 2020 Jan 28.

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.

Background: Contamination of reagents and cross contamination across samples is a long-recognized issue in molecular biology laboratories. While often innocuous, contamination can lead to inaccurate results. Cantalupo et al., for example, found HeLa-derived human papillomavirus 18 (H-HPV18) in several of The Cancer Genome Atlas (TCGA) RNA-sequencing samples. This work motivated us to assess a greater number of samples and determine the origin of possible contaminations using viral sequences. To detect viruses with high specificity, we developed the publicly available workflow, VirDetect, that detects virus and laboratory vector sequences in RNA-seq samples. We applied VirDetect to 9143 RNA-seq samples sequenced at one TCGA sequencing center (28/33 cancer types) over 5 years.

Results: We confirmed that H-HPV18 was present in many samples and determined that viral transcripts from H-HPV18 significantly co-occurred with those from xenotropic mouse leukemia virus-related virus (XMRV). Using laboratory metadata and viral transcription, we determined that the likely contaminant was a pool of cell lines known as the "common reference", which was sequenced alongside TCGA RNA-seq samples as a control to monitor quality across technology transitions (i.e. microarray to GAII to HiSeq), and to link RNA-seq to previous generation microarrays that standardly used the "common reference". One of the cell lines in the pool was a laboratory isolate of MCF-7, which we discovered was infected with XMRV; another constituent of the pool was likely HeLa cells.

Conclusions: Altogether, this indicates a multi-step contamination process. First, MCF-7 was infected with an XMRV. Second, this infected cell line was added to a pool of cell lines, which contained HeLa. Finally, RNA from this pool of cell lines contaminated several TCGA tumor samples most-likely during library construction. Thus, these human tumors with H-HPV or XMRV reads were likely not infected with H-HPV 18 or XMRV.
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http://dx.doi.org/10.1186/s12864-020-6483-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986043PMC
January 2020

Genetic determinants of the molecular portraits of epithelial cancers.

Nat Commun 2019 12 11;10(1):5666. Epub 2019 Dec 11.

Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

The ability to characterize and predict tumor phenotypes is crucial to precision medicine. In this study, we present an integrative computational approach using a genome-wide association analysis and an Elastic Net prediction method to analyze the relationship between DNA copy number alterations and an archive of gene expression signatures. Across breast cancers, we are able to quantitatively predict many gene signatures levels within individual tumors with high accuracy based upon DNA copy number features alone, including proliferation status and Estrogen-signaling pathway activity. We can also predict many other key phenotypes, including intrinsic molecular subtypes, estrogen receptor status, and TP53 mutation. This approach is also applied to TCGA Pan-Cancer, which identify repeatedly predictable signatures across tumor types including immune features in lung squamous and basal-like breast cancers. These Elastic Net DNA predictors could also be called from DNA-based gene panels, thus facilitating their use as biomarkers to guide therapeutic decision making.
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http://dx.doi.org/10.1038/s41467-019-13588-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906458PMC
December 2019

Gain-of-Function Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer.

Cancer Discov 2020 02 26;10(2):288-305. Epub 2019 Nov 26.

Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOA, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOA with inactivation of the canonical tumor suppressor induces metastatic DGC in a mouse model. Biochemically, RHOA exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. mutation and loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP-TAZ, PI3K-AKT, and β-catenin. RHOA murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled with sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers. SIGNIFICANCE: The functional significance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOA mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and define how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors...
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http://dx.doi.org/10.1158/2159-8290.CD-19-0811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007383PMC
February 2020

A Consensus Molecular Classification of Muscle-invasive Bladder Cancer.

Eur Urol 2020 04 26;77(4):420-433. Epub 2019 Sep 26.

Institut Curie, PSL Research University, CNRS, UMR144, Equipe Labellisée Ligue Contre le Cancer, Paris, France.

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application.

Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the published classification schemes.

Design, Setting, And Participants: We used 1750 MIBC transcriptomic profiles from 16 published datasets and two additional cohorts.

Outcome Measurements And Statistical Analysis: We performed a network-based analysis of six independent MIBC classification systems to identify a consensus set of molecular classes. Association with survival was assessed using multivariable Cox models.

Results And Limitations: We report the results of an international effort to reach a consensus on MIBC molecular subtypes. We identified a consensus set of six molecular classes: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal/squamous (35%), and neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes. We provide a single-sample classifier that assigns a consensus class label to a tumor sample's transcriptome. Limitations of the work are retrospective clinical data collection and a lack of complete information regarding patient treatment.

Conclusions: This consensus system offers a robust framework that will enable testing and validation of predictive biomarkers in future prospective clinical trials.

Patient Summary: Bladder cancers are heterogeneous at the molecular level, and scientists have proposed several classifications into sets of molecular classes. While these classifications may be useful to stratify patients for prognosis or response to treatment, a consensus classification would facilitate the clinical use of molecular classes. Conducted by multidisciplinary expert teams in the field, this study proposes such a consensus and provides a tool for applying the consensus classification in the clinical setting.
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http://dx.doi.org/10.1016/j.eururo.2019.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690647PMC
April 2020

Assessment of Long-term Distant Recurrence-Free Survival Associated With Tamoxifen Therapy in Postmenopausal Patients With Luminal A or Luminal B Breast Cancer.

JAMA Oncol 2019 Sep;5(9):1304-1309

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Importance: Patients with estrogen receptor (ER)-positive breast cancer have a long-term risk for fatal disease. However, the tumor biological factors that influence the long-term risk and the benefit associated with endocrine therapy are not well understood.

Objective: To compare the long-term survival from tamoxifen therapy for patients with luminal A or luminal B tumor subtype.

Design, Setting, And Participants: Secondary analysis of patients from the Stockholm Tamoxifen (STO-3) trial conducted from 1976 to 1990, which randomized postmenopausal patients with lymph node-negative breast cancer to receive adjuvant tamoxifen or no endocrine therapy. Tumor tissue sections were assessed in 2014 using immunohistochemistry and Agilent microarrays. Only patients with luminal A or B subtype tumors were evaluated. Complete long-term follow-up data up to the end of the STO-3 trial on December 31, 2012, were obtained from the Swedish National registers. Data analysis for the secondary analysis was conducted in 2017 and 2018.

Interventions: Patients were randomized to receive at least 2 years of tamoxifen therapy or no endocrine therapy; patients without recurrence who reconsented were further randomized to 3 additional years of tamoxifen therapy or no endocrine therapy.

Main Outcomes And Measures: Distant recurrence-free interval (DRFI) by luminal A and luminal B subtype and trial arm was assessed by Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs) that were adjusted for patient and tumor characteristics.

Results: In the STO-3 treated trial arm, 183 patients had luminal A tumors and 64 patients had luminal B tumors. In the untreated arm, 153 patients had luminal A tumors and 62 had luminal B tumors. Age at diagnosis ranged from 45 to 73 years. A statistically significant difference in DRFI by trial arm was observed (log rank, P < .001 [luminal A subtype, n = 336], P = .04 [luminal B subtype, n = 126]): the 25-year DRFI for luminal A vs luminal B subtypes was 87% (95% CI, 82%-93%) vs 67% (95% CI, 56%-82%) for treated patients, and 70% (95% CI, 62%-79%) vs 54% (95% CI, 42%-70%) for untreated patients, respectively. Patients with luminal A tumors significantly benefited from tamoxifen therapy for 15 years after diagnosis (HR, 0.57; 95% CI, 0.35-0.94), and those with luminal B tumors benefited from tamoxifen therapy for 5 years (HR, 0.38; 95% CI, 0.24-0.59).

Conclusions And Relevance: Patients with luminal A subtype tumors had a long-term risk of distant metastatic disease, which was reduced by tamoxifen treatment, whereas patients with luminal B tumors had an early risk of distant metastatic disease, and tamoxifen benefit attenuated over time.
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http://dx.doi.org/10.1001/jamaoncol.2019.1856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692699PMC
September 2019

Before and After: Comparison of Legacy and Harmonized TCGA Genomic Data Commons' Data.

Cell Syst 2019 07;9(1):24-34.e10

National Cancer Institute, Bethesda, MD 20892, USA.

We present a systematic analysis of the effects of synchronizing a large-scale, deeply characterized, multi-omic dataset to the current human reference genome, using updated software, pipelines, and annotations. For each of 5 molecular data platforms in The Cancer Genome Atlas (TCGA)-mRNA and miRNA expression, single nucleotide variants, DNA methylation and copy number alterations-comprehensive sample, gene, and probe-level studies were performed, towards quantifying the degree of similarity between the 'legacy' GRCh37 (hg19) TCGA data and its GRCh38 (hg38) version as 'harmonized' by the Genomic Data Commons. We offer gene lists to elucidate differences that remained after controlling for confounders, and strategies to mitigate their impact on biological interpretation. Our results demonstrate that the hg19 and hg38 TCGA datasets are very highly concordant, promote informed use of either legacy or harmonized omics data, and provide a rubric that encourages similar comparisons as new data emerge and reference data evolve.
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http://dx.doi.org/10.1016/j.cels.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707074PMC
July 2019

Prognostic value of B cells in cutaneous melanoma.

Genome Med 2019 05 28;11(1):36. Epub 2019 May 28.

Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Background: Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and predictive value in skin cutaneous melanoma (SKCM). Less is known about the significance of tumor-infiltrating B cells in SKCM. Our goal was to understand the prognostic and predictive value of B cell phenotypic subsets in SKCM using RNA sequencing.

Methods: We used our previously published algorithm, V'DJer, to assemble B cell receptor (BCR) repertoires and estimate diversity from short-read RNA sequencing (RNA-seq). We applied machine learning-based cellular phenotype classifiers to measure relative similarity of bulk tumor sample gene expression profiles and different B cell phenotypes. We assessed these aspects of B cell biology in 473 SKCM from the Cancer Genome Atlas Project (TCGA) as well as in RNA-seq data corresponding to tumor samples procured from patients who received CTLA-4 and PD-1 inhibitors for metastatic SKCM.

Results: We found that the BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex. However, increased clonality of the BCR repertoire was favorably prognostic in SKCM and was prognostic even after first conditioning on various clinical factors. Mutation burden was not correlated with any BCR measurement, and no specific mutation had an altered BCR repertoire. Lack of an assembled BCR in pre-treatment tumor tissues was associated with a lack of anti-tumor response to a CTLA-4 inhibitor in metastatic SKCM.

Conclusions: These findings suggest an important prognostic and predictive role for B cell characteristics in SKCM. This has implications for melanoma immunobiology and potential development of immunogenomics features to predict survival and response to immunotherapy.
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http://dx.doi.org/10.1186/s13073-019-0647-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540526PMC
May 2019

The Immune Microenvironment in Hormone Receptor-Positive Breast Cancer Before and After Preoperative Chemotherapy.

Clin Cancer Res 2019 08 6;25(15):4644-4655. Epub 2019 May 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Hormone receptor-positive/HER2-negative (HR/HER2) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR/HER2 breast tumors.

Experimental Design: HR/HER2 breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8 cells, CD68 cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.

Results: Ninety-six patients were analyzed from two cohorts ( = 55, Dana-Farber cohort; = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset ( = 302). In paired pre-/postchemotherapy samples, sTIL and CD8 cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy.

Conclusions: The immune microenvironment of HR/HER2 tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677598PMC
August 2019

FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer.

Cell Rep 2019 03;26(11):3076-3086.e6

Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

The transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship. Depleting USP21 downregulates the FOXM1 transcriptional network and causes a significant delay in cell cycle progression. Significantly, USP21 depletion sensitized BLBC cell lines and mouse xenograft tumors to paclitaxel, an anti-mitotic, frontline therapy in BLBC treatment. USP21 is the most frequently amplified deubiquitinase in BLBC patient tumors, and its amplification co-occurs with the upregulation of FOXM1 protein. Altogether, these data suggest a role for USP21 in the proliferation and potentially treatment of FOXM1-high, USP21-high BLBC.
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http://dx.doi.org/10.1016/j.celrep.2019.02.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425951PMC
March 2019

Androgen Receptor mRNA Expression in Urothelial Carcinoma of the Bladder: A Retrospective Analysis of Two Independent Cohorts.

Transl Oncol 2019 Apr 2;12(4):661-668. Epub 2019 Mar 2.

Department of Urology and Pediatric Urology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Introduction: Gender-specific differences have led to the androgen receptor (AR) being considered a possible factor in the pathophysiology of urothelial carcinoma of the bladder (UCB), but the exact role remains unclear.

Materials And Methods: The association of AR mRNA expression with clinicopathological features was retrospectively analyzed in two previously described cohorts. The first cohort consisted of 41 patients with all stages of UCB treated at Aarhus University Hospital, Denmark. The second cohort consisted of 323 patients with muscle-invasive bladder cancer (MIBC) accumulated by the Cancer Genome Atlas (TCGA) Research Network.

Results: AR mRNA expression is significantly higher in non-muscle-invasive bladder cancer (NMIBC) when compared to MIBC (P = .0004), with no relevant changes within the different stages of MIBC. AR mRNA expression was significantly associated with TCGA molecular subtypes (P < .0001). In the total cohort, there was no association between AR expression and gender (P = .23). When analyzed separately, females showed a significantly worse disease-free (P = .03) and overall survival (P = .02) when expressing AR mRNA above median level, while the same was not observed for men. Multivariable Cox's regression analyses revealed AR mRNA expression to be an independent prognostic marker for disease-free survival in women (P = .007).

Conclusions: AR mRNA expression is significantly higher in NMIBC than in MIBC, while high AR mRNA expression is associated with worse survival in females with MIBC. Further studies need to investigate the gender-specific role of AR in UCB.
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http://dx.doi.org/10.1016/j.tranon.2019.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403442PMC
April 2019

The Prognostic Significance of Low-Frequency Somatic Mutations in Metastatic Cutaneous Melanoma.

Front Oncol 2018 4;8:584. Epub 2019 Jan 4.

Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia.

Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. After limiting our DNA sequencing analysis to MM samples ( = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Four genes were potentially prognostic [; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., ) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for and . Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort ( = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up ( = 224) showed that somatic mutations in and reached borderline prognostic significance [log-rank favorable ( = 0.09) and adverse ( = 0.07), respectively]. Somatic mutations in , and to a lesser extent , were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity ( = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., ), such as and , may have prognostic significance in MM.
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http://dx.doi.org/10.3389/fonc.2018.00584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329304PMC
January 2019

Differences in race, molecular and tumor characteristics among women diagnosed with invasive ductal and lobular breast carcinomas.

Cancer Causes Control 2019 Jan 8;30(1):31-39. Epub 2019 Jan 8.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, 135 Dauer Dr, Chapel Hill, NC, 27599, USA.

Background: The dominant invasive breast cancer histologic subtype, ductal carcinoma, shows intrinsic subtype diversity. However, lobular breast cancers are predominantly Luminal A. Both histologic subtypes show distinct relationships with patient and tumor characteristics, but it is unclear if these associations remain after accounting for intrinsic subtype.

Methods: Generalized linear models were used to estimate relative frequency differences (RFDs) and 95% confidence intervals (95% CIs) for the associations between age, race, tumor characteristics, immunohistochemistry (IHC) and RNA-based intrinsic subtype, TP53 status, and histologic subtype in the Carolina Breast Cancer Study (CBCS, n = 3,182) and The Cancer Genome Atlas (TCGA, n = 808).

Results: Relative to ductal tumors, lobular tumors were significantly more likely to be Luminal A [CBCS RNA RFD: 44.9%, 95% CI (39.6, 50.1); TCGA: RFD: 50.5%, 95% CI (43.9, 57.1)], were less frequent among young (≤ 50 years) and black women, were larger in size, low grade, less frequently had TP53 pathway defects, and were diagnosed at later stages. These associations persisted among Luminal A tumors (n = 242).

Conclusions: While histology is strongly associated with molecular characteristics, histologic associations with age, race, size, grade, and stage persisted after restricting to Luminal A subtype. Histology may continue to be clinically relevant among Luminal A breast cancers.
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http://dx.doi.org/10.1007/s10552-018-1121-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396692PMC
January 2019
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