Biomedical subjects

Marc S Greenblatt

Publications and source records attributed to Marc S Greenblatt.

6 recordsLinked to original sources

PubMed2025

Calibration of additional computational tools expands ClinGen recommendation options for variant classification with PP3/BP4 criteria.

PURPOSE: We previously developed an approach to calibrate computational tools for clinical variant classification, updating recommendations for the reliable use of variant impact predictors to provide evidence strength up to Strong. A new generation of tools using distinctive approaches has since been released, and these methods must be independently calibrated for clinical application. METHODS: Using our local posterior probability-based calibration and our established data set of ClinVar pathogenic and benign variants, we determined the strength of evidence provided by 3 new tools (AlphaMissense, ESM1b, and VARITY) and calibrated scores meeting each evidence strength. RESULTS: All 3 tools reached the Strong level of evidence for variant pathogenicity and Moderate for benignity, although sometimes for few variants. Compared with previously recommended tools, these yielded at best only modest improvements in the trade-offs between evidence strength and false-positive predictions. CONCLUSION: At calibrated thresholds, 3 new computational predictors provided evidence for variant pathogenicity at similar strength to the 4 previously recommended predictors (and comparable with functional assays for some variants). This calibration broadens the scope of computational tools for application in clinical variant classification. Their new approaches offer promise for future advancement of the field.

Humans↗

PubMed2006

Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study.

PURPOSE: The aim of study was to determine the clinical characteristics and mutational profiles of the mismatch repair genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients with small bowel cancer (SBC). EXPERIMENTAL DESIGN: A questionnaire was mailed to 55 members of the International Society for Gastrointestinal Hereditary Tumours, requesting information regarding patients with HNPCC-associated SBC and germ line mismatch repair gene mutations. RESULTS: The study population consisted of 85 HNPCC patients with identified mismatch repair gene mutations and SBCs. SBC was the first HNPCC-associated malignancy in 14 of 41 (34.1%) patients for whom a personal history of HNPCC-associated cancers was available. The study population harbored 69 different germ line mismatch repair gene mutations, including 31 mutations in MLH1, 34 in MSH2, 3 in MSH6, and 1 in PMS2. We compared the distribution of the mismatch repair mutations in our study population with that in a control group, including all pathogenic mismatch repair mutations of the International Society for Gastrointestinal Hereditary Tumours database (excluding those in our study population). In patients with MSH2 mutations, patients with HNPCC-associated SBCs had fewer mutations in the MutL homologue interaction domain (2.9% versus 19.9%, P = 0.019) but an increased frequency of mutations in codons 626 to 733, a domain that has not previously been associated with a known function, versus the control group (26.5% versus 2.8%, P < 0.001). CONCLUSIONS: In HNPCC patients, SBC can be the first and only cancer and may develop as soon as the early teens. The distribution of MSH2 mutations found in patients with HNPCC-associated SBCs significantly differed from that found in the control group (P < 0.001).

Adaptor Proteins, Signal Transducing↗

PubMed2006

An automated procedure to identify biomedical articles that contain cancer-associated gene variants.

The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and imprecise. More effective mechanisms for identifying articles containing mutation information would be beneficial both for the curation of mutation databases and for individual researchers. We developed an automated method that uses information extraction, classifier, and relevance ranking techniques to determine the likelihood of MEDLINE abstracts containing information regarding genomic variation data suitable for inclusion in mutation databases. We targeted the CDKN2A (p16) gene and the procedure for document identification currently used by CDKN2A Database curators as a measure of feasibility. A set of abstracts was manually identified from a MEDLINE search as potentially containing specific CDKN2A mutation events. A subset of these abstracts was used as a training set for a maximum entropy classifier to identify text features distinguishing "relevant" from "not relevant" abstracts. Each document was represented as a set of indicative word, word pair, and entity tagger-derived genomic variation features. When applied to a test set of 200 candidate abstracts, the classifier predicted 88 articles as being relevant; of these, 29 of 32 manuscripts in which manual curation found CDKN2A sequence variants were positively predicted. Thus, the set of potentially useful articles that a manual curator would have to review was reduced by 56%, maintaining 91% recall (sensitivity) and more than doubling precision (positive predictive value). Subsequent expansion of the training set to 494 articles yielded similar precision and recall rates, and comparison of the original and expanded trials demonstrated that the average precision improved with the larger data set. Our results show that automated systems can effectively identify article subsets relevant to a given task and may prove to be powerful tools for the broader research community. This procedure can be readily adapted to any or all genes, organisms, or sets of documents.

Computational Biology↗

PubMed2005

Phase I/II trial of paclitaxel and vinorelbine in advanced non-small cell lung cancer.

Chemotherapeutic combination regimens for advanced non-small cell lung cancer traditionally have been based on platin compounds. However, a mechanistic rationale could lead to effective non-platin combinations. Paclitaxel and vinorelbine are antimicrotubule agents with different mechanisms of action, both of which have single agent activity against non-small cell lung cancer. A Phase I/II trial of paclitaxel Day 1 and vinorelbine Days 1-3 every 21 days was, therefore, performed for patients with Stage IIIB or Stage IV non-small cell lung cancer who had not previously received chemotherapy for metastatic disease. In the Phase I investigation, up to 4 patients were treated at each dose level. The maximum tolerated dose level was found to be paclitaxel 150 mg/m2 IV Day 1 and vinorelbine 16 mg/m2 IV Days 1-3, with dose-limiting toxicities of fatigue, myalgia, and mucositis at higher doses. This dose level was then expanded with an additional 15 patients. Of the 23 patients treated for up to 10 cycles at or near the maximum tolerated dose level (19 patients with paclitaxel 150 mg/m2 IV Day 1 and vinorelbine 16 mg/m2 Days 1-3, and 4 patients with paclitaxel 150 mg/m2 IV Day 1 and vinorelbine 13 mg/m2 Days 1-3), 7 patients achieved partial response and 5 patients achieved minor response. Fatigue, myalgia, peripheral neuropathy, and transient leukopenia were the most common cumulative toxicities seen. The non-platin chemotherapy doublet of paclitaxel and vinorelbine given on this convenient 3-day schedule is worthy of further investigation in the treatment of non-small cell lung cancer.

Adult↗

PubMed2005

Factor V Leiden, prothrombin 20210A and the risk of venous thrombosis among cancer patients.

Cancer patients have an increased risk of venous thrombosis (VT). The association of factor V Leiden (FVL) and the prothrombin 20210A variant with VT in cancer patients is not established. We genotyped 101 cancer patients with VT and 101 cancer patients without VT for these polymorphisms. Five cases and three controls were heterozygous for FVL, yielding an odds ratio of 1.7 (95% confidence interval (CI) 0.3-10.7). Five cases and no controls were heterozygous for prothrombin 20210A, for an odds ratio of 6.7 (95% CI 0.9-infinity). Prothrombin 20210A may be associated with VT risk among cancer patients.

Aged↗

PubMed2004

The CDKN2A database: Integrating allelic variants with evolution, structure, function, and disease association.

In this report, we introduce the CDKN2A Database, an online database of germline and somatic variants of the CDKN2A tumor suppressor gene recorded in human disease through the year 2002, annotated with evolutionary, structural, and functional information. The CDKN2A Database improves upon existing resources by: 1) including both somatic mutations and germline variants, thereby adding the perspective of somatic cell carcinogenesis to that of hereditary cancer predisposition; 2) including information that assists with the interpretation of allelic variants, such as other primary data (sequences, structures, alignments, functional measurements, and literature references) and annotations (extensive text, figures, and a tree-based phylogenetic classification); and 3) providing the information in a format that allows a user to either download the database or to easily manipulate it online. We describe the database structure, content, current uses, and potential implications (http://biodesktop.uvm.edu/perl/p16).

Alleles↗