A commentary on the discrepancy between blood and tumour BRCA testing: An open question.
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ABSTRACT:
SUBMITTER: De Paolis E
PROVIDER: S-EPMC9543799 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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A commentary on the discrepancy between blood and tumour BRCA testing: An open question.
De Paolis Elisa E Marchetti Claudia C Concolino Paola P Scambia Giovanni G Urbani Andrea A Fagotti Anna A Minucci Angelo A
BJOG : an international journal of obstetrics and gynaecology 20220405 9
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Project description:Tumour testing of the BRCA1/2 genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB). Results from tumour BRCA sequencing of 641 consecutive unselected cancer patients were discussed during weekly MTB meetings with the early involvement of clinical geneticists for appropriate referral to genetic counselling. The overall tumour detection rate of BRCA1/2 PVs was 8.7% (56/641), ranging from 24.4% (31/127) in high-grade ovarian cancer to 3.9% (12/304) in tumours not associated with germline BRCA1/2 PVs. Thirty-seven patients with PVs (66%) were evaluated by a clinical geneticist, and in 24 of them (64.9%), germline testing confirmed the presence of the PV in blood. Nine of these patients (37.5%) were not eligible for germline testing according to the criteria in use at our institution. Cascade testing was subsequently performed on 18 relatives. The tumour-to-germline diagnostic pipeline, developed in the framework of our institutional MTB, compared with guideline-based germline testing following genetic counselling, proved to be effective in identifying a higher number of germline BRCA PVs carriers.
| S-EPMC9026437 | biostudies-literature
Project description:Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1-3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8-13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.
| S-EPMC7048239 | biostudies-literature
Project description:The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.
| S-EPMC8003427 | biostudies-literature
Project description:ObjectivesWe aimed to evaluate the acceptability, feasibility, and understanding of a donor ethnic-ancestry question with Australian blood donors.BackgroundEthnic-ancestry assists blood collection agencies to meet the demand for rare blood-types. However, there is no standard ethnicity question used by health/blood services around the world and we do not know how blood donors in Australia will respond to being asked for this information.Methods/materialsA survey and ethnic-ancestry question was administered to a sample of donors (n = 506) to evaluate their views on being asked for their ethnic-ancestry, test a comprehensive ethnic-ancestry list, and determine the level of information required by donors.ResultsDonors reported being very comfortable providing their ethnic-ancestry and the majority of donors found an ethnic-ancestry option they were happy with (91.3%). Overall donors reported a high level of understanding of why ethnic-ancestry was important to blood donation. However, when provided more information on why ethnic-ancestry is required, donors reported increased understanding.ConclusionThe findings from this study demonstrated that it is acceptable and feasible to introduce a comprehensive ethnic-ancestry question for Australian blood donors. We also found that a greater understanding is achieved when a more comprehensive explanation for inclusion of the question is provided.
| S-EPMC9320970 | biostudies-literature
Project description:Tumour DNA sequencing is essential for precision medicine since it guides therapeutic decisions but also fosters the identification of patients who may benefit from germline testing. Notwithstanding, the tumour-to-germline testing workflow presents a few caveats. The low sensitivity for indels at loci with sequences of identical bases (homopolymers) of ion semiconductor-based sequencing techniques represents a well-known limitation, but the prevalence of indels overlooked by these techniques in high-risk populations has not been investigated. In our study, we addressed this issue at the homopolymeric regions of BRCA1/2 in a retrospectively selected cohort of 157 patients affected with high-grade ovarian cancer and negative at tumour testing by ION Torrent sequencing. Variant allele frequency (VAF) of indels at each of the 29 investigated homopolymers was systematically revised with the IGV software. Thresholds to discriminate putative germline variants were defined by scaling the VAF to a normal distribution and calculating the outliers that exceeded the mean + 3 median-adjusted deviations of a control population. Sanger sequencing of the outliers confirmed the occurrence of only one of the five putative indels in both tumour and blood from a patient with a family history of breast cancer. Our results indicated that the prevalence of homopolymeric indels overlooked by ion semiconductor techniques is seemingly low. A careful evaluation of clinical and family history data would further help minimise this technique-bound limitation, highlighting cases in which a deeper look at these regions would be recommended.
| S-EPMC10182972 | biostudies-literature
Project description:BRCA testing received much publicity following Angelina Jolie's editorial "My Medical Choice" in May 2013 and updated NICE clinical guidance (CG164) in June 2013. We assessed the effect of these two concurrent events on BRCA testing in one UK catchment area and relate this to socioeconomic deprivation. A database of 1393 patients who received BRCA testing was collated. This included individuals with breast/ovarian cancer, and those unaffected by cancer, where a relative has a ≥10% probability of carrying a BRCA variant which affects function. A segmented regression was conducted to estimate changes in testing. To examine the relative distribution of testing by deprivation, the deprivation status of patients who received testing was examined. Between April 2010 and March 2017, testing increased 11-fold and there was an 84% increase (P = 0.006) in BRCA1/2 testing in the month following both publications. In the pre-publication period, there was no statistically significant difference in testing between advantaged and disadvantaged areas (OR 1.21, 95% CI 0.99-1.48; P = 0.06). In the post-publication period helped by a larger sample size, the difference was statistically significant (OR 1.18, 95% CI 1.08-1.29; P = 0.0002) and of a similar magnitude to the pre-publication period. Testing increased following Jolie's editorial and NICE guidance update. However, further research is needed to examine differences in testing by the deprivation group which adjusts for confounders.
| S-EPMC6777468 | biostudies-literature
Project description:BackgroundHemodynamic monitoring is imperative for patients with cardiogenic shock undergoing Intra-aortic Balloon Pump (IABP) therapy. Blood pressure monitoring encompasses non-invasive, invasive peripheral arterial pressure (IPAP), and invasive central aortic pressure (ICAP) methods. However, marked disparities exist between IPAP and ICAP. This study examined the discrepancies between IPAP and ICAP and their clinical significance.MethodsA retrospective analysis was conducted on cardiogenic shock patients who underwent IABP therapy and were admitted to the Coronary Care Unit (CCU) of a tertiary hospital in China from March 2017 to November 2022. The Bland-Altman plot illustrated the discrepancy between IPAP and ICAP. A clinically significant difference between ICAP and IPAP measurements was defined as ≥ 10 mmHg, which could necessitate alterations in blood pressure management according to current guidelines that recommend maintaining a mean arterial pressure (MAP) ≥ 70 mmHg.ResultsIn total, 162 patients were included in the final analysis. In patients without vasopressors, the difference between ICAP and IPAP was 5.73 mmHg (95% limits of agreement [LOA], -16.98 to 28.44), whereas, in patients with vasopressors, it was 4.36 mmHg (95% LOA, -17.31 to 26.03). ICAP measurements exceeded IPAP in patients undergoing IABP therapy. However, the difference was not statistically significant between the two groups. Multivariate logistic regression revealed that higher serum lactate levels (Odds ratio [OR], 1.14; 95% confidence interval [CI], 1.03-1.27; p = 0.013) and age ≥ 60 years (OR, 13.20; 95% CI, 1.50-115.51; p = 0.020) were associated with an increased likelihood of a clinically significant MAP discrepancy. Conversely, a history of coronary heart disease was associated with a decreased likelihood (OR, 0.34; 95% CI, 0.13-0.90; p = 0.031).ConclusionsNotable discrepancies between ICAP and IPAP measurements exist in cardiogenic shock patients undergoing IABP therapy. ICAP exceeds IPAP, and factors such as age ≥ 60 years, elevated lactic acid levels, and absence of coronary heart disease contribute to this discrepancy. Enhanced vigilance is warranted for these patients, and the consideration of peripheral invasive monitoring in conjunction with IABP therapy is advised.
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Project description:IntroductionBlood pressure (BP) monitoring is an essential component of sepsis management. The Surviving Sepsis Guidelines recommend invasive arterial BP (IABP) monitoring, although the benefits over non-invasive BP (NIBP) monitoring are unclear. This study investigated discrepancies between IABP and NIBP measurement and their clinical significance. We hypothesized that IABP monitoring would be associated with changes in management among patients with sepsis requiring vasopressors.MethodsWe performed a retrospective study of adult patients admitted to the critical care resuscitation unit at a quaternary medical center between January 1-December 31, 2017. We included patients with sepsis conditions AND IABP monitoring. We defined a clinically significant BP discrepancy (BPD) between NIBP and IABP measurement as a difference of > 10 millimeters of mercury (mm Hg) AND change of BP management to maintain mean arterial pressure ≥ 65 mm Hg.ResultsWe analyzed 127 patients. Among 57 (45%) requiring vasopressors, 9 (16%) patients had a clinically significant BPD vs 2 patients (3% odds ratio [OR] 6.4; 95% CI: 1.2-30; P = 0.01) without vasopressors. In multivariable logistic regression, higher Sequential Organ Failure Assessment (SOFA) score (OR 1.33; 95% CI: 1.02-1.73; P = 0.03) and serum lactate (OR 1.27; 95% CI: 1.003-1.60, P = 0.04) were associated with increased likelihood of clinically significant BPD. There were no complications (95% CI: 0-0.02) from arterial catheter insertions.ConclusionAmong our population of septic patients, the use of vasopressors was associated with increased odds of a clinically significant blood pressure discrepancy between IABP and NIBP measurement. Additionally, higher SOFA score and serum lactate were associated with higher likelihood of clinically significant blood pressure discrepancy. Further studies are needed to confirm our observations and investigate the benefits vs the risk of harm of IABP monitoring in patients with sepsis.
| S-EPMC9183768 | biostudies-literature
Project description:BRCA mutation-associated breast cancer differs from sporadic breast cancer with regard to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available at the time of breast cancer diagnosis, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA mutation carriers with breast cancer. This article reviews surgical options for management of affected BRCA mutation carriers with emphasis on the risks of ipsilateral recurrence and contralateral breast cancer. The roles of breast-conserving surgery, prophylactic mastectomy, and oophorectomy are reviewed. In addition, the sensitivity of BRCA mutation-associated breast cancer to endocrine therapy, platinum chemotherapy, and poly (ADP-ribose) polymerase inhibitors is reviewed.
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Project description: Not available
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