Genome Sequencing of Multiple Primary Lung Cancers Harbouring Mixed Histology and Spontaneously Regressing Small-Cell Lung Cancer.

Up to 15% of lung cancer patients present two or more anatomically separate primary lung lesions, known as multiple primary lung cancers (MPLCs). While surgical resection or stereotactic body radiation therapy (SBRT) is the standard of care for most early-stage lung cancer cases, this may not be an option for patients with widespread tumours, highlighting the need for the improved targeted management of MPLC patients, which remains challenging. Moreover, the spontaneous regression (SR) of small-cell lung cancer (SCLC) is rare, with only four cases accounted for between 1988 and 2018.

KMT2C and KMT2D aberrations in breast cancer.

KMT2C and KMT2D are histone lysine methyltransferases responsible for the monomethylation of histone 3 lysine 4 (H3K4) residues at gene enhancer sites. KMT2C/D are the most frequently mutated histone methyltransferases (HMTs) in breast cancer, occurring at frequencies of 10-20% collectively. Frequent damaging and truncating somatic mutations indicate a tumour-suppressive role of KMT2C/D in breast oncogenesis.

Testing for pharmacogenomic predictors of ppRNFL thinning in individuals exposed to vigabatrin.

Background: The anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown.

Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer.

HER2-positive (HER2+) breast cancer accounts for 20-25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10-05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients.

Corrigendum: Mucinous adenocarcinoma of the rectum: a whole genome sequencing study.

[This corrects the article DOI: 10.3389/fonc.2020.

Tumour Genome Characterization of a Rare Case of Pulmonary Enteric Adenocarcinoma and Prior Colon Adenocarcinoma.

Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of lung adenocarcinoma first described in the early 1990s in a lung tumour with overlapping lung and small intestine features. It is a rare tumour with fewer than 300 cases described in the published literature and was only formally classified in 2011. Given these characteristics the diagnosis is challenging, but even more so in a patient with prior gastrointestinal malignancy.

Ultraviolet light-induced collagen degradation inhibits melanoma invasion.

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

Background: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab.

Methods: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly.

Female Immunity Protects from Cutaneous Squamous Cell Carcinoma.

Purpose: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation.

Mucinous Adenocarcinoma of the Rectum: A Whole Genome Sequencing Study.

Introduction: Mucinous adenocarcinoma of the rectum is an infrequently encountered histological subtype that is associated with an impaired response to chemoradiotherapy and a worse overall prognosis. A genomic profile analysis of mucinous rectal tumors has not yet been performed. The aim of this study was to comprehensively describe the burden of somatic mutations and copy number variation as well as perform mutational signature and microbial analysis of an in-house collected cohort of mucinous adenocarcinoma of the rectum.

Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer.

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance.

Personalised mapping of tumour development in synchronous colorectal cancer patients.

Synchronous colorectal cancers (syCRCs) are two or more primary tumours identified simultaneously in a patient. Previous studies report high inter-tumour heterogeneity between syCRCs, suggesting independent origin and different treatment response, making their management particularly challenging, with no specific guidelines currently in place. Here, we performed in-depth bioinformatic analyses of genomic and transcriptomic data of a total of eleven syCRCs and one metachronous CRC collected from three patients.

Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size.

Mucinous adenocarcinoma is a pharmacogenomically distinct subtype of colorectal cancer.

Mucinous colorectal cancer is a unique histological subtype that is known to respond poorly to cytotoxic chemotherapy and radiotherapy. There are a number of genes known to be associated with resistance to 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. The aim of this study was to compare the somatic mutation frequency and copy number variation (CNV) in these genes between mucinous and non-mucinous colorectal cancer.

Mucinous adenocarcinoma of the colon and rectum: A genomic analysis.

Background And Objectives: Mucinous adenocarcinoma is a distinct subtype of colorectal cancer (CRC) with a worse prognosis when compared with non-mucinous adenocarcinoma. The aim of this study was to compare somatic mutations and copy number alteration (CNA) between mucinous and non-mucinous CRC.

Methods: Data from The Cancer Genome Atlas-colon adenocarcinoma and rectum adenocarcinoma projects were utilized.

Genomic profiling of a dedifferentiated mucosal melanoma following exposure to immunotherapy.

The treatment landscape for metastatic melanoma has been revolutionised by the introduction of immunotherapy and targeted therapies. Despite these advances, some patients exhibit primary or acquired resistance to treatment. We present the case of a resected mucosal melanoma that on relapse underwent transformation to a dedifferentiated state.

Identification of coding and non-coding mutational hotspots in cancer genomes.

Background: The identification of mutations that play a causal role in tumour development, so called "driver" mutations, is of critical importance for understanding how cancers form and how they might be treated. Several large cancer sequencing projects have identified genes that are recurrently mutated in cancer patients, suggesting a role in tumourigenesis. While the landscape of coding drivers has been extensively studied and many of the most prominent driver genes are well characterised, comparatively less is known about the role of mutations in the non-coding regions of the genome in cancer development.

The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer.

Background: Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance.

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.

Unlabelled: Targeted therapies and immunotherapies have transformed melanoma care, extending median survival from ∼9 to over 25 months, but nevertheless most patients still die of their disease. The aim of precision medicine is to tailor care for individual patients and improve outcomes. To this end, we developed protocols to facilitate individualized treatment decisions for patients with advanced melanoma, analyzing 364 samples from 214 patients.

Onco-STS: a web-based laboratory information management system for sample and analysis tracking in oncogenomic experiments.

Background: Whole genomes, whole exomes and transcriptomes of tumour samples are sequenced routinely to identify the drivers of cancer. The systematic sequencing and analysis of tumour samples, as well other oncogenomic experiments, necessitates the tracking of relevant sample information throughout the investigative process. These meta-data of the sequencing and analysis procedures include information about the samples and projects as well as the sequencing centres, platforms, data locations, results locations, alignments, analysis specifications and further information relevant to the experiments.

Protective variant for hippocampal atrophy identified by whole exome sequencing.

We used whole-exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in-silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole-brain analysis and meta-analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease.

Ultraviolet radiation accelerates BRAF-driven melanomagenesis by targeting TP53.

Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model.

The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis.

Acral melanoma is a subtype of melanoma with distinct epidemiological, clinical and mutational profiles. To define the genomic alterations in acral melanoma, we conducted whole-genome sequencing and SNP array analysis of five metastatic tumours and their matched normal genomes. We identified the somatic mutations, copy number alterations and structural variants in these tumours and combined our data with published studies to identify recurrently mutated genes likely to be the drivers of acral melanomagenesis.

SF3B1 mutations are associated with alternative splicing in uveal melanoma.

Unlabelled: Uveal melanoma, the most common eye malignancy, causes severe visual morbidity and is fatal in approximately 50% of patients. Primary uveal melanoma can be cured by surgery or radiotherapy, but the metastatic disease is treatment refractory. To understand comprehensively uveal melanoma genetics, we conducted single-nucleotide polymorphism arrays and whole-genome sequencing on 12 primary uveal melanomas.