Dataset Information

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

ABSTRACT: Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS₃₁₃) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS₃₁₃ was quantified using Cox regression analyses. We assessed PRS₃₁₃ interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS₃₁₃ was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS₃₁₃ was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10^th percentile and 20.5% at the 90^th percentile of PRS₃₁₃. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS₃₁₃ alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS₃₁₃ is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.

SUBMITTER: Kramer I

PROVIDER: S-EPMC7675034 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Kramer Iris I Hooning Maartje J MJ Mavaddat Nasim N Hauptmann Michael M Keeman Renske R Steyerberg Ewout W EW Giardiello Daniele D Antoniou Antonis C AC Pharoah Paul D P PDP Canisius Sander S Abu-Ful Zumuruda Z Andrulis Irene L IL Anton-Culver Hoda H Aronson Kristan J KJ Augustinsson Annelie A Becher Heiko H Beckmann Matthias W MW Behrens Sabine S Benitez Javier J Bermisheva Marina M Bogdanova Natalia V NV Bojesen Stig E SE Bolla Manjeet K MK Bonanni Bernardo B Brauch Hiltrud H Bremer Michael M Brucker Sara Y SY Burwinkel Barbara B Castelao Jose E JE Chan Tsun L TL Chang-Claude Jenny J Chanock Stephen J SJ Chenevix-Trench Georgia G Choi Ji-Yeob JY Clarke Christine L CL Collée J Margriet JM Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Daly Mary B MB Devilee Peter P Dörk Thilo T Dos-Santos-Silva Isabel I Dunning Alison M AM Dwek Miriam M Eccles Diana M DM Evans D Gareth DG Fasching Peter A PA Flyger Henrik H Gago-Dominguez Manuela M García-Closas Montserrat M García-Sáenz José A JA Giles Graham G GG Goldgar David E DE González-Neira Anna A Haiman Christopher A CA Håkansson Niclas N Hamann Ute U Hartman Mikael M Heemskerk-Gerritsen Bernadette A M BAM Hollestelle Antoinette A Hopper John L JL Hou Ming-Feng MF Howell Anthony A Ito Hidemi H Jakimovska Milena M Jakubowska Anna A Janni Wolfgang W John Esther M EM Jung Audrey A Kang Daehee D Kets C Marleen CM Khusnutdinova Elza E Ko Yon-Dschun YD Kristensen Vessela N VN Kurian Allison W AW Kwong Ava A Lambrechts Diether D Le Marchand Loic L Li Jingmei J Lindblom Annika A Lubiński Jan J Mannermaa Arto A Manoochehri Mehdi M Margolin Sara S Matsuo Keitaro K Mavroudis Dimitrios D Meindl Alfons A Milne Roger L RL Mulligan Anna Marie AM Muranen Taru A TA Neuhausen Susan L SL Nevanlinna Heli H Newman William G WG Olshan Andrew F AF Olson Janet E JE Olsson Håkan H Park-Simon Tjoung-Won TW Peto Julian J Petridis Christos C Plaseska-Karanfilska Dijana D Presneau Nadege N Pylkäs Katri K Radice Paolo P Rennert Gad G Romero Atocha A Roylance Rebecca R Saloustros Emmanouil E Sawyer Elinor J EJ Schmutzler Rita K RK Schwentner Lukas L Scott Christopher C See Mee-Hoong MH Shah Mitul M Shen Chen-Yang CY Shu Xiao-Ou XO Siesling Sabine S Slager Susan S Sohn Christof C Southey Melissa C MC Spinelli John J JJ Stone Jennifer J Tapper William J WJ Tengström Maria M Teo Soo Hwang SH Terry Mary Beth MB Tollenaar Rob A E M RAEM Tomlinson Ian I Troester Melissa A MA Vachon Celine M CM van Ongeval Chantal C van Veen Elke M EM Winqvist Robert R Wolk Alicja A Zheng Wei W Ziogas Argyrios A Easton Douglas F DF Hall Per P Schmidt Marjanka K MK

American journal of human genetics 20201005 5

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS<sub>313</sub>) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Me ...[more]

PMID: 33022221

Similar Datasets

Project description:ImportanceRadiation therapy for breast cancer is associated with increased risk of a second primary contralateral breast cancer, but the genetic factors modifying this association are not well understood.ObjectiveTo determine whether a genetic risk score comprising single nucleotide polymorphisms in the nonhomologous end-joining DNA repair pathway is associated with radiation-associated contralateral breast cancer.Design, setting, and participantsThis case-control study included a case group of women with contralateral breast cancer that was diagnosed at least 1 year after a first primary breast cancer who were individually matched to a control group of women with unilateral breast cancer. Inclusion criteria were receiving a first invasive breast cancer diagnosis prior to age 55 years between 1985 and 2008. Women were recruited through 8 population-based cancer registries in the United States, Canada, and Denmark as part of the Women's Environment, Cancer, and Radiation Epidemiology Studies I (November 2000 to August 2004) and II (March 2010 to December 2012). Data analysis was conducted from July 2017 to August 2019.ExposuresStray radiation dose to the contralateral breast during radiation therapy for the first breast cancer. A novel genetic risk score comprised of genetic variants in the nonhomologous end-joining DNA repair pathway was considered the potential effect modifier, dichotomized as high risk if the score was above the median of 74 and low risk if the score was at or below the median.Main outcomes and measuresThe main outcome was risk of contralateral breast cancer associated with stray radiation dose stratified by genetic risk score, age, and latency.ResultsA total of 5953 women were approached for study participation, and 3732 women (62.7%) agreed to participate. The median (range) age at first diagnosis was 46 (23-54) years. After 5 years of latency or more, among women who received the first diagnosis when they were younger than 40 years, exposure to 1.0 Gy (to convert to rad, multiply by 100) or more of stray radiation was associated with a 2-fold increased risk of contralateral breast cancer compared with women who were not exposed (rate ratio, 2.0 [95% CI, 1.1-3.6]). The risk was higher among women with a genetic risk score above the median (rate ratio, 3.0 [95% CI, 1.1-8.1]), and there was no association among women with a genetic risk score below the median (rate ratio, 1.3 [95% CI, 0.5-3.7]). Among younger women with a high genetic risk score, the attributable increased risk for contralateral breast cancer associated with stray radiation dose was 28%.Conclusions and relevanceThis study found an increased risk of contralateral breast cancer that was attributable to stray radiation exposure among women with a high genetic risk score and who received a first breast cancer diagnosis when they were younger than 40 years after 5 years or more of latency. This genetic risk score may help guide treatment and surveillance for women with breast cancer.

Project description:BackgroundPolygenic risk scores (PRS) could potentially improve breast cancer screening recommendations. Before a PRS can be considered for implementation, it needs rigorous evaluation, using performance measures that can inform about its future clinical value.ObjectivesTo evaluate the prognostic performance of a regression model with a previously developed, prevalence-based PRS and age as predictors for breast cancer incidence in women from the Estonian biobank (EstBB) cohort; to compare it to the performance of a model including age only.MethodsWe analyzed data on 30,312 women from the EstBB cohort. They entered the cohort between 2002 and 2011, were between 20 and 89 years, without a history of breast cancer, and with full 5-year follow-up by 2015. We examined PRS and other potential risk factors as possible predictors in Cox regression models for breast cancer incidence. With 10-fold cross-validation we estimated 3- and 5-year breast cancer incidence predicted by age alone and by PRS plus age, fitting models on 90% of the data. Calibration, discrimination, and reclassification were calculated on the left-out folds to express prognostic performance.ResultsA total of 101 (3.33‰) and 185 (6.1‰) incident breast cancers were observed within 3 and 5 years, respectively. For women in a defined screening age of 50-62 years, the ratio of observed vs PRS-age modelled 3-year incidence was 0.86 for women in the 75-85% PRS-group, 1.34 for the 85-95% PRS-group, and 1.41 for the top 5% PRS-group. For 5-year incidence, this was respectively 0.94, 1.15, and 1.08. Yet the number of breast cancer events was relatively low in each PRS-subgroup. For all women, the model's AUC was 0.720 (95% CI: 0.675-0.765) for 3-year and 0.704 (95% CI: 0.670-0.737) for 5-year follow-up, respectively, just 0.022 and 0.023 higher than for the model with age alone. Using a 1% risk prediction threshold, the 3-year NRI for the PRS-age model was 0.09, and 0.05 for 5 years.ConclusionThe model including PRS had modest incremental performance over one based on age only. A larger, independent study is needed to assess whether and how the PRS can meaningfully contribute to age, for developing more efficient screening strategies.

Project description:Background:Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. Methods:Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status. Results:The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction?=?0.009), adult height (P-interaction?=?0.025) and current use of combined MHT (P-interaction?=?0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P?=?0.013 for global and 0.18 for tail-based tests). Conclusions:The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.

Project description:ImportanceTo date, few studies have examined the extent to which polygenic single-nucleotide variation (SNV) (formerly single-nucleotide polymorphism) scores modify risk for carriers of pathogenic variants (PVs) in breast cancer susceptibility genes. In previous reports, polygenic risk modification was reduced for BRCA1 and BRCA2 PV carriers compared with noncarriers, but limited information is available for carriers of CHEK2, ATM, or PALB2 PVs.ObjectiveTo examine an 86-SNV polygenic risk score (PRS) for BRCA1, BRCA2, CHEK2, ATM, and PALB2 PV carriers.Design, setting, and participantsA retrospective case-control study using data on 150 962 women tested with a multigene hereditary cancer panel between July 19, 2016, and January 11, 2019, was conducted in a commercial testing laboratory. Participants included women of European ancestry between the ages of 18 and 84 years.Main outcomes and measuresMultivariable logistic regression was used to examine the association of the 86-SNV score with invasive breast cancer after adjusting for age, ancestry, and personal and/or family cancer history. Effect sizes, expressed as standardized odds ratios (ORs) with 95% CIs, were assessed for carriers of PVs in each gene as well as for noncarriers.ResultsThe median age at hereditary cancer testing of the population was 48 years (range, 18-84 years); there were 141 160 noncarriers in addition to carriers of BRCA1 (n = 2249), BRCA2 (n = 2638), CHEK2 (n = 2564), ATM (n = 1445), and PALB2 (n = 906) PVs included in the analysis. The 86-SNV score was associated with breast cancer risk in each of the carrier populations (P < 1 × 10-4). Stratification was more pronounced for noncarriers (OR, 1.47; 95% CI, 1.45-1.49) and CHEK2 PV carriers (OR, 1.49; 95% CI, 1.36-1.64) than for carriers of BRCA1 (OR, 1.20; 95% CI, 1.10-1.32) or BRCA2 (OR, 1.23; 95% CI, 1.12-1.34) PVs. Odds ratios for ATM (OR, 1.37; 95% CI, 1.21-1.55) and PALB2 (OR, 1.34; 95% CI, 1.16-1.55) PV carrier populations were intermediate between those for BRCA1/2 and CHEK2 noncarriers.Conclusions and relevanceIn this study, the 86-SNV score was associated with modified risk for carriers of BRCA1, BRCA2, CHEK2, ATM, and PALB2 PVs. This finding supports previous reports of reduced PRS stratification for BRCA1 and BRCA2 PV carriers compared with noncarriers. Modification of risk in CHEK2 carriers associated with the 86-SNV score appeared to be similar to that observed in women without a PV. Larger studies are needed to provide more refined estimates of polygenic modification of risk for women with PVs in other moderate-penetrance genes.

Dataset Information

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Publications

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets