| 51. |
- McCrary, J. Matt, et al.
(författare)
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Genetic counselling legislation and practice in cancer in EU Member States
- 2024
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Ingår i: European Journal of Public Health. - 1101-1262. ; 34:4, s. 666-675
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Tidskriftsartikel (refereegranskat)abstract
- Background: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. Methods: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. Results: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the ‘who, what, when and where’ of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the ‘most important change’ which would improve practice. Conclusions: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.
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| 52. |
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| 53. |
- Moghadasi, Setareh, et al.
(författare)
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The BRCA1 c. 5096G > A p.Arg1699Gln (R1699Q) intermediate risk variant : breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium
- 2018
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Ingår i: Journal of Medical Genetics. - : BMJ PUBLISHING GROUP. - 0022-2593 .- 1468-6244. ; 55:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: We previously showed that the BRCA1 variant c. 5096G> A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1* R1699Q carriers.Methods: Data were collected from 129 BRCA1* R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions.Results: In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83).Conclusion: O ur results confirm that BRCA1* R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingooophorectomy should be considered based on family history.
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| 54. |
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| 55. |
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| 56. |
- Mustjoki, S, et al.
(författare)
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Impact of malignant stem cell burden on therapy outcome in newly diagnosed chronic myeloid leukemia patients
- 2013
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 0887-6924 .- 1476-5551. ; 27:7, s. 1520-1526
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) stem cells appear resistant to tyrosine kinase inhibitors (TKIs) in vitro, but their impact and drug sensitivity in vivo has not been systematically assessed. We prospectively analyzed the proportion of Philadelphia chromosome-positive leukemic stem cells (LSCs, Ph+CD34+CD38=) and progenitor cells (LPCs, Ph+CD34+CD38+) from 46 newly diagnosed CML patients both at the diagnosis and during imatinib or dasatinib therapy (ClinicalTrials.gov NCT00852566). At diagnosis, the proportion of LSCs varied markedly (1-100%) between individual patients with a significantly lower median value as compared with LPCs (79% vs 96%, respectively, P = 0.0001). The LSC burden correlated with leukocyte count, spleen size, hemoglobin and blast percentage. A low initial LSC percentage was associated with less therapy-related hematological toxicity and superior cytogenetic and molecular responses. After initiation of TKI therapy, the LPCs and LSCs rapidly decreased in both therapy groups, but at 3 months time point the median LPC level was significantly lower in dasatinib group compared with imatinib patients (0.05% vs 0.68%, P = 0.032). These data detail for the first time the prognostic significance of the LSC burden at diagnosis and show that in contrast to in vitro data, TKI therapy rapidly eradicates the majority of LSCs in patients.
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| 57. |
- Nacer, Deborah F., et al.
(författare)
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Molecular characteristics of breast tumors in patients screened for germline predisposition from a population-based observational study
- 2023
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Ingår i: Genome Medicine. - 1756-994X. ; 15, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPathogenic germline variants (PGVs) in certain genes are linked to higher lifetime risk of developing breast cancer and can influence preventive surgery decisions and therapy choices. Public health programs offer genetic screening based on criteria designed to assess personal risk and identify individuals more likely to carry PGVs, dividing patients into screened and non-screened groups. How tumor biology and clinicopathological characteristics differ between these groups is understudied and could guide refinement of screening criteria.MethodsSix thousand six hundred sixty breast cancer patients diagnosed in South Sweden during 2010–2018 were included with available clinicopathological and RNA sequencing data, 900 (13.5%) of which had genes screened for PGVs through routine clinical screening programs. We compared characteristics of screened patients and tumors to non-screened patients, as well as between screened patients with (n = 124) and without (n = 776) PGVs.ResultsBroadly, breast tumors in screened patients showed features of a more aggressive disease. However, few differences related to tumor biology or patient outcome remained significant after stratification by clinical subgroups or PAM50 subtypes. Triple-negative breast cancer (TNBC), the subgroup most enriched for PGVs, showed the most differences between screening subpopulations (e.g., higher tumor proliferation in screened cases). Significant differences in PGV prevalence were found between clinical subgroups/molecular subtypes, e.g., TNBC cases were enriched for BRCA1 PGVs. In general, clinicopathological differences between screened and non-screened patients mimicked those between patients with and without PGVs, e.g., younger age at diagnosis for positive cases. However, differences in tumor biology/microenvironment such as immune cell composition were additionally seen within PGV carriers/non-carriers in ER + /HER2 − cases, but not between screening subpopulations in this subgroup.ConclusionsCharacterization of molecular tumor features in patients clinically screened and not screened for PGVs represents a relevant read-out of guideline criteria. The general lack of molecular differences between screened/non-screened patients after stratification by relevant breast cancer subsets questions the ability to improve the identification of screening candidates based on currently used patient and tumor characteristics, pointing us towards universal screening. Nevertheless, while that is not attained, molecular differences identified between PGV carriers/non-carriers suggest the possibility of further refining patient selection within certain patient subsets using RNA-seq through, e.g., gene signatures.
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| 58. |
- Osorio, A., et al.
(författare)
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Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2
- 2011
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 104:8, s. 1356-1361
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers. British Journal of Cancer (2011) 104, 1356-1361. doi:10.1038/bjc.2011.91 www.bjcancer.com Published online 22 March 2011 (C) 2011 Cancer Research UK
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| 59. |
- Parsons, Michael T, et al.
(författare)
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Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants : An ENIGMA resource to support clinical variant classification
- 2019
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Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; , s. 1557-1578
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Tidskriftsartikel (refereegranskat)abstract
- The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.
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