Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research

Correction: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

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Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

PENGARUH METODE ECOLA (EXTENDING CONCEPTH TRHOUGH LANGUAGE ACTIVITIES) DALAM PEMBELAJARAN MEMBACA KRITIS TAJUK RENCANA

Penelitian ini bertujuan untuk memperoleh gambaran secara objektif tentang ada tidaknya perbedaan yang signifikan antara kemampuan siswa dalam membaca kritis tajuk rencana atau teks editorial kelas eksperimen dengan menggunakan metode ECOLAdan kelas kontrol dengan metode ceramah. Populasi dalam penelitian ini adalah seluruh siswa kelas VIII SMP Negeri 16 Bandung ajaran tahun 2015/2016. Sampel dalam penelitian ini adalah dua kelas yang dipilih secara purposive sampling, yakni pertimbangan dalam mengambil sampel tersebut, disebabkan kelas VIII G dan VIII H memiliki rata-rata nilai yang hampir sama dalam pembelajaran bahasa Indonesia dilihat dari Ujian Tengah Semester. Kelas yang digunakan adalah kelas VIII H sebagai kelas eksperimen dan kelas VIII G sebagai kelas kontrol. Penelitian ini menggunakan metode eksperimen kuasi dengan desain penelitian Nonequivalent Control Group Design. Pada desain ini dilakukan tes awal dan tes akhir di kelas eksperimen dan kelas kontrol. Pengolahan data dilakukan uji realibilitas antar penimbang, uji normalitas, homogenitas, dan hipotesis. Berdasarkan hasil penelitian, didapatkan bahwa nilai rata-rata kelas eksperimen lebih tinggi daripada nilai rata-rata kelas kontrol. Rata-rata nilai tes awal kelas eksperimen yaitu 63 dan nilai rata-rata tes akhir 82. Sedangkan rata-rata nilai tes awal kontrol yaitu 54 dan rata-rata nilai tes akhir 66. Berdasarkan perolehan nilai tersebut didapatkan perbedaan nilai rata-rata kelas eksperimen 19 dan perbedaan nilai rata-rata kelas kontrol yaitu 13. Berdasarkan hasil pengujian hipotesis diperoleh nilaithitung= 5,01>ttabel = 1,99866, maka Ho ditolak dan Ha diterima. Hal ini menunjukkan bahwa metode ECOLA berpengaruh dan dapat digunakan dalam pembelajaran membaca kritis tajuk rencana. ;--- This research aims toget the objective informationwhether there is a significance differences or not between students’ abilityin editorial critical reading text in an experimental class using ECOLA methodwith a control class using lecture method. The population of the research are all students of VIII grade class of16 Junior High School of Bandung in 2015/2016 school year.The sample are two classes of students which are selected through purposive sampling, consideringG and H class have a same average scoresin Indonesia Language subject,taken from Mid-Semester Test score. The H class was the experimental classand the G class control. The research utilizes a quasi-experimental methodwithNonequivalent Control Group Designwith a pre and a post-test. Reliability test was employed between counselor, normalcy test, homogenates, andhypothesis. The result shows that the average score of experimental classis higher than the control class. The experimental class’ average pre-test score was 63 the post-test was 82 whilethe control class’ average pre-test score was 54 andpost-test score was 66. The difference between pre and post-test of experimental class was 19 and control class was 13. Hypothesis test result shows thatthitung = 5,01>ttabel= 1,99866, then Hois rejectedand Hais accepted. It concludes thatECOLAis influential and implementable in editorial critical reading