| 1. |
- Esteller, Manel, et al.
(författare)
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DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis
- 2001
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 10:26, s. 3001-3007
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cells have aberrant patterns of DNA methylation including hypermethylation of gene promoter CpG islands and global demethylation of the genome. Genes that cause familial cancer, as well as other genes, can be silenced by promoter hypermethylation in sporadic tumors, but the methylation of these genes in tumors from kindreds with inherited cancer syndromes has not been well characterized. Here, we examine CpG island methylation of 10 genes (hMLH1, BRCA1, APC, LKB1, CDH1, p16(INK4a), p14(ARF), MGMT, GSTP1 and RARbeta2) and 5-methylcytosine DNA content, in inherited (n = 342) and non-inherited (n = 215) breast and colorectal cancers. Our results show that singly retained alleles of germline mutated genes are never hypermethylated in inherited tumors. However, this epigenetic change is a frequent second "hit", associated with the wild-type copy of these genes in inherited tumors where both alleles are retained. Global hypomethylation was similar between sporadic and hereditary cases, but distinct differences existed in patterns of methylation at non-familial genes. This study demonstrates that hereditary cancers "mimic" the DNA methylation patterns present in the sporadic tumors.
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| 2. |
- Rosmarin, Dan, et al.
(författare)
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Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens : Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis
- 2014
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Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 32:10, s. 1031-1039
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.PATIENTS AND METHODS: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n = 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens.RESULTS: Global capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846T>A and *2A (combined odds ratio, 5.51; P = .0013) and with the common TYMS polymorphisms 5'VNTR2R/3R and 3'UTR 6bp ins-del (combined odds ratio, 1.31; P = 9.4 × 10(-6)). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens.CONCLUSION: A panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.
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| 3. |
- Stenzinger, Albrecht, et al.
(författare)
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Implementation of precision medicine in healthcare—A European perspective
- 2023
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Ingår i: Journal of Internal Medicine. - 0954-6820 .- 1365-2796. ; 294:4, s. 437-454
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Forskningsöversikt (refereegranskat)abstract
- The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient—that is, precision or personalized medicine (PM). In several European countries—such as in England, France, Denmark, and Spain—the governments have adopted national strategies and taken “top-down” decisions to invest in national infrastructure for PM. In other countries—such as Sweden, Germany, and Italy with regionally organized healthcare systems—the profession has instead taken “bottom-up” initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders—that is, healthcare, academia, policymakers, industry, and patients—must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.
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