Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.

Serum miRNAs are differentially expressed between patients with early-stage NSCLC and controls. The utility of miR-1254 and miR-574-5p serum-based biomarkers as minimally invasive screening and triage tools for subsequent diagnostic evaluation warrants additional validation.

Chemoresistance to many commercially available cancer therapeutic drugs is a common occurrence and contributes to cancer mortality as it often leads to disease progression. There have been a number of studies evaluating the mechanisms of resistance and the biological factors involved. microRNAs have recently been identified as playing a role in the regulation of key genes implicated as cancer therapeutic targets or in mechanisms of chemoresistance including EGFR, MDR1, PTEN, Bak1, and PDCD4 among others. This article briefly reviews chemoresistance mechanisms, discusses how microRNAs can play a role in those mechanisms, and summarizes current research involving microRNAs as both regulators of key target genes for chemoresistance and biomarkers for treatment response. It is clear from the accumulating literature that microRNAs can play an important role in chemoresistance and hold much promise for the development of targeted therapies and personalized medicine. This review brings together much of this new research as a starting point for identifying key areas of interest and potentials for future study.

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the cornerstone of the MMRF Personalized Medicine Initiative. The accrual goal is 1000 patients with newly-diagnosed active multiple with sufficient tumor material for the comprehensive analysis of each tumor genome. Each eligible patient will be followed from initial diagnosis longitudinally for a minimum of 8 years. Additional tumor samples will be collected and comprehensively analyzed when possible for each patient at time of suspect CR, recurrence or progression of disease. The clinical study (NCT0145429) opened in July 2011 and now includes 56 sites in the US and Canada that have enrolled over 300 patients as of Aug. 1, 2013. The frontline treatments permitted in this study include current standard of care therapies containing a proteasome inhibitor, an IMiD or both. The comprehensive analysis of each tumor and matched normal genome involves; Long-Insert Whole Genome Sequencing (WGS) to identify somatic copy number alterations and structural changes, Whole Exome Sequencing (WES) to identify somatic single nucleotide variants and indels, and RNA sequencing (RNAseq) to define transcript expression levels and fusion transcripts. In addition, BRAF pyrosequencing and immunophenotyping analysis are being done in CAP-CLIA certified labs. An extensive, open-access, public clinical and molecular database, the CoMMpass Researcher Gateway (RG) (https://research.themmrf.org), is being developed to facilitate the rapid dissemination of the results and provides the myeloma community with a mechanism to analyze the results. The clinical endpoints and outcomes also include Quality of Life measures and health care resource utilization. An initial interim analysis on the first 178 cases has just been completed and made publicly available through the CoMMpass RG. At the molecular level, BRAF analysis on this serial sample set of newly diagnosed patients identified V600E mutations at rate of 5.7%, confirming our previous observations from a mixture of non-consecutive treated and untreated patient samples in our previous genomic efforts. The flow cytometry panel was designed to provide a comprehensive immunofingerprint of each patient that could be used for minimal residual disease monitoring and to monitor potentially therapeutic options; MS4A1/CD20, CD52, KIT/CD117, and FGFR3. These studies have identified tumors which are 100% positive for these actionable antigens at frequencies of; 16.0% for CD20, 5.7% for CD52, 49.7% for CD117, and 8.5% for FGFR3. Of the 178 cases, 34 were profiled through WGS, WES and RNAseq before this interim analysis. We identified 553 variants (median 19 per patient, range 11-55) were the variant allele detected by WES was also detected by RNAseq, suggesting the variant is potentially biologically relevant. Of these genes, 36 were seen more than once and 7 were identified in three or more patients. This includes NRAS (23.5%), KRAS (14.7%), BRAF (8.8%), DIS3 (8.8%), FAM46C (8.8%), TRAF3 (8.8%), and ZNF100 (8.8%). Interestingly, all three ZNF100 variants show preferential expression of the mutant allele. Within this cohort the only recurrent fusion gene identified is the classic IgH-MMSET fusion transcripts associate with t(4;14). The MMRF CoMMpass is providing unprecedented molecular characterization and correlating clinical datasets that will help define the determinants of response to anti-myeloma agents, reveal new, actionable targets and/or those shared with other cancers and facilitate future clinical trial designs, thus serving as a stepping stone toward personalized medicine for myeloma patients. Disclosures: Auclair: MMRC: Employment. Harrison:MMRC: Employment. Jagannath:Celgene: Honoraria; Millennium: Honoraria. Siegel:Celgene: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau. Vij:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau. Zimmerman:Celgene: Honoraria; Millenium: Honoraria; Onyx: Honoraria. Capone:MMRC: Employment. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

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