The Cancer Gene Census (CGC) catalogues genes with mutations causally implicated in cancer and explains how dysfunction of these genes drives cancer.
With COSMIC v99, new high-quality genes have been added to the CGC ─ three to Tier 1 and three to Tier 2. The genes are HGF, RAD50, RRAS2, GSK3B, MUC6 and RAP1B.
More, cancer hallmark annotations have been added to each of the 8 existing CGC Tier 1 genes (SRC, SRSF2, STAT3, STAT5B, STK11, SUFU, TBX3, TNFRSF14). Cancer hallmark annotations summarize the effect of Tier 1 genes on the phenotypic traits shared by cancers.
The CGC has been compiled over 19 years and is periodically reviewed. This ensures that gene assignment to the Census reflects the latest evidence indicative of the strength of a causal association between a gene and one, or more, cancer types, and consistency in the application of the COSMIC inclusion criteria for CGC Tier 1 and Tier 2 assignment. Based on this, and following a recent review, TSHR has been re-assigned from Tier 1 of the Census to Tier 2, and its previous designation as an oncogene rescinded.
→ Want more details? Read the full COSMIC v99 release notes here.
v99 is the second release available through COSMIC's new, improved download files. These new files contain the same gold standard COSMIC data found in its current files, but presented in a more accessible and interoperable manner.
The COSMIC team wants to lead by example in encouraging data to be FAIR (Findable, Accessible, Interoperable and Reusable) compliant, and as part of this goal, they will be phasing out their current files for COSMIC v100 in May 2024. This means that the current download files will be retired and only the new style files will be available to download.
→ Learn more about COSMIC's new files and transition support here.
Skin cancer is one of the most common forms of cancer, with nearly 3 million people globally affected each year.* Of every 3 diagnosed cancers, 1 is a skin cancer.** While basal cell carcinoma, squamous cell carcinoma, and melanoma are the most common types, there are several rare skin cancers that are often underrepresented in scientific literature.
The latest Catalogue of Somatic Mutations in Cancer (COSMIC) release, v98, focuses on rarer skin cancers like adnexal tumors, Merkel cell carcinoma, Kaposi sarcoma, dermatofibrosarcoma protuberans, and extramammary Paget's disease—providing deeper insight into the somatic mutations behind them and their clinical implications.
The inclusion of these rare skin tumors in COSMIC will allow clinicians to better understand the molecular mechanisms behind these cancers, which in turn aids in more accurate diagnosis and personalized treatment planning. Now, researchers and drug developers have more resources to help identify potential drug targets and develop new precision therapies for rare skin cancers.
In COSMIC v98, 776 new samples were curated from publications and 25,236 new variants were found in the rare skin tumors newly included. 17 new skin tumor types or subtypes were added to the histology classification system. Users can explore all of the variant data and sample metadata using the COSMIC Cancer Browser on the website. All the tumor types in COSMIC derive from samples that have been found to have somatic mutations in them.
The COSMIC v98 release marks a significant step forward in addressing the underrepresentation of rare skin cancers in scientific literature and databases.
→ Learn more about COSMIC here. (more…)
We are pleased to announce the release of the latest version of the Human Somatic Mutation Database, a new somatic database developed by QIAGEN that contains extensive genomic content relevant to solid tumors and hematological malignancies. HSMD 2.1.1 enhances the database with the latest cutting-edge cancer content, including new clinical trials, new drugs, and new variants that have been clinically observed or curated from scientific literature to help users better understand and define precise function and actionability.
HSMD 2.1.1 release highlights
View the full list of new content updates here.
About HSMD
Combining over 2 decades of expert curation and data from real-world clinical oncology cases, HSMD is a new somatic database from QIAGEN that serves as a single, trusted data source for clinical labs to validate, assess, and better understand the clinical significance of detected variants.
HSMD aggregates manually curated content from the QIAGEN Knowledge Base, the industry’s largest collection of biological and clinical findings, with data from over 500,000 real-world clinical oncology cases that have been analyzed and interpreted by QIAGEN’s professional clinical interpretation service, to eliminate the need to manually collect information across knowledge bases and provide deep genomic insight into the molecular characterizations of your patient’s tumor.
Easy to search with new content added weekly, HSMD enables users to explore key genes or mutations with driving properties or clinical relevance, and lets users search for associated treatment options, off-label therapies, resistance markers, and regional and/or disease-specific clinical trials.
Learn more about HSMD here.
[NEW!] HSMD Software Developer Now Available: Integrate HSMD into your in-house analytical tool for increased efficiency. You’ll be able to link out to the full HSMD online content via endpoints (API keys). HSMD Software Developer access provides integration keys for +1.5 million cancer-associated variants.
We are pleased to announce the availability of a new release for COSMIC, the Catalogue of Somatic Mutations in Cancer. COSMIC Actionability v8 adds new actionability data to the world’s largest, expert-curated somatic mutation database. The release includes 22 new fully curated somatic genes, 387 new clinical trials, and 166 new oncology drugs.
In this article, we provide a summary of the COSMIC Actionability v8 release highlights.
COSMIC, the Catalogue of Somatic Mutations in Cancer, is an expert-curated database encompassing the wide variety of somatic mutation mechanisms causing human cancer. Owned and maintained by the Wellcome Sanger Institute, COSMIC is exclusively licensed through QIAGEN.
COSMIC’s team of variant scientists manually curates key cancer genes to provide in-depth information on mutation distributions and effects. The team relies on a semi-automated curation process of cancer genomes to provide broad somatic annotations toward target discovery and identification of patterns and signatures. To date, COSMIC contains over 23 million somatic mutations associated with human cancers.
COSMIC Actionability is a standalone product within the COSMIC database that focuses on providing information on the availability and development of drugs targeting somatic mutations in cancer. COSMIC’s certified curation team integrates data from case studies, clinical trials, and regulatory bodies to represent a full picture of the current precision oncology pipeline (from drug development, through safety and clinical phases, to market and repurposing).
Actionability contains information on three core units: mutations, diseases and drugs. By capturing relations between these units, COSMIC’s team identifies existing and upcoming drugs that target specific genetic variants in different cancer types. COSMIC Actionability is a cutting-edge, ‘living-tool’ that provides the most up-to-date data for precision oncology applications.
→ View the full Actionability v8 release notes here.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab by downloading sample data here.
We are pleased to announce the release of the latest version of the Human Somatic Mutation Database, a new somatic database developed by QIAGEN that contains extensive genomic content relevant to solid tumors and hematological malignancies. Expanding on the database’s current content and capabilities, HSMD 2.0 now contains data on structural variants, improved data visualization, and tools to enable seamless integration of the database into in-house workflows.
HSMD 2.0 release highlights
View the full list of new content updates here.
About HSMD
Combining over 2 decades of expert curation and data from real-world clinical oncology cases, HSMD is a new somatic database from QIAGEN that serves as a single, trusted data source for clinical labs to validate, assess, and better understand the clinical significance of detected variants.
HSMD aggregates manually curated content from the QIAGEN Knowledge Base, the industry’s largest collection of biological and clinical findings, with data from over 419,000 real-world clinical oncology cases that have been analyzed and interpreted by QIAGEN’s professional clinical interpretation service, to eliminate the need to manually collect inform-ation across knowledge bases and provide deep genomic insight into the molecular characterizations of your patient’s tumor.
Easy to search with new content added weekly, HSMD enables users to explore key genes or mutations with driving properties or clinical relevance, and lets users search for associated treatment options, off-label therapies, resistance markers, and regional and/or disease-specific clinical trials.
Learn more about HSMD here.
As NGS is increasingly used in precision oncology, there is an industry-wide issue of standardization: a high degree of variability in variant interpretation currently exists across laboratories. On September 30, in a live panel discussion, experts in NGS testing and clinical informatics explore the issues surrounding standardization and how to overcome them with real-world applications.
⇒ Learn more and register here.
Many labs struggle with prioritizing clinically- and biologically-relevant variants among the millions of variants detected using NGS. Labs are starting to consolidate smaller panels into one large comprehensive cancer panel to test all cancer types. This presents fresh challenges: interpretation of the data and meeting turnaround times.
Fortunately, with COSMIC’s Cancer Mutation Census and Actionability, labs have the trusted data they need for accurate prioritization at their fingertips.
Here's how.
CMC delivers a score for each variant based on manually-curated information regarding cancer genes and genetic variants. It also provides data on variant frequencies in cancer and non-cancer populations. It utilizes data from many reliable sources, including ClinVar, gnomAD, DNA conservation as reported by GERP, and COSMIC Mutations per AA.
CMC’s algorithmic evaluation of variant significance across the whole set of coding mutations in COSMIC lets you identify variants with the highest potential of biological relevance. The latest version of CMC—v96—describes over 4.9 million somatic variants. It segregates them into four tiers (see Figure 1, below) in order of highest confidence and evidence of driving cancer (Tier 1) to the lowest (Tier 4).
The benefit?
During your NGS data analysis, you can easily match the CMC score to the identified mutations in your NGS test using genomic coordinates, cDNA, or protein change. This lets you rank the mutations in your NGS data according to the CMC score—prioritizing potential biological cancer-driving mutations.
Figure 1. CMC tiers allow you to rapidly classify somatic variants by their potential to drive cancer.
COSMIC Actionability delivers the latest data on the availability and development of drugs targeting specific somatic mutations in cancer. Actionability covers clinically-relevant mutations and alteration types in relevant genes for some of the most frequently sequenced cancer types such as lung, breast, melanoma, ovarian, and colon cancer. This data is updated quarterly; for more information on the latest Actionability release, see below.
With Actionability, you can prioritize clinically-actionable mutations related to your patient’s specific cancer type. This lets you know which of those potentially biologically-relevant mutations are also therapeutically actionable.
Like CMC, Actionability also classifies alterations into four tiers:
Actionability currently covers 62 tier 1, 21 tier 2, 527 tier 3, and 91 tier 4 alterations and alteration types, including those associated with the most common tumor profiling biomarkers and cancer types (see Table 1, below).
Table 1. Genes and cancer types currently included in Actionability data. List of genes adapted from Illumina's TSO500 tumor profiling biomarkers for multiple cancer types [1]. Note: some genes are not yet fully curated, but have been prioritized for curation in Actionability V7 (tentatively launching October 2022).
CMC and Actionability help you rank biologically and clinically relevant mutations easily and efficiently. With the complete set of COSMIC downloadable files, you can further refine the priorities of relevant mutations with the mutational frequency in your patient’s cancer type, as well as resistance mutations.
COSMIC Actionability is updated with new content every quarter. The latest release, V6, contains the following:
See the complete release statistics in Figure 2, below.
Figure 2. COSMIC Actionability V6 release statistics.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab and the quality of the database's content by downloading sample data here.
References
The latest COSMIC Actionability release is here with a focus on the ERBB2 gene. Before we delve into the trove of data the new release offers, we explain what COSMIC Actionability is and how it’s designed to support your precision oncology activities.
COSMIC, the Catalogue of Somatic Mutations in Cancer, is an online, expert-curated database encompassing the wide variety of somatic mutation mechanisms causing human cancer. Founded and maintained by the Wellcome Sanger Institute and exclusively licensed through QIAGEN Digital Insights, COSMIC holds details on millions of mutations across thousands of cancer types to help users identify biomarkers and annotate variants.
COSMIC Actionability is a feature within the database that indicates the availability of drugs that target mutations in cancer and tracks the progress of clinical studies towards making new drugs available. These drugs are covered at all stages of development—from early case studies to safety and clinical phases, all the way to market. Actionability data is updated and structured so you can get the latest information on drug repurposing, monitor the drug development landscape and identify emerging biomarkers that may be useful in label expansion.
ERBB2 is an oncogene that encodes a transmembrane protein with tyrosine kinase activity and is involved in pathways that lead to cell growth and differentiation. ERBB2 is also known as human epidermal growth factor receptor 2 (HER2) [1].
ERBB2 gene amplification happens in many different types of cancer. It has been identified in 20% of patients with gastric cancer [2] and about 20% of invasive breast cancer cases [3]. ERBB2 amplification is now a mainstream therapeutic target in breast and gastric cancer and can be easily detected using immunohistochemistry (IHC) techniques.
ERBB2 mutations have only just emerged as a therapeutic target in solid tumors. Historically, and due to how low its occurrence is, ERBB2 mutations have not received as much attention as ERBB2 amplification. Now, newer clinical studies of targeted therapies for ERBB2-mutant cancers are delivering encouraging results in solid tumors, especially breast cancer and non-small cell lung cancer.
Previous clinical trials have indicated that treatment efficacy varies according to the location of the ERBB2 mutation. While ERBB2 mutations appear more often in the tyrosine kinase domain region, there is still some variation in mutational hotspots in different cancer types.
In one study, patients with ERBB2 kinase domain point mutations treated with neratinib (pan-HER tyrosine kinase inhibitor) had a response rate of 21.4%, while patients with exon 20 insertions had a 7.1% response [1]. These variant-specific dissimilarities in clinical outcomes show that a more in-depth understanding of ERBB2 mutations is crucial to developing effective therapies.
Drug discovery and development can be very expensive and slow. Repurposing existing drugs to treat diseases with little to no effective therapies is a valid approach many are starting to take. New candidate therapies based on existing drugs can quickly move through the regulatory process and become more easily embedded into care pathways.
To repurpose drugs safely, effectively and efficiently, data on their failure–why the drugs are not effective or safe, why they have been withdrawn, and why development has been halted—must be readily available for investigation. That’s precisely what COSMIC Actionability provides.
What COSMIC Actionability v5 tells you about drugs for ERBB2 alterations where development has been stopped
Currently, 111 different drug combinations that have been tested in trials on cancer patients with ERBB2 alterations now have the status ‘Terminated’ or ‘Withdrawn’. Of these trials, 3 selected patients with ERBB2 mutations, 78 selected patients with evidence of ERBB2 expression, and 47 specified overexpression.
Out of the 78 combinations tested in trials that selected patients with evidence of ERBB2 expression, reasons for termination were identified for 53. Twenty-five of the trials were terminated due to slow accrual, 9 for lack of efficacy, 6 for safety/toxicity and 10 due to changed business priorities.
Within the group terminated due to lack of efficacy, 7 of them have this reason identified on the ClinicalTrials.gov website. The other 2 had their reason for termination in ASCO postings, which are not available on ClinicalTrials.gov or PubMed.
Again, of the 47 combinations tested in overexpression-selected trials, the reason for termination was identified for 34: 19 for slow accrual, 4 for adverse events or toxicity issues, 4 due to changed business priorities and 3 due to lack of efficacy. One was terminated because the sponsor company decided to suspend the development of the compound, Aderbasib. The reason for the suspension is not available in the download file, but online sources suggest it was because later research contradicted earlier positive results in phase II trials. The press releases are not available anymore.
Label expansion studies are frequently conducted to seek regulatory approval to expand the indications for a drug. Supplementary clinical data is needed to show the drug can safely and effectively treat patient groups other than the ones for which it was initially intended. COSMIC Actionability keeps track of how many trials are currently in development and if you can use an approved drug in other indications.
Which ERBB2-focused trials are currently investigating approved drugs in other indications and their phases
There are 34 combinations in ongoing trials that either selected or plan to correlate efficacy with ERBB2 expression or mutation that are looking at an approved drug combination for another indication. One is approved, but the trial is not complete. One of the trials is in phase III, 24 are in phase II, and 8 are in phase I. In addition, 8 of the 34 trials are repurposing trials looking at gastrointestinal cancers.
With COSMIC Actionability, monitoring the drug development landscape and identifying emerging biomarkers with significant responses is simple and efficient.
Now more than ever, there are multitudes of molecules, biologics, vaccines and innovative therapies at all phases of clinical drug development. COSMIC Actionability allows users to monitor the global, ever- changing landscape of investigational drugs in specific diseases.
Drugs in development, terminated, or withdrawn for ERBB2 amplification in gastric cancers (including GIST at GE junction)
Currently, there are 29 ongoing trial cohorts looking at 25 different drug combinations targeting ERBB2 overexpression in gastrointestinal cancers. Separately, 1 trial was terminated due to changed business priorities, and a further 3 have unknown status.
Are there any ERBB2 point mutations that show significant response with off-label use of FDA-approved therapies?
There are 3 trials looking at FDA-approved drugs for other indications that either select or plan to correlate efficacy with ERBB2 mutations. All the trials are in phase II. One has been terminated due to slow accrual. Another has been completed with an ORR of 19% ─ likely not high enough to take it to phase III. The remaining trial is active but not recruiting, with an ORR of 55% and PFS of 8.2 months, OS of 17.2 months. It has no control, so no statistically significant results, but it is likely to go on to phase III.
COSMIC Actionability is indispensable to investigations focused on drugs targeting specific mutations in cancer. The new release, Actionability v5, focuses on ERBB2 alterations and highlights just how useful COSMIC Actionability can be for any target of choice. With its regularly updated content, you can stay up-to-date on the latest drug developments in the precision oncology space.
Learn more about COSMIC and how the industry-leading database can help you identify biomarkers, annotate variants, and explore the etiology of human cancers here.
See first-hand how COSMIC can be used in your lab and the quality of the database's content by downloading sample data here.
References
