| 1. |
- Brédart, Anne, et al.
(författare)
-
Clinicians’ use of breast cancer risk assessment tools according to their perceived importance of breast cancer risk factors : an international survey
- 2019
-
Ingår i: Journal of Community Genetics. - : Springer Science and Business Media LLC. - 1868-310X .- 1868-6001. ; 10:1, s. 61-71
-
Tidskriftsartikel (refereegranskat)abstract
- The BOADICEA breast cancer (BC) risk assessment model and its associated Web Application v3 (BWA) tool are being extended to incorporate additional genetic and non-genetic BC risk factors. From an online survey through the BOADICEA website and UK, Dutch, French and Swedish national genetic societies, we explored the relationships between the usage frequencies of the BWA and six other common BC risk assessment tools and respondents’ perceived importance of BC risk factors. Respondents (N = 443) varied in age, country and clinical seniority but comprised mainly genetics health professionals (82%) and BWA users (93%). Oncology professionals perceived reproductive, hormonal (exogenous) and lifestyle BC risk factors as more important in BC risk assessment compared to genetics professionals (p values < 0.05 to 0.0001). BWA was used more frequently by respondents who gave high weight to breast tumour pathology and low weight to personal BC history as BC risk factors. BWA use was positively related to the weight given to hormonal BC risk factors. The importance attributed to lifestyle and BMI BC risk factors was not associated with the use of BWA or any of the other tools. Next version of the BWA encompassing additional BC risk factors will facilitate more comprehensive BC risk assessment in genetics and oncology practice.
|
|
| 2. |
- Henriksson, Isabelle, et al.
(författare)
-
Hereditary colorectal cancer diagnostics in southern Sweden : retrospective evaluation and future considerations with emphasis on Lynch syndrome
- 2019
-
Ingår i: Journal of Community Genetics. - : Springer Science and Business Media LLC. - 1868-310X .- 1868-6001. ; 10:2, s. 259-266
-
Tidskriftsartikel (refereegranskat)abstract
- Overlapping phenotypes between different hereditary colorectal cancer (CRC) syndromes together with a growing demand for cancer genetic testing and improved sequencing technology call for adjusted patient selection and adapted diagnostic routines. Here we present a retrospective evaluation of family history of cancer, laboratory diagnostic procedure, and outcome for 372 patients tested for Lynch syndrome (LS), i.e., the single most common hereditary cause of CRC. Based on number of affected family members and age at cancer diagnosis in families with genetically confirmed LS, we developed local patient selection criteria for a simplified one-step gene panel mutation screening strategy targeting also less common Mendelian CRC syndromes. Pros and cons of this strategy are discussed.
|
|
| 3. |
- Parsons, Michael T, et al.
(författare)
-
Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants : An ENIGMA resource to support clinical variant classification
- 2019
-
Ingår i: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; , s. 1557-1578
-
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.
|
|
| 4. |
- Staaf, Johan, et al.
(författare)
-
Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study
- 2019
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 25, s. 1526-1533
-
Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.
|
|
