Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome.

Objectives: Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy.

Methods: Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation.

Distinct histopathological features are associated with molecular subtypes and outcome in low grade serous ovarian carcinoma.

Low grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors.

Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification.

Purpose: High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined.

In Vivo Modeling of Patient Genetic Heterogeneity Identifies New Ways to Target Cholangiocarcinoma.

Unlabelled: Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy of the bile ducts within the liver characterized by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult, and developing modes of patient stratification and targeted therapies remains challenging. Here we model the interactions between rare mutations with more common driver genes and combine in silico analysis of patient data with highly multiplexed in vivo CRISPR-spCas9 screens to perform a functional in vivo study into the role genetic heterogeneity plays in driving ICC.

Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification.

Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes.

Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome.

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC.

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.

The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.

Clinical and molecular characterization of ovarian carcinoma displaying isolated lymph node relapse.

Background: Disease relapse is the primary cause of death from ovarian carcinoma. Isolated lymph node relapse is a rare pattern of ovarian carcinoma recurrence, with a reported median postrelapse survival of 2.5 to 4 years.

Enhanced response rate to pegylated liposomal doxorubicin in high grade serous ovarian carcinomas harbouring BRCA1 and BRCA2 aberrations.

Background: Approximately 10-15% of ovarian carcinomas (OC) are attributed to inherited susceptibility, the majority of which are due to mutations in BRCA1 or BRCA2 (BRCA1/2). These patients display superior clinical outcome, including enhanced sensitivity to platinum-based chemotherapy. Here, we seek to investigate whether BRCA1/2 status influences the response rate to single-agent pegylated liposomal doxorubicin (PLD) in high grade serous (HGS) OC.

Novel PEX11B Mutations Extend the Peroxisome Biogenesis Disorder 14B Phenotypic Spectrum and Underscore Congenital Cataract as an Early Feature.

Purpose: Peroxisomes perform complex metabolic and catabolic functions essential for normal growth and development. Mutations in 14 genes cause a spectrum of peroxisomal disease in humans. Most recently, PEX11B was associated with an atypical peroxisome biogenesis disorder (PBD) in a single individual.

Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS.

Loss of ALDH18A1 function is associated with a cellular lipid droplet phenotype suggesting a link between autosomal recessive cutis laxa type 3A and Warburg Micro syndrome.

Autosomal recessive cutis laxa type 3A is caused by mutations in ALDH18A1, a gene encoding the mitochondrial enzyme Δ(1)-pyrroline-5-carboxylate synthase (P5CS). It is a rare disorder with only six pathogenic mutations and 10 affected individuals from five families previously described in the literature. Here we report the identification of novel compound heterozygous missense mutations in two affected siblings from a Lebanese family by whole-exome sequencing.

Quantifying single nucleotide variant detection sensitivity in exome sequencing.

Background: The targeted capture and sequencing of genomic regions has rapidly demonstrated its utility in genetic studies. Inherent in this technology is considerable heterogeneity of target coverage and this is expected to systematically impact our sensitivity to detect genuine polymorphisms. To fully interpret the polymorphisms identified in a genetic study it is often essential to both detect polymorphisms and to understand where and with what probability real polymorphisms may have been missed.

CAG-encoded polyglutamine length polymorphism in the human genome.

Background: Expansion of polyglutamine-encoding CAG trinucleotide repeats has been identified as the pathogenic mutation in nine different genes associated with neurodegenerative disorders. The majority of individuals clinically diagnosed with spinocerebellar ataxia do not have mutations within known disease genes, and it is likely that additional ataxias or Huntington disease-like disorders will be found to be caused by this common mutational mechanism. We set out to determine the length distributions of CAG-polyglutamine tracts for the entire human genome in a set of healthy individuals in order to characterize the nature of polyglutamine repeat length variation across the human genome, to establish the background against which pathogenic repeat expansions can be detected, and to prioritize candidate genes for repeat expansion disorders.