scholarly journals Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer

2020 ◽  
Vol 112 (12) ◽  
pp. 1275-1279 ◽  
Author(s):  
Anne S Reiner ◽  
Mark E Robson ◽  
Lene Mellemkjær ◽  
Marc Tischkowitz ◽  
Esther M John ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Contralateral Breast Cancer ◽  
Contralateral Breast ◽  
Pathogenic Variant ◽  
Chek2 1100Delc ◽  
Variants Of Uncertain Significance ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Uncertain Significance

Abstract Whether radiation therapy (RT) affects contralateral breast cancer (CBC) risk in women with pathogenic germline variants in moderate- to high-penetrance breast cancer–associated genes is unknown. In a population-based case-control study, we examined the association between RT; variants in ATM, BRCA1/2, or CHEK2*1100delC; and CBC risk. We analyzed 708 cases of women with CBC and 1399 controls with unilateral breast cancer, all diagnosed with first invasive breast cancer between 1985 and 2000 and aged younger than 55 years at diagnosis and screened for variants in breast cancer–associated genes. Rate ratios (RR) and 95% confidence intervals (CIs) were estimated using multivariable conditional logistic regression. RT did not modify the association between known pathogenic variants and CBC risk (eg, BRCA1/2 pathogenic variant carriers without RT: RR = 3.52, 95% CI = 1.76 to 7.01; BRCA1/2 pathogenic variant carriers with RT: RR = 4.46, 95% CI = 2.96 to 6.71), suggesting that modifying RT plans for young women with breast cancer is unwarranted. Rare ATM missense variants, not currently identified as pathogenic, were associated with increased risk of RT-associated CBC (carriers of ATM rare missense variants of uncertain significance without RT: RR = 0.38, 95% CI = 0.09 to 1.55; carriers of ATM rare missense variants of uncertain significance with RT: RR = 2.98, 95% CI = 1.31 to 6.80). Further mechanistic studies will aid clinical decision-making related to RT.

scholarly journals Genetic testing for breast cancer risk, from BRCA1/2 to a seven gene panel: an ethical analysis

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Erik Gustavsson ◽  
Giovanni Galvis ◽  
Niklas Juth
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Cost Effectiveness ◽  
Gene Panel ◽  
Special Focus ◽  
Secondary Findings ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Increased Risk ◽  
Uncertain Significance

Abstract Background Genetic testing is moving from targeted investigations of monogenetic diseases to broader testing that may provide more information. For example, recent health economic studies of genetic testing for an increased risk of breast cancer suggest that it is associated with higher cost-effectiveness to screen for pathogenic variants in a seven gene panel rather than the usual two gene test for variants in BRCA1 and BRCA2. However, irrespective of the extent to which the screening of the panel is cost-effective, there may be ethical reasons to not screen for pathogenic variants in a panel, or to revise the way in which testing and disclosing of results are carried out. Main text In this paper we discuss the ethical aspects of genetic testing for an increased risk of breast cancer with a special focus on the ethical differences between screening for pathogenic variants in BRCA1/2 and a seven gene panel. The paper identifies that the panel increases the number of secondary findings as well as the number of variants of uncertain significance as two specific issues that call for ethical reflection. Conclusions We conclude that while the problem of handling secondary findings should not be overstated with regard to the panel, the fact that the panel also generate more variants of uncertain significance, give rise to a more complex set of problems that relate to the value of health as well as the value of autonomy. Therefore, it is insufficient to claim that the seven gene panel is preferable by only referring to the higher cost effectiveness of the panel.

Functional analysis of patient-derived PALB2 missense variants of uncertain significance.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1531-1531
Author(s):  
Shijie Wu ◽  
Jiaojiao Zhou ◽  
Yiding Chen
Keyword(s):  
Breast Cancer ◽  
Functional Analysis ◽  
In Silico ◽  
Cancer Genetic Counseling ◽  
Wild Type ◽  
Variants Of Uncertain Significance ◽  
Missense Variants ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
The Impact

1531 Background: Inherited PALB2 pathogenic variants are associated with an increased lifetime risk for breast cancer development. However, the interpretation of numerous PALB2 missense variants of uncertain significance (VUS) identified in germline genetic testing remains a challenge. Here, we assessed the impact of breast cancer patient-derived VUS on PALB2 function and identified pathogenic PALB2 missense variants that may increase cancer risk. Methods: A total of seven potentially pathogenic PALB2 VUS identified in 2,279 breast cancer patients were selected for functional analysis. All these selected VUS were assessed by SIFT, Align-GVGD, and PolyPhen2 in silico and were predicted to be deleterious by at least two in silico algorithms. The p.L35P [c.104T > C] variant was also included, for which pathogenicity has been recently confirmed. The effects of the VUS on the homologous recombination (HR) activity of PALB2 were tested by U2OS/DR-GFP reporting system. Functional characterization was further validated by protein co-immunoprecipitation and RAD51 recruitment assay. Results: PALB2 variants p.L24F [c.72G > C] and p.L35P [c.104T > C] showed the most significant disruption to the HR activity of PALB2 relative to the wild-type condition, retaining only 52.2% ( p = 0.0013) and 8.5% ( p < 0.0001) of HR activity respectively. Moderate but statistically significant HR deficiency was observed for four other variants (p.P405A [c.1213C > G], p.T1012I [c.3035C > T], p.E1018D [c.3054G > C], and p.T1099M [c.3296C > T]). We found no statistical differences for the p.K628N [c.1884G > T] and p.R663C [c.1987C > T] in the HR activity compared to wild-type PALB2. The p.L24F and p.L35P variants compromised the BRCA1-PALB2 interaction and reduced RAD51 foci formation in response to DNA damage. Conclusions: We have identified a novel patient-derived pathogenic PALB2 missense variant, p.L24F [c.72G > C], that compromises PALB2-mediated HR activity. We suggest the integration of the identified pathogenic variants into breast cancer genetic counseling and individualized treatment regimens for better clinical outcomes.

scholarly journals Machine Learning Methods to Identify Genetic Correlates of Radiation-Associated Contralateral Breast Cancer in the WECARE Study

2019 ◽  
Author(s):  
Sangkyu Lee ◽  
Xiaolin Liang ◽  
Meghan Woods ◽  
Anne S. Reiner ◽  
Duncan Thomas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Machine Learning ◽  
Contralateral Breast Cancer ◽  
Area Under The Curve ◽  
Contralateral Breast ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Unilateral Breast Cancer ◽  
Validation Data ◽  
Increased Risk

AbstractThe purpose of this study is to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve of 0.62 (p=0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.

scholarly journals Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance

eLife ◽  
2022 ◽  
Vol 11 ◽  
Author(s):  
Hirokazu Kimura ◽  
Raymond M Paranal ◽  
Neha Nanda ◽  
Laura D Wood ◽  
James R Eshleman ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Ductal Adenocarcinoma ◽  
Proliferation Assay ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Deleterious Alleles ◽  
Increased Risk ◽  
Uncertain Significance

Pathogenic germline CDKN2A variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC). CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinical management. 29 germline CDKN2A VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. 12 of the 29 CDKN2A VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of CDKN2A VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic/likely pathogenic CDKN2A in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.

Factors leading to the decision for contralateral prophylactic mastectomy in patients with breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1528-1528
Author(s):  
M. Yi ◽  
K. K. Hunt ◽  
B. K. Arun ◽  
I. Bedrosian ◽  
A. M. Gutierrez Barrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Testing ◽  
Primary Breast Cancer ◽  
Contralateral Breast Cancer ◽  
Prophylactic Mastectomy ◽  
Contralateral Prophylactic Mastectomy ◽  
Contralateral Breast ◽  
Cancer Center ◽  
Tumor Characteristics ◽  
Increased Risk

1528 Background: Women with breast cancer have an increased risk of developing contralateral breast cancer in their lifetime. Thus increasing numbers of women have been electing to undergo contralateral prophylactic mastectomy (CPM) at the time of their initial breast cancer treatment. The objective of this study was to identify factors that determine the decision for CPM in patients at a major cancer center. Methods: 2,544 women with Stage 0-III unilateral primary breast cancer who underwent surgery to the breast at our institution from January 2000 to August 2006 were identified from a prospectively maintained database. Patient and tumor characteristics were evaluated and comparisons were made between patients who did or did not undergo CPM using logistic regression. Results: Of the 2,544 patients, 1254 (49.3%) underwent total mastectomy for their known cancer; 282 (22.5%) of these patients underwent immediate or delayed CPM. Overall, 171 patients (6.7%) had genetic testing; and the use of testing increased in the latter years of the study (3.% in 2000–2002 vs. 8.2% in 2003–2006, p<.0001). 49 of 171 patients had genetic testing prior to surgery. 10 had a deleterious BRCA1/2 mutation, 9 of whom had a CPM (p=.002). 14 patients without a mutation also had a CPM. Multivariate analysis revealed factors associated with use of CPM were: age younger than 50, white race, family history of breast cancer, higher clinical tumor stage, invasive lobular histology, and use of reconstruction (Table). Conclusions: Both patient and tumor characteristics influence selection of CPM. Although the use of genetic testing is increasing, most women elect to undergo CPM without having genetic testing. Evidence-driven models are needed to better inform women of their absolute risk of contralateral breast cancer as well as competing risk from their primary breast cancer in order to empower them in their active-decision-making. [Table: see text] No significant financial relationships to disclose.

Reclassification of BRCA1 and BRCA2 variants of uncertain significance: a multifactorial analysis of multicentre prospective cohort

2018 ◽  
Vol 55 (12) ◽  
pp. 794-802 ◽  
Author(s):  
Jee-Soo Lee ◽  
Sohee Oh ◽  
Sue Kyung Park ◽  
Min-Hyuk Lee ◽  
Jong Won Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
External Validation ◽  
Brca1 And Brca2 ◽  
Clinical Genetic ◽  
Validation Data ◽  
Data Set ◽  
Variants Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Uncertain Significance ◽  
Highly Correlated

BackgroundBRCA1 and BRCA2 (BRCA1/2) variants classified ambiguously as variants of uncertain significance (VUS) are a major challenge for clinical genetic testing in breast cancer; their relevance to the cancer risk is unclear and the association with the response to specific BRCA1/2-targeted agents is uncertain. To minimise the proportion of VUS in BRCA1/2, we performed the multifactorial likelihood analysis and validated this method using an independent cohort of patients with breast cancer.MethodsWe used a data set of 2115 patients with breast cancer from the nationwide multicentre prospective Korean Hereditary Breast Cancer study. In total, 83 BRCA1/2 VUSs (BRCA1, n=26; BRCA2, n=57) were analysed. The multifactorial probability was estimated by combining the prior probability with the overall likelihood ratio derived from co-occurrence of each VUS with pathogenic variants, personal and family history, and tumour characteristics. The classification was compared with the interpretation according to the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG/AMP) guidelines. An external validation was conducted using independent data set of 810 patients.ResultsWe were able to redefine 38 VUSs (BRCA1, n=10; BRCA2, n=28). The revised classification was highly correlated with the ACMG/AMP guideline-based interpretation (BRCA1, p for trend=0.015; BRCA2, p=0.001). Our approach reduced the proportion of VUS from 19% (154/810) to 8.9% (72/810) in the retrospective validation data set.ConclusionThe classification in this study would minimise the ‘uncertainty’ in clinical interpretation, and this validated multifactorial model can be used for the reliable annotation of BRCA1/2 VUSs.

Excess Risk for Contralateral Breast Cancer in CHEK2*1100delC Germline Mutation Carriers

2004 ◽  
Vol 83 (1) ◽  
pp. 91-93 ◽  
Author(s):  
Annegien Broeks ◽  
Lot de Witte ◽  
Anke Nooijen ◽  
Angelina Huseinovic ◽  
Jan G.M. Klijn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Germline Mutation ◽  
Contralateral Breast Cancer ◽  
Contralateral Breast ◽  
Excess Risk ◽  
Chek2 1100Delc ◽  
Mutation Carriers

Tumor Stage Affects Risk and Prognosis of Contralateral Breast Cancer: Results From a Large Swedish-Population–Based Study

2012 ◽  
Vol 30 (28) ◽  
pp. 3478-3485 ◽  
Author(s):  
Voralak Vichapat ◽  
Hans Garmo ◽  
Marit Holmqvist ◽  
Göran Liljegren ◽  
Fredrik Wärnberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Primary Tumor ◽  
Primary Breast Cancer ◽  
Contralateral Breast Cancer ◽  
Cox Regression ◽  
Short Interval ◽  
Contralateral Breast ◽  
Increased Risk

Purpose The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC. Patients and Methods In a cohort of 42,670 women with breast cancer in the Uppsala/Örebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer–specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling. Results An increased risk for CBC was observed among women who had primary breast cancer with ≥ 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed ≤ 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for ≥ 10 years. Conclusion Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy.

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