Felicity Newell

Felicity Newell
Queensland University of Technology | QUT · Institute of Health and Biomedical Innovation

About

79
Publications
27,497
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10,466
Citations
Citations since 2017
53 Research Items
8631 Citations
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201720182019202020212022202305001,0001,500
201720182019202020212022202305001,0001,500

Publications

Publications (79)
Article
The incidence of oesophageal adenocarcinoma (OAC) is rising in Western countries, with a 5-year overall survival (OS) rate of 14%. Curative treatment based on oesophagectomy is only suitable for ~50% of patients due to late-stage diagnosis. While the addition of preoperative chemotherapy or chemoradiotherapy has improved OS in OAC patients, little...
Article
Full-text available
Melanoma is a cancer of melanocytes, with multiple subtypes based on body site location. Cutaneous melanoma is associated with skin exposed to ultraviolet radiation; uveal melanoma occurs in the eyes; mucosal melanoma occurs in internal mucous membranes; and acral melanoma occurs on the palms, soles, and nail beds. Here, we present the largest whol...
Article
The clinical classification of variants may change with new information, however there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant data from ClinVar between January 2015 and July 2021....
Article
Full-text available
Background Next-generation sequencing is used in cancer research to identify somatic and germline mutations, which can predict sensitivity or resistance to therapies, and may be a useful tool to reveal drug repurposing opportunities between tumour types. Multigene panels are used in clinical practice for detecting targetable mutations. However, the...
Article
e16028 Background: : Prognosis of oesophageal adenocarcinoma (OAC) remains poor globally. Traditional histopathology classifications have minimal impact on clinical management and outcomes. To improve patient outcomes, prognostic and therapeutic stratification is required within this cohort of morphologically homogenous cancers. Identification and...
Article
Full-text available
Background Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials. Methods We analysed somatic mutations from 229 MPM samples, including previously publishe...
Article
Full-text available
Oncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programmes in the cell of origin. Here we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype arises on the pa...
Article
Full-text available
Background Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprises four molecular subtypes with differing etiology, prognoses, and responses to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. As p...
Article
Full-text available
Background The Wnt receptors ROR1 and ROR2 are generating increased interest as cancer therapeutic targets but remain understudied in pancreatic ductal adenocarcinoma (PDAC). Compared to canonical Wnt/ β-catenin signalling, the role of noncanonical Wnt signalling in PDAC remains largely unknown. Only one study has investigated the prognostic signif...
Article
We concurrently examine the whole genome, transcriptome, methylome, and immune cell infiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treated with anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden (TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligand expression,...
Article
Importance Spitz nevi are benign melanocytic neoplasms that classically present in childhood. Isolated Spitz nevi have been associated with oncogenic gene fusions in approximately 50% of cases. The rare agminated variant of Spitz nevi, thought to arise from cutaneous genetic mosaicism, is characterized by development of clusters of multiple lesions...
Article
Full-text available
Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas (n = 539; 3...
Preprint
Full-text available
Background Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pr...
Article
Full-text available
Mucosal melanoma is a rare subtype of melanoma. To date, there has been no comprehensive systematic collation and statistical analysis of the aberrations and aggregated frequency of driver events across multiple studies. Published studies using whole genome, whole exome, targeted gene panel, or individual gene sequencing were identified. Datasets f...
Article
Aggregate population genomics data from large cohorts is vital for assessing germline variant pathogenicity. However, there are no specifications on how sequencing quality metrics should be considered, and whether exome‐derived and genome‐derived allele frequencies should be considered in isolation. Germline genome sequence data was simulated for n...
Article
Full-text available
Adjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature...
Article
Full-text available
Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX , DAXX and MEN1 wild-type genotypes....
Conference Paper
Endometrial cancer is a major gynaecological cancer with a high incidence resulting in over 500 Australian women dying every year. Good pre-clinical models are urgently needed to study the biology of this disease, and to develop and test novel treatment strategies. Most current pre-clinical research is conducted in cell lines that often do not rese...
Article
Full-text available
The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particular BRCA1 or BRCA2 deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicati...
Preprint
Full-text available
Oncogenic alterations to DNA are not transforming in all cellular contexts 1,2 . This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype has a unique tr...
Article
Full-text available
To increase understanding of the genomic landscape of acral melanoma, a rare form of melanoma occurring on palms, soles or nail beds, whole genome sequencing of 87 tumors with matching transcriptome sequencing for 63 tumors was performed. Here we report that mutational signature analysis reveals a subset of tumors, mostly subungual, with an ultravi...
Article
Tumor mutation burden (TMB) has been proposed as a key determinant of immunogenicity in several cancers, including melanoma. The evidence presented thus far, however, is often contradictory and based mostly on RNA-sequencing data for the quantification of immune cell phenotypes. Few studies have investigated TMB across acral, mucosal, and cutaneous...
Article
Das Wissen über die genetischen Treiber und therapeutischen Zielstrukturen von Melanomen der Schleimhäute ist bisher lückenhaft, weil nur wenig umfassende Daten zu den Mutationen bei dieser seltenen Tumorart vorliegen. Um die genomische Landschaft des mukosalen Melanoms besser zu verstehen, beschreiben wir hier die Analyse von 67 Tumoren mittels Wh...
Article
Full-text available
Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of t...
Article
Full-text available
Pancreatic cancer is predicted to be the second leading cause of cancer-related death by 2025. The best chemotherapy only extends survival by an average of 18 weeks. The extensive fibrotic stroma surrounding the tumor curbs therapeutic options as chemotherapy drugs cannot freely penetrate the tumor. RNA interference (RNAi) has emerged as a promisin...
Conference Paper
Background Declining costs of next-generation sequencing technologies has led to their more widespread use for the identification of targetable mutations. Nonetheless, while multigene panels are being assimilated into clinical practice, the use of whole-exome and whole-genome sequencing (WES and WGS) remains limited, as its added value is unclear i...
Article
Full-text available
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type. To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tu...
Article
9511 Background: Several factors have been proposed as biomarkers for response to PD1 therapy, including tumor mutational burden (TMB), immune gene expression, PD-L1 expression and TILs, while few specific mechanisms of resistance have been identified. The relative importance of these factors or detailed examination of biomarkers of response to com...
Article
Full-text available
Background: Whole genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. Patients and methods...
Article
Approximately 10-15% of breast cancers are associated with a strong family history of disease. Pathogenic variants in 1, 2 or other moderate to highly penetrant susceptibility genes (e.g. TP53, ATM, CHEK2, PALB2 and PTEN) account for a number of breast cancer families. However, for over 50% of families the underlying genetic contribution to their r...
Article
Full-text available
Background Oesophageal adenocarcinoma (EAC) incidence is increasing and has a poor survival rate. Barrett’s oesophagus (BE) is a precursor condition that is associated with EAC and often occurs in conjunction with chronic gastro-oesophageal reflux, however many individuals diagnosed with BE never progress to cancer. An understanding of the genomic...
Article
The benign melanocytic nevus is the most common tumor in humans and rarely transforms into cutaneous melanoma. Elucidation of the nevus genome is required to better understand the molecular steps of progression to melanoma. We performed whole genome sequencing on a series of 14 benign melanocytic nevi consisting of both congenital and acquired type...
Article
Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15‐30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantl...
Data
Figure S1. Detailed morphology and additional IHC of MDL1. (A) Case MDL1 contained LCIS and DCIS, and invasive components with both ductal [D] and lobular [L] growth patterns. H&E stained sections show the admixed relationship between these morphological components. DCIS and invasive ductal components were E‐cadherin and b‐catenin positive. LCIS an...
Data
Figure S5. Detailed morphology and additional IHC of MDL6 Additional immunohistochemical staining of β‐catenin and p120‐catenin for different morphological components of case.
Data
Figure S2. Detailed morphology and additional IHC of MDL2. MDL2 contained DCIS and LCIS (not shown) and invasive components with both ductal [D] and lobular [L] growth patterns. Stained sections show the admixed relationship between tumour nests and single cells and single cell files. The three different morphological components were membrane posit...
Data
Figure S6. Detailed morphology and additional IHC of MDL7. Additional immunohistochemical staining of β‐catenin and p120‐catenin for different morphological components of case.
Data
Figure S3. Detailed morphology and additional IHC of MDL3. MDL3 contained DCIS (not shown) and invasive components with both ductal [D] and lobular [L] growth patterns. H&E stained section show the admixed relationship between tumour nests and single cells. The DCIS and invasive ductal components were E‐cadherin, β‐catenin and P120‐catenin positive...
Data
Figure S4. Detailed morphology and additional IHC of MDL5. IDC and ILC components stained for β‐catenin and p120‐catenin.
Data
Table S1. Pathology information and experimental summary of MDL cases Table S2. Summary of chromosomal copy number alterations Table S3. Exome data Table S4. Curated nucleotide variant list Table S5. Validation of alterations by iPlex, and list of iPlex primers Table S6. MDL4 RNASeq data
Article
Full-text available
Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are an archetypal example of intra-tumour morphological heterogeneity. The mechanisms underlying coexistence of these different morphologic entities are poorly understood, although theories include that these components either represent ‘collision’ of independent...
Article
Full-text available
Technological innovation and increased affordability have contributed to the widespread adoption of genome sequencing technologies in biomedical research. In particular large cancer research consortia have embraced next generation sequencing, and have used the technology to define the somatic mutation landscape of multiple cancer types. These studi...
Data
Protein coding mutations detected using BGISEQ-500 and HiSeq X Ten data. A summary of the genes affected by the protein coding mutations which were identified in 3 mesothelioma samples (patient ID: 9869, 11202 and 11398). (TIF)
Article
Full-text available
Melanoma of the skin is a common cancer only in Europeans, whereas it arises in internal body surfaces (mucosal sites) and on the hands and feet (acral sites) in people throughout the world. Here we report analysis of whole-genome sequences from cutaneous, acral and mucosal subtypes of melanoma. The heavily mutated landscape of coding and non-codin...
Article
Full-text available
The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signa...
Article
Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA re...
Article
Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor;...
Article
Treatment options for patients with brain metastases (BM) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilised, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscap...
Article
Full-text available
Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA sampl...
Article
Full-text available
Genetic variation modulates gene expression transcriptionally or post-transcriptionally, and can profoundly alter an individual's phenotype. Measuring allelic differential expression at heterozygous loci within an individual, a phenomenon called allele-specific expression (ASE), can assist in identifying such factors. Massively parallel DNA and RNA...
Article
Full-text available
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (...
Article
Full-text available
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a...
Article
Somatic rearrangements, which are commonly found in human cancer genomes, contribute to the progression and maintenance of cancers. Conventionally, the verification of somatic rearrangements comprises many manual steps and Sanger sequencing. This is labor intensive when verifying a large number of rearrangements in a large cohort. To increase the v...
Article
Full-text available
Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a backgr...
Article
Full-text available
Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantia...
Article
Full-text available
Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to er...
Data
Full-text available
(A) The number of normal het SNP array probes on LOH regions in the mixture experiment. (B) The distribution of BAF for the normal het SNPs on LOH regions in the mixture experiment. Among 260257 heterozygous SNP probes in the normal tissue, qpure looks for those that are in regions of LOH in the tumour. In the mixture experiment the number of SNP a...
Data
Full-text available
Prediction model of tumor cellularity using d-score in the mixing experiment. (A) fit simple linear regression model with mixture clustering (B) fit spline regression model with mixture clustering (C) fit simple linear regression model with k-means clustering (D) fit spline regression model with k-means clustering. In the plots the solid line is th...
Data
D-score estimates using different thresholds to select probes in LOH regions for samples with different percentage of tumor DNA. The amount of tumor DNA in the samples decreased from the left to the right. The “mycutoff” value is equal to the median of all the selected SNPs minus the standard deviation of middle 50 quantile. The figure showed that...
Data
Full-text available
Pair-wise correlations between cellularity estimates across four different methods: pathology, qpure, KRAS sequencing and ASCAT for the 76 pancreatic tumour samples. As the pair-wise correlaitons get bigger the font size gets bigger. The red line in the scatter plot showed a linear correlation between each pair of the estimates. (PDF)
Data
Full-text available