The BOADICEA model of genetic susceptibility to breast and ovarian cancer: updating, validation, predictions Antonis Antoniou Cancer Research - UK Genetic

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<ul><li><p>The BOADICEA model of genetic susceptibility to breast and ovarian cancer: updating, validation, predictions Antonis Antoniou</p><p>Cancer Research - UK Genetic Epidemiology UnitStrangeways Research LaboratoriesUniversity of Cambridge, UK</p></li><li><p>Model Development (version 1)Data: </p><p>Anglian Breast Cancer Study (ABC families) 1484 breast cancer cases, unselected for family history</p><p>British Families (B families) 156 multiple case families</p><p>BRCA1/2 status available.</p><p>Antoniou et al, Br J Cancer (2002)</p></li><li><p>Methods (v.1)Complex segregation analysis of breast and ovarian cancer occurrence.</p><p>Modelled simultaneous effects:BRCA1BRCA2BRCAxPolygenicBest fitting model for residual familial clustering of breast cancer: PolygenicPolygenic = large number of genes, small effect, multiplicative effect on risk </p></li><li><p>Updating - current data number of families1 Peto et al, JNCI (1999)2 Lalloo et al, Lancet (2003)3 Antoniou et al, AJHG (2003)Population based studies</p></li><li>Model componentsBirth cohort effect: </li><li><p>Model components - ResultsBRCA1BRCA2AlleleFrequenciesMutation testingsensitivityBRCA1: 70%BRCA2: 80%BRCA1: 0.06% (0.04-0.10%), carriers: 0.12%BRCA2:0.10% (0.07-0.15%) carriers: 0.2%</p></li><li><p>Model components - Results=Age</p><p>2030405060702</p><p>3.63.22.31.91.30.7</p></li><li><p>BRCA1 average cumulative risk by birth cohort</p><p>Chart1</p><p>0.00110.00110.00110.00090.00120.0012</p><p>0.02090.02090.0210.02430.02580.0063</p><p>0.10480.10820.11410.11790.13170.12</p><p>0.26320.28450.29190.32640.3450.38</p><p>0.35840.38570.41950.4630.4780.53</p><p>0.4550.49780.53180.5670.57910.65</p></li><li><p>Predicted Familial Relative Risks (affected mother)Age</p><p>25303540455055606570BOADICEA</p><p>6.83.93.42.62.31.91.71.51.41.3Claus et al1</p><p>10.36.15.62.32.01.51.41.11.11.0Observed2</p><p>5.7</p><p>2.0</p><p>1.6</p><p>1.41 Claus et al AJHG (1991)</p><p>2 Collaborative group on hormonal factors in breast cancer. Lancet (2001) </p></li><li><p>Predicted BRCA1/2 carrier frequency (%)among unselected breast cancer casesAge dx3040506070BRCA13.3 (5.5)*2.2 (2.9)0.7 (1.2)0.5 (0.3)0.4 (0.0)BRCA22.8 (0.8)2.0 (0.2)1.6 (0.4)1.2 (0.3)1.0 (0.1)* Predictions by BRCAPRO (CancerGene v3.1)</p></li><li><p>Predicted number of mutations</p><p>Observed</p><p>Expected</p><p>Observed</p><p>ExpectedBRCA1</p><p>21</p><p>21.4</p><p>54</p><p>55.5BRCA2</p><p>18</p><p>16.0</p><p>54</p><p>53.6Non-Carriers</p><p>117</p><p>118.6</p><p>2248</p><p>2246.9B FamiliesAll</p></li><li><p>Chart4</p><p>0.09720.04320.064890.06</p><p>0.18710.08110.12220.091</p><p>0.260.11190.17230.13</p><p>0.32880.13690.2180.17</p><p>0.38040.15740.25030.195</p><p>BOADICEA</p><p>BRCAPRO</p><p>Claus et al</p><p>T-Cuzick</p><p>Age</p><p>Breast Cancer Risk</p><p>Predicted Breast Cancer Risk</p><p>Sheet1</p><p>Sheet1</p><p>000</p><p>000</p><p>000</p><p>000</p><p>000</p><p>000</p><p>Present model</p><p>BRCAPRO</p><p>Claus et al</p><p>Age</p><p>Breast Cancer risk</p><p>Predicted Breast Cancer Risks</p><p>Sheet2</p><p>AgeBCBC BRCAPROClausT-CuzickOCOC BRCAPRO</p><p>500.09720.04320.064890.060.00350.0129</p><p>550.18710.08110.12220.0910.01040.0275</p><p>600.260.11190.17230.130.01620.0397</p><p>650.32880.13690.2180.170.02110.04877</p><p>700.38040.15740.25030.1950.02490.05519</p><p>Sheet3</p><p>Chart5</p><p>0.00910.0129</p><p>0.01740.0275</p><p>0.02560.0397</p><p>0.03260.04877</p><p>0.03780.05519</p><p>.</p><p>BOADICEA</p><p>BRCAPRO</p><p>Age</p><p>Ovarian cancer risk</p><p>Predicted ovarian cancer risk</p><p>Sheet1</p><p>AgeBC RiskBC BRCAPROClausOC RiskOC BRCAPROT-Cuzick</p><p>Sheet1</p><p>000</p><p>000</p><p>000</p><p>000</p><p>000</p><p>000</p><p>Present model</p><p>BRCAPRO</p><p>Claus et al</p><p>Age</p><p>Breast Cancer risk</p><p>Predicted Breast Cancer Risks</p><p>Sheet2</p><p>Present Model</p><p>BRCAPRO</p><p>Age</p><p>Ovarian cancer risk</p><p>Predicted Ovarian Cancer risks (Fam 1)</p><p>Sheet3</p><p>AgeBCBC BRCAPROClausOCOC BRCAPRO</p><p>500.06380.04320.06920.00910.0129</p><p>550.12780.08110.13040.01740.0275</p><p>600.18320.11190.18340.02560.0397</p><p>650.23620.13690.23030.03260.04877</p><p>700.28040.15740.27090.03780.05519</p><p>Sheet3</p><p>Present model</p><p>BRCAPRO</p><p>Claus et al</p><p>Age</p><p>Breast Cancer Risk</p><p>Predicted Breast Cancer Risk</p><p>Present model</p><p>BRCAPRO</p><p>Age</p><p>Ovarian cancer risk</p><p>Predicted ovarian cancer risk</p></li><li><p>Model FeaturesCurrently implemented in MENDEL [Lange et al, Gen Epid (1988)].</p><p>Flexible platform for updating the model and incorporating other genetic and environmental effects.</p><p>Aim: Use as the basis for developing a risk assessment package to be used in genetic clinics.</p></li><li><p>Current/Future Work and ExtensionsOvarian Cancer modifying effect on BRCA1/2 risks</p><p>Other BRCA1/2 associated cancers (eg prostate, pancreas)/contralateral breast cancer.</p><p>Allowance for other genetic/non-genetic factors (eg CHEK2, parity etc).</p><p>Allele frequencies for other populations.</p><p>Validation in external datasets.</p></li><li><p>Discussion pointsIdentify data resources for validation.</p><p>Predictions by different models vary. </p><p>Need to compare the predictions by various models in validation studies.</p></li><li><p>AcknowledgmentsDoug Easton</p><p>Paul Pharoah Bruce PonderJulian Peto (Bfams/UK case-control study)Mike Stratton (B fams)Gareth Evans, Fiona Lalloo (Manchester study)S. Narod, H. A. Risch, J. E. Eyfjord,J. L. Hopper, N. Loman, H. Olsson, O. Johannsson, . Borg, B. Pasini, P. Radice,S. Manoukian, D. M. Eccles, N. Tang, E. Olah, H. Anton-Culver, E. Warner,J. Lubinski, J. Gronwald, B. Gorski, H. Tulinius, S. Thorlacius, H. Eerola,H. Nevanlinna, K. Syrjkoski, O.-P. Kallioniemi, D. ThompsonBRCA1/2 Meta-analysis group:Cambridge University High Performance Computing Facility</p></li><li><p>Genetic Modification of BC Risk in BRCA1/2 carriers0</p><p>Antonis Antoniou</p></li></ul>

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