Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Patterns of deficits in brain function in bipolar disorder and schizophrenia:a cluster analytic study

Historically, bipolar disorder and schizophrenia have been considered distinct disorders with different etiologies. Growing evidence suggests that overlapping genetic influences contribute to risk for these disorders and that each disease is genetically heterogeneous. Using cluster analytic methods, we empirically identified homogeneous subgroups of patients, their relatives, and controls based on distinct neurophysiologic profiles. Seven phenotypes were collected from two independent cohorts at two institutions. K-means clustering was used to identify neurophysiologic profiles. In the analysis of all participants, three distinct profiles emerged: "globally impaired", "sensory processing", and "high cognitive". In a secondary analysis, restricted to patients only, we observed a similar clustering into three profiles. The neurophysiological profiles of the Schizophrenia (SZ) and Bipolar Disorder (BPD) patients did not support the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic distinction between these two disorders. Smokers in the globally impaired group smoked significantly more cigarettes than those in the sensory processing or high cognitive groups. Our results suggest that empirical analyses of neurophysiological phenotypes can identify potentially biologically relevant homogenous subgroups independent of diagnostic boundaries. We hypothesize that each neurophysiology subgroup may share similar genotypic profiles, which may increase statistical power to detect genetic risk factors. © 2012 Elsevier Ireland Ltd

Board of director gender and corporate tax aggressiveness: An empirical analysis

This study examines the impact of board of director gender diversity on corporate tax aggressiveness. Based on a sample of 418 U.S. firms covering the 2006–2009 period (1672 firm-year observations), our ordinary least squares regression results show a negative and statistically significant association between female representation on the board and tax aggressiveness after controlling for endogeneity. Our results are consistent across several measures of tax aggressiveness and additional robustness checks