Winnie Liang - Academia.edu (original) (raw)

Papers by Winnie Liang

PLOS ONE, 2021

Although combination BRAF and MEK inhibitors are highly effective for the 40–50% of cutaneous met... more Although combination BRAF and MEK inhibitors are highly effective for the 40–50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that ...

Biology

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic pla... more The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and...

Biology Methods and Protocols

Circular RNAs (circRNAs) are evolutionarily conserved RNA species that are formed when exons “bac... more Circular RNAs (circRNAs) are evolutionarily conserved RNA species that are formed when exons “back-splice” to each other. Current computational algorithms to detect these back-splicing junctions produce divergent results, and hence there is a need for a method to distinguish true-positive circRNAs. To this end, we developed Assembly based CircRNA Validator (ACValidator) for in silico verification of circRNAs. ACValidator extracts reads from a user-defined window on either side of a circRNA junction and assembles them to generate contigs. These contigs are aligned against the circRNA sequence to find contigs spanning the back-spliced junction. When evaluated on simulated datasets, ACValidator achieved over ∼80% sensitivity on datasets with an average of 10 circRNA-supporting reads and with read lengths of at least 100 bp. In experimental datasets, ACValidator produced higher verification percentages for samples treated with ribonuclease R compared to nontreated samples. Our workflow ...

Neuro-Oncology

NEURO-ONCOLOGY • JUNE 2018 toxicity is proposed in combination with a mitotic inhibitor. MITOTIC ... more NEURO-ONCOLOGY • JUNE 2018 toxicity is proposed in combination with a mitotic inhibitor. MITOTIC INHIBITOR: Nativis Voyager ® system is a non-sterile, non-invasive, nonthermal, portable, investigational medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE ®) cognate, based on Lorenz Force, for the treatment of brain cancer. The AIA cognate is hypothesized to stabilize microtubule disassembly by changing the charge dynamics at the tubulin monomer subunit and strengthening the bond between monomers. CONCLUSIONS: Early data suggest the repurposed drug cocktail in combination with mitotic inhibition can provide a meaningful therapeutic and minimally toxic benefit in DMG. This type of approach using existing FDA-approved medications would speed protocol development from the bench to the bedside. A compassionate use study will begin enrolling pediatric patients, using the repurposed drug cocktail in combination with a newly developed Nativis Voyager Pediatric system. Clinical trial information: CT02296580

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the cornerstone of the MMRF Per... more 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 num...

Blood

Multiple Myeloma (MM) is a genetically heterogeneous disease of plasma cells that generally exhib... more Multiple Myeloma (MM) is a genetically heterogeneous disease of plasma cells that generally exhibits chromosomal abnormalities and distinct gene expression signatures. Previous studies have sought to identify gene expression indices using microarray technology to discern genes associated with survival outcomes to predict whether a newly diagnosed patient has an aggressive form of the disease. One such MM-specific index is the UAMS 70 gene index, which is composed of 51 over- and 19 under-expressed genes. This index was developed using Affymetrix U133Plus2.0 microarray data from 532 MM patients at diagnosis by computing log-rank test statistics on gene expression quartiles. Despite consistently achieving a high performance across a variety of MM datasets, issues arise when applying this index to RNAseq data. Here we address those issues, deriving an independent index based on the RNAseq data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study (NCT01454297), and benchm...

Blood

Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new can... more Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new cancer cases each year in the United States. The Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297) is a fully accrued, longitudinal, observational clinical trial with 1143 newly diagnosed MM patients from sites in the United States, Canada, Spain, and Italy. Tumor samples are collected and characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. Clinical parameters are collected at baseline and every three months through the eight-year observation period. Although ongoing, longitudinal collection of molecular and clinical data from CoMMpass patients has aided in our understanding of the molecular mechanisms underpinning relapse in MM. The CoMMpass IA13 dataset includes 136 patients with longitudinal time points, including 25 patients with multiple progression events. We analyzed 100 patients with WES data at ba...

Blood

Multiple myeloma (MM) is a pathological description for a plasma cell malignancy that exhibits a ... more Multiple myeloma (MM) is a pathological description for a plasma cell malignancy that exhibits a high degree of genetic diversity between patients. Whole genome analysis methods have elucidated multiple distinct subtypes of disease, however, we have a very limited understanding of what drives each independent subtype. To address this issue, we developed a comprehensive analysis approach to identify MM subtypes and associated genetic features in untreated patient samples from the MMRF CoMMpass study (NCT01454297). In this study we attempt to characterize each sample using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing. For this analysis we have limited the baseline cohort from the 982 patients with at least one assay completed to the 591 which are completely characterized. Most cohort level analyses focus on specific genetic aberrations such as copy number (CN) (eg. GISTIC) or somatic mutations (eg. MutSig) to identify genes which are important in the cancer. However, i...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal stud... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunumodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the five-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. This will be the first public presentation of the interim analysis seven cohort with 760 enrolled patients of whom 565 are molecularly characterized. This cohort of patients includes 14 patients with baseline and secondary samples along with 7 patients with characterized tumor samples from the bone marrow and peripheral blood. Although the median follow-up t...

Blood

Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperd... more Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperdyploidy, and immunoglobulin gene rearrangements. To promote rapid advances in the field, Multiple Myeloma Research Foundation (MMRF) initiative is an intensive and comprehensive longitudinal study (CoMMpass) designed to create a rich discovery ecosystem to through in-depth clinical and molecular profiling to understand the molecular perturbations of the disease in the context of therapy. The large study population empowered us to stratify mutational landscapes among different ethnicities to influence on broader disparities in tumor dynamics. Methods: Clinical data, tumor/normal sample collection, and mutational landscape analysis described in this abstract are derived from MMRF CoMMpass IA7 release that is composed of self-identified 93 African American (AA) and 377 European American (EA). The post-processing and primary analysis was done on baseline samples only. Whole exome sequencing ...

Blood

2920 Human myeloma cell lines (HMCL) provide both a discovery and validation platform to improve ... more 2920 Human myeloma cell lines (HMCL) provide both a discovery and validation platform to improve our understanding of the molecular pathogenesis of multiple myeloma. We have completed a project to characterize the underlying genetics of all commercially available HMCL with a primary goal of identifying appropriate model systems for findings from large scale patient studies like the multiple myeloma genomics initiative (MMGI). We first purchased all 33 commercially available HMCL from DSMZ, JCRB, ECACC, and ATCC. Subsequently each HMCL was thawed and cultured under strict parameters, which yielded cells for analysis, by Agilent 400k CGH, whole exome sequencing (Agilent 70Mb Exon+UTR), and mRNA sequencing. The combination of these three assays provides a detailed map of the genetic complexity underlying this deadly disease. For variant discovery, alignment was done using BWA followed by indel realignment, quality recalibration and duplicate removal. High quality calls were identified ...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT0145429) is a longitudinal stu... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT0145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma. The study opened July 2011 and now includes over 650 patients from 91 sites in the United States, Canada and European Union. Each patient is required to receive an approved proteasome inhibitor, immunumodulatory agent, or both. Enriched tumor and matched constitutional samples are comprehensively analyzed using Long-Insert Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES) and RNA sequencing (RNAseq). Clinical parameters, Quality of Life measurements and health care resource utilization values are collected at study entry and every three months for a minimum of five years. Additional bone marrow aspirates are collected and analyzed at each recurrence or progression of disease. An extensive clinical and molecular database, the MMRF Researcher Gateway (https://research.themmrf.org), has been developed to facilitate the rap...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal stud... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1147 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunomodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the eight-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. Data available as of January 1, 2016 is included in this first formal interim analysis, which includes 995 enrolled patients of whom 851 are molecularly characterized. This cohort of patients includes 74 patients with at least two sequential samples, plus 15 patients with characterized tumor samples from the bone marrow and peripheral blood. The median foll...

Communications Biology

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To... more Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing (n = 24) and whole exome sequencing (WES; n = 13) of primary tumors and matched normal tissue, WES (n = 10) of matched primary/metastatic/normal samples and RNA sequencing (n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent TP53 (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic SETD2 (42%) and DMD (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.

Molecular and Cellular Biology / Genetics

PLOS ONE, 2021

Although combination BRAF and MEK inhibitors are highly effective for the 40–50% of cutaneous met... more Although combination BRAF and MEK inhibitors are highly effective for the 40–50% of cutaneous metastatic melanomas harboring BRAFV600 mutations, targeted agents have been ineffective for BRAFV600wild-type (wt) metastatic melanomas. The SU2C Genomics-Enabled Medicine for Melanoma Trial utilized a Simon two-stage optimal design to assess whether comprehensive genomic profiling improves selection of molecular-based therapies for BRAFV600wt metastatic melanoma patients who had progressed on standard-of-care therapy, which may include immunotherapy. Of the response-evaluable patients, binimetinib was selected for 20 patients randomized to the genomics-enabled arm, and nine were treated on the alternate treatment arm. Response rates for 27 patients treated with targeted recommendations included one (4%) partial response, 18 (67%) with stable disease, and eight (30%) with progressive disease. Post-trial genomic and protein pathway activation mapping identified additional drug classes that ...

Biology

The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic pla... more The RNA-binding protein HuD (a.k.a., ELAVL4) is involved in neuronal development and synaptic plasticity mechanisms, including addiction-related processes such as cocaine conditioned-place preference (CPP) and food reward. The most studied function of this protein is mRNA stabilization; however, we have recently shown that HuD also regulates the levels of circular RNAs (circRNAs) in neurons. To examine the role of HuD in the control of coding and non-coding RNA networks associated with substance use, we identified sets of differentially expressed mRNAs, circRNAs and miRNAs in the striatum of HuD knockout (KO) mice. Our findings indicate that significantly downregulated mRNAs are enriched in biological pathways related to cell morphology and behavior. Furthermore, deletion of HuD altered the levels of 15 miRNAs associated with drug seeking. Using these sets of data, we predicted that a large number of upregulated miRNAs form competing endogenous RNA (ceRNA) networks with circRNAs and...

Biology Methods and Protocols

Circular RNAs (circRNAs) are evolutionarily conserved RNA species that are formed when exons “bac... more Circular RNAs (circRNAs) are evolutionarily conserved RNA species that are formed when exons “back-splice” to each other. Current computational algorithms to detect these back-splicing junctions produce divergent results, and hence there is a need for a method to distinguish true-positive circRNAs. To this end, we developed Assembly based CircRNA Validator (ACValidator) for in silico verification of circRNAs. ACValidator extracts reads from a user-defined window on either side of a circRNA junction and assembles them to generate contigs. These contigs are aligned against the circRNA sequence to find contigs spanning the back-spliced junction. When evaluated on simulated datasets, ACValidator achieved over ∼80% sensitivity on datasets with an average of 10 circRNA-supporting reads and with read lengths of at least 100 bp. In experimental datasets, ACValidator produced higher verification percentages for samples treated with ribonuclease R compared to nontreated samples. Our workflow ...

Neuro-Oncology

NEURO-ONCOLOGY • JUNE 2018 toxicity is proposed in combination with a mitotic inhibitor. MITOTIC ... more NEURO-ONCOLOGY • JUNE 2018 toxicity is proposed in combination with a mitotic inhibitor. MITOTIC INHIBITOR: Nativis Voyager ® system is a non-sterile, non-invasive, nonthermal, portable, investigational medical device that uses a specific, localized ultra-low radio frequency energy (ulRFE ®) cognate, based on Lorenz Force, for the treatment of brain cancer. The AIA cognate is hypothesized to stabilize microtubule disassembly by changing the charge dynamics at the tubulin monomer subunit and strengthening the bond between monomers. CONCLUSIONS: Early data suggest the repurposed drug cocktail in combination with mitotic inhibition can provide a meaningful therapeutic and minimally toxic benefit in DMG. This type of approach using existing FDA-approved medications would speed protocol development from the bench to the bedside. A compassionate use study will begin enrolling pediatric patients, using the repurposed drug cocktail in combination with a newly developed Nativis Voyager Pediatric system. Clinical trial information: CT02296580

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial is the cornerstone of the MMRF Per... more 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 num...

Blood

Multiple Myeloma (MM) is a genetically heterogeneous disease of plasma cells that generally exhib... more Multiple Myeloma (MM) is a genetically heterogeneous disease of plasma cells that generally exhibits chromosomal abnormalities and distinct gene expression signatures. Previous studies have sought to identify gene expression indices using microarray technology to discern genes associated with survival outcomes to predict whether a newly diagnosed patient has an aggressive form of the disease. One such MM-specific index is the UAMS 70 gene index, which is composed of 51 over- and 19 under-expressed genes. This index was developed using Affymetrix U133Plus2.0 microarray data from 532 MM patients at diagnosis by computing log-rank test statistics on gene expression quartiles. Despite consistently achieving a high performance across a variety of MM datasets, issues arise when applying this index to RNAseq data. Here we address those issues, deriving an independent index based on the RNAseq data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass Study (NCT01454297), and benchm...

Blood

Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new can... more Multiple myeloma (MM) is a hematological malignancy of plasma cells accounting for ~2% of new cancer cases each year in the United States. The Multiple Myeloma Research Foundation CoMMpass Study (NCT01454297) is a fully accrued, longitudinal, observational clinical trial with 1143 newly diagnosed MM patients from sites in the United States, Canada, Spain, and Italy. Tumor samples are collected and characterized using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing at diagnosis and each progression event. Clinical parameters are collected at baseline and every three months through the eight-year observation period. Although ongoing, longitudinal collection of molecular and clinical data from CoMMpass patients has aided in our understanding of the molecular mechanisms underpinning relapse in MM. The CoMMpass IA13 dataset includes 136 patients with longitudinal time points, including 25 patients with multiple progression events. We analyzed 100 patients with WES data at ba...

Blood

Multiple myeloma (MM) is a pathological description for a plasma cell malignancy that exhibits a ... more Multiple myeloma (MM) is a pathological description for a plasma cell malignancy that exhibits a high degree of genetic diversity between patients. Whole genome analysis methods have elucidated multiple distinct subtypes of disease, however, we have a very limited understanding of what drives each independent subtype. To address this issue, we developed a comprehensive analysis approach to identify MM subtypes and associated genetic features in untreated patient samples from the MMRF CoMMpass study (NCT01454297). In this study we attempt to characterize each sample using whole genome (WGS), exome (WES), and RNA (RNAseq) sequencing. For this analysis we have limited the baseline cohort from the 982 patients with at least one assay completed to the 591 which are completely characterized. Most cohort level analyses focus on specific genetic aberrations such as copy number (CN) (eg. GISTIC) or somatic mutations (eg. MutSig) to identify genes which are important in the cancer. However, i...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal stud... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunumodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the five-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. This will be the first public presentation of the interim analysis seven cohort with 760 enrolled patients of whom 565 are molecularly characterized. This cohort of patients includes 14 patients with baseline and secondary samples along with 7 patients with characterized tumor samples from the bone marrow and peripheral blood. Although the median follow-up t...

Blood

Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperd... more Introduction: Multiple Myeloma (MM) is a complex malignancy of plasma cells well-described hyperdyploidy, and immunoglobulin gene rearrangements. To promote rapid advances in the field, Multiple Myeloma Research Foundation (MMRF) initiative is an intensive and comprehensive longitudinal study (CoMMpass) designed to create a rich discovery ecosystem to through in-depth clinical and molecular profiling to understand the molecular perturbations of the disease in the context of therapy. The large study population empowered us to stratify mutational landscapes among different ethnicities to influence on broader disparities in tumor dynamics. Methods: Clinical data, tumor/normal sample collection, and mutational landscape analysis described in this abstract are derived from MMRF CoMMpass IA7 release that is composed of self-identified 93 African American (AA) and 377 European American (EA). The post-processing and primary analysis was done on baseline samples only. Whole exome sequencing ...

Blood

2920 Human myeloma cell lines (HMCL) provide both a discovery and validation platform to improve ... more 2920 Human myeloma cell lines (HMCL) provide both a discovery and validation platform to improve our understanding of the molecular pathogenesis of multiple myeloma. We have completed a project to characterize the underlying genetics of all commercially available HMCL with a primary goal of identifying appropriate model systems for findings from large scale patient studies like the multiple myeloma genomics initiative (MMGI). We first purchased all 33 commercially available HMCL from DSMZ, JCRB, ECACC, and ATCC. Subsequently each HMCL was thawed and cultured under strict parameters, which yielded cells for analysis, by Agilent 400k CGH, whole exome sequencing (Agilent 70Mb Exon+UTR), and mRNA sequencing. The combination of these three assays provides a detailed map of the genetic complexity underlying this deadly disease. For variant discovery, alignment was done using BWA followed by indel realignment, quality recalibration and duplicate removal. High quality calls were identified ...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT0145429) is a longitudinal stu... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT0145429) is a longitudinal study of 1000 patients with newly-diagnosed multiple myeloma. The study opened July 2011 and now includes over 650 patients from 91 sites in the United States, Canada and European Union. Each patient is required to receive an approved proteasome inhibitor, immunumodulatory agent, or both. Enriched tumor and matched constitutional samples are comprehensively analyzed using Long-Insert Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES) and RNA sequencing (RNAseq). Clinical parameters, Quality of Life measurements and health care resource utilization values are collected at study entry and every three months for a minimum of five years. Additional bone marrow aspirates are collected and analyzed at each recurrence or progression of disease. An extensive clinical and molecular database, the MMRF Researcher Gateway (https://research.themmrf.org), has been developed to facilitate the rap...

Blood

The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal stud... more The Multiple Myeloma Research Foundation (MMRF) CoMMpass trial (NCT145429) is a longitudinal study of 1147 patients with newly-diagnosed multiple myeloma from clinical sites in the United States, Canada, Spain, and Italy. Each patient receives a treatment regimen containing a proteasome inhibitor, immunomodulatory agent, or both. Clinical parameters are collected at study enrollment and every three months through the eight-year observation period. To identify molecular determinants of clinical outcome each baseline and progression tumor specimen is characterized using Whole Genome Sequencing, Exome Sequencing, and RNA sequencing. Data available as of January 1, 2016 is included in this first formal interim analysis, which includes 995 enrolled patients of whom 851 are molecularly characterized. This cohort of patients includes 74 patients with at least two sequential samples, plus 15 patients with characterized tumor samples from the bone marrow and peripheral blood. The median foll...

Communications Biology

Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To... more Osteosarcoma (OS) is a rare, metastatic, human adolescent cancer that also occurs in pet dogs. To define the genomic underpinnings of canine OS, we performed multi-platform analysis of OS tumors from 59 dogs, including whole genome sequencing (n = 24) and whole exome sequencing (WES; n = 13) of primary tumors and matched normal tissue, WES (n = 10) of matched primary/metastatic/normal samples and RNA sequencing (n = 54) of primary tumors. We found that canine OS recapitulates features of human OS including low point mutation burden (median 1.98 per Mb) with a trend towards higher burden in metastases, high structural complexity, frequent TP53 (71%), PI3K pathway (37%), and MAPK pathway mutations (17%), and low expression of immune-associated genes. We also identified novel features of canine OS including putatively inactivating somatic SETD2 (42%) and DMD (50%) aberrations. These findings set the stage for understanding OS development in dogs and humans, and establish genomic contexts for future comparative analyses.

Molecular and Cellular Biology / Genetics