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Annual Review of Genomics and Human... Aug 2020I briefly describe my early life and how, through a series of serendipitous events, I became a genetic epidemiologist. I discuss how the Elston-Stewart algorithm was...
I briefly describe my early life and how, through a series of serendipitous events, I became a genetic epidemiologist. I discuss how the Elston-Stewart algorithm was discovered and its contribution to segregation, linkage, and association analysis. New linkage findings and paternity testing resulted from having a genotyping lab. The different meanings of interaction-statistical and biological-are clarified. The computer package S.A.G.E. (Statistical Analysis for Genetic Epidemiology), based on extensive method development over two decades, was conceived in 1986, flourished for 20 years, and is now freely available for use and further development. Finally, I describe methods to estimate and test hypotheses about familial correlations, and point out that the liability model often used to estimate disease heritability estimates the heritability of that liability, rather than of the disease itself, and so can be highly dependent on the assumed distribution of that liability.
Topics: Algorithms; Genetic Linkage; History, 20th Century; History, 21st Century; Humans; Models, Genetic; Molecular Epidemiology
PubMed: 31935127
DOI: 10.1146/annurev-genom-103119-125052 -
Current Molecular Medicine 2022
Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Molecular Medicine; Neoplasms; Transcription Factors; Tumor Hypoxia
PubMed: 35603885
DOI: 10.2174/156652402204220325161921 -
The New England Journal of Medicine Sep 2023
Topics: Humans; Artificial Intelligence; Molecular Medicine
PubMed: 37754302
DOI: 10.1056/NEJMc2308776 -
International Journal of Molecular... Apr 2023Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, originating from keratinocytes of the spinous layer. Numerous risk factors have been... (Review)
Review
Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, originating from keratinocytes of the spinous layer. Numerous risk factors have been discovered for the initiation and growth of this type of cancer, such as exposure to UV and ionizing radiation, chemical carcinogens, the presence of immunosuppression states, chronic inflammation, infections with high-risk viral strains, and, last but not least, the presence of diseases associated with genetic alterations. The important socio-economic impact, as well as the difficulty associated with therapy for advanced forms, has made the molecular mechanisms underlying this neoplasia more and more intensively studied, with the intention of achieving a better understanding and advancing the treatment of this pathology. This review aims to provide a brief foray into the molecular, genetic, and epigenetic aspects of this cancer, as well as the treatment methods, ranging from the first used to the latest targeted therapies.
Topics: Humans; Carcinoma, Squamous Cell; Skin Neoplasms; Pathology, Molecular; Keratinocytes; Immunosuppression Therapy
PubMed: 37047618
DOI: 10.3390/ijms24076646 -
Clinics in Laboratory Medicine Jun 2022
Topics: COVID-19; Humans; Pandemics; Pathology, Molecular
PubMed: 35636829
DOI: 10.1016/j.cll.2022.04.001 -
International Journal of Molecular... Nov 2023The integration of molecular approaches in medicine allows for a more precise understanding of the mechanisms underlying infectious diseases, paving the way for targeted...
The integration of molecular approaches in medicine allows for a more precise understanding of the mechanisms underlying infectious diseases, paving the way for targeted therapies, personalized medicine, and the development of new diagnostic tools [...].
Topics: Humans; Molecular Medicine; Precision Medicine; Communicable Diseases
PubMed: 37958882
DOI: 10.3390/ijms242115899 -
Clinics in Laboratory Medicine Sep 2022
Topics: Humans; Medical Oncology; Neoplasms; Pathology, Molecular
PubMed: 36150827
DOI: 10.1016/j.cll.2022.06.001 -
Archives of Pathology & Laboratory... Aug 2022Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among...
CONTEXT.—
Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among laboratories in the genes analyzed for this purpose. Recently, the Association for Molecular Pathology CMN working group recommended a core 34-gene set as a minimum target list for evaluation of CMNs. This list was recommended based on literature review, and its diagnostic yield in clinical practice is unknown.
OBJECTIVE.—
To determine the diagnostic yield of the core 34 genes and assess the potential impact of including selected additional genes.
DESIGN.—
We retrospectively reviewed 185 patients with known or suspected CMNs tested using a 62-gene next-generation sequencing panel that included all 34 core genes.
RESULTS.—
The Association for Molecular Pathology's core 34 genes had a diagnostic yield of 158 of 185 (85.4%) to detect at least 1 variant with strong/potential clinical significance and 107 of 185 (57.8%) to detect at least 2 such variants. The 62-gene panel had a diagnostic yield of 160 of 185 (86.5%) and 112 of 185 (60.5%), respectively. Variants of unknown significance were identified in 49 of 185 (26.5%) using the core 34 genes versus 76 of 185 (41.1%) using the 62-gene panel.
CONCLUSIONS.—
This study demonstrates that the Association for Molecular Pathology-recommended core 34-gene set has a high diagnostic yield in CMNs. Inclusion of selected additional genes slightly increases the rate of abnormal results, while also increasing the detection of variants of unknown significance. We recommend inclusion of CUX1, DDX41, ETNK1, RIT1, and SUZ12 in addition to the Association for Molecular Pathology's 34-gene core set for routine evaluation of CMNs.
Topics: High-Throughput Nucleotide Sequencing; Humans; Mutation; Myeloproliferative Disorders; Pathology, Molecular; Retrospective Studies
PubMed: 34784413
DOI: 10.5858/arpa.2021-0124-OA -
Surgical Pathology Clinics Sep 2021Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic... (Review)
Review
Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic acids and the ability to perform molecular testing are addressed. In addition, molecular methods used commonly in clinical diagnostic laboratories, including newer technologies such as next-generation sequencing and digital droplet polymerase chain reaction, as well as their applications, are reviewed. Finally, we discuss considerations in designing a molecular test menu to deliver accurate and timely results in an efficient and cost-effective manner.
Topics: High-Throughput Nucleotide Sequencing; Humans; Molecular Diagnostic Techniques; Pathology, Molecular; Polymerase Chain Reaction
PubMed: 34373088
DOI: 10.1016/j.path.2021.05.001 -
Journal of Cancer Research and Clinical... Aug 2022Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the...
PURPOSE
Several targeted agents demonstrated efficacy in early clinical trials for gastrointestinal (GI) cancers, but in many cases, phase-III trials and/or approval by the European Medicines Agency (EMA) are lacking. The primary focus of this study was to assess the regulatory processes associated with use and reimbursement of off-label treatment in precision oncology and to evaluate the benefit of targeted therapy in a real-world population in Germany.
METHODS
Our cohort comprises 137 patients with GI cancers and is biased towards cancer entities with a high frequency of known targetable alterations, such as cholangiocarcinoma. Genetic testing was used to identify molecular targets, and therapy response was evaluated based on CT scans.
RESULTS
A molecular target for precision oncology was identified in 53 patients and 43 requests for cost coverage were submitted to health insurance companies. 60% of the requests received approval after initial application and another 7% after appeal. Half of the rejected requests were denied despite ESCAT IA level evidence. The median time between initiation of molecular testing and start of therapy was 75 days. 35 patients received matched targeted therapies (n = 28) or, in the case of MSI, immunotherapy (IO) (n = 7). We observed a trend in favor of molecular therapy when compared to the immediate prior treatment.
CONCLUSION
Relevant treatment options were identified by molecular testing in a significant subset of patients. When targeted therapies that lack EMA approval are considered, treatment initiation may be delayed by the duration of the molecular analysis and the regulatory processes.
Topics: Antineoplastic Agents; Cohort Studies; Gastrointestinal Neoplasms; Humans; Molecular Targeted Therapy; Pathology, Molecular; Precision Medicine
PubMed: 34436668
DOI: 10.1007/s00432-021-03774-5