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

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  • The BOADICEA model of genetic susceptibility to breast and ovarian cancer: updating, validation, predictions Antonis Antoniou

    Cancer Research - UK Genetic Epidemiology UnitStrangeways Research LaboratoriesUniversity of Cambridge, UK

  • Model Development (version 1)Data:

    Anglian Breast Cancer Study (ABC families) 1484 breast cancer cases, unselected for family history

    British Families (B families) 156 multiple case families

    BRCA1/2 status available.

    Antoniou et al, Br J Cancer (2002)

  • Methods (v.1)Complex segregation analysis of breast and ovarian cancer occurrence.

    Modelled simultaneous effects:BRCA1BRCA2BRCAxPolygenicBest fitting model for residual familial clustering of breast cancer: PolygenicPolygenic = large number of genes, small effect, multiplicative effect on risk

  • 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

  • Model componentsBirth cohort effect:
  • 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%

  • Model components - Results=Age

    2030405060702

    3.63.22.31.91.30.7

  • BRCA1 average cumulative risk by birth cohort

    Chart1

    0.00110.00110.00110.00090.00120.0012

    0.02090.02090.0210.02430.02580.0063

    0.10480.10820.11410.11790.13170.12

    0.26320.28450.29190.32640.3450.38

    0.35840.38570.41950.4630.4780.53

    0.4550.49780.53180.5670.57910.65

  • Predicted Familial Relative Risks (affected mother)Age

    25303540455055606570BOADICEA

    6.83.93.42.62.31.91.71.51.41.3Claus et al1

    10.36.15.62.32.01.51.41.11.11.0Observed2

    5.7

    2.0

    1.6

    1.41 Claus et al AJHG (1991)

    2 Collaborative group on hormonal factors in breast cancer. Lancet (2001)

  • 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)

  • Predicted number of mutations

    Observed

    Expected

    Observed

    ExpectedBRCA1

    21

    21.4

    54

    55.5BRCA2

    18

    16.0

    54

    53.6Non-Carriers

    117

    118.6

    2248

    2246.9B FamiliesAll

  • Chart4

    0.09720.04320.064890.06

    0.18710.08110.12220.091

    0.260.11190.17230.13

    0.32880.13690.2180.17

    0.38040.15740.25030.195

    BOADICEA

    BRCAPRO

    Claus et al

    T-Cuzick

    Age

    Breast Cancer Risk

    Predicted Breast Cancer Risk

    Sheet1

    Sheet1

    000

    000

    000

    000

    000

    000

    Present model

    BRCAPRO

    Claus et al

    Age

    Breast Cancer risk

    Predicted Breast Cancer Risks

    Sheet2

    AgeBCBC BRCAPROClausT-CuzickOCOC BRCAPRO

    500.09720.04320.064890.060.00350.0129

    550.18710.08110.12220.0910.01040.0275

    600.260.11190.17230.130.01620.0397

    650.32880.13690.2180.170.02110.04877

    700.38040.15740.25030.1950.02490.05519

    Sheet3

    Chart5

    0.00910.0129

    0.01740.0275

    0.02560.0397

    0.03260.04877

    0.03780.05519

    .

    BOADICEA

    BRCAPRO

    Age

    Ovarian cancer risk

    Predicted ovarian cancer risk

    Sheet1

    AgeBC RiskBC BRCAPROClausOC RiskOC BRCAPROT-Cuzick

    Sheet1

    000

    000

    000

    000

    000

    000

    Present model

    BRCAPRO

    Claus et al

    Age

    Breast Cancer risk

    Predicted Breast Cancer Risks

    Sheet2

    Present Model

    BRCAPRO

    Age

    Ovarian cancer risk

    Predicted Ovarian Cancer risks (Fam 1)

    Sheet3

    AgeBCBC BRCAPROClausOCOC BRCAPRO

    500.06380.04320.06920.00910.0129

    550.12780.08110.13040.01740.0275

    600.18320.11190.18340.02560.0397

    650.23620.13690.23030.03260.04877

    700.28040.15740.27090.03780.05519

    Sheet3

    Present model

    BRCAPRO

    Claus et al

    Age

    Breast Cancer Risk

    Predicted Breast Cancer Risk

    Present model

    BRCAPRO

    Age

    Ovarian cancer risk

    Predicted ovarian cancer risk

  • Model FeaturesCurrently implemented in MENDEL [Lange et al, Gen Epid (1988)].

    Flexible platform for updating the model and incorporating other genetic and environmental effects.

    Aim: Use as the basis for developing a risk assessment package to be used in genetic clinics.

  • Current/Future Work and ExtensionsOvarian Cancer modifying effect on BRCA1/2 risks

    Other BRCA1/2 associated cancers (eg prostate, pancreas)/contralateral breast cancer.

    Allowance for other genetic/non-genetic factors (eg CHEK2, parity etc).

    Allele frequencies for other populations.

    Validation in external datasets.

  • Discussion pointsIdentify data resources for validation.

    Predictions by different models vary.

    Need to compare the predictions by various models in validation studies.

  • AcknowledgmentsDoug Easton

    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

  • Genetic Modification of BC Risk in BRCA1/2 carriers0

    Antonis Antoniou

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