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Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment?

Prosperi MC, Ingham SL, Howell A, Lalloo F, Buchan IE, Evans DG - BMC Med Inform Decis Mak (2014)

Bottom Line: Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables.Random survival forests did not yield higher performance compared to Cox proportional hazards.We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Population Health, Centre for Health Informatics, University of Manchester, Manchester, UK. mattia.prosperi@manchester.ac.uk.

ABSTRACT

Background: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information.

Methods: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell's concordance index (1 - c-index).

Results: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3-50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers.

Conclusions: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation.

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Related in: MedlinePlus

Kaplan-Meier estimates of being cancer-free for BRCA1 (upper panels) and BRCA2 (lower panels) carriers: overall, stratified by menopausal stage, and by oophorectomy.
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Fig1: Kaplan-Meier estimates of being cancer-free for BRCA1 (upper panels) and BRCA2 (lower panels) carriers: overall, stratified by menopausal stage, and by oophorectomy.

Mentions: Incidence of cancer for all BRCA2 carriers was 323 events per 23,796 person-years of follow-up (PYFY), i.e. 0.014 (95% confidence interval, CI 0.012 0.015). It was 105/10,120 (0.010, 95% CI 0.008-0.012) and 72/3,265 (0.022, 95% CI 0.017- 0.028) for menopause and ovulating strata, respectively. The median (95% CI) Kaplan-Meier estimate of survival time was 48.9 (47.3-50.4) years in the whole BRCA2 population, 56.3 (52.3-58.7) for menopause stratum, and 36.8 (34.9-41.4) for the ovulating population (p > 0.0001, log-rank test). Women who underwent an oophorectomy had a higher survival probability than those who did not (p > 0.0001, log-rank test). At age 50 years, probability (95% CI) of survival was 0.88 (0.82-0.95) for those who had oophorectomy (102 women, 23 breast cancer events), versus 0.34 (0.30-0.40) for the others. At age 60 it was 0.70 (0.59-0.83) versus 0.11 (0.07-0.15). As in the BRCA1 population, there was only one case of breast cancer after risk reducing mastectomy (out of 17 women operated). Figure 1 shows Kaplan-Meier graphs for the whole BRCA1/2 population, for the menopausal stage strata, and for those who had/had not oophorectomy after the diagnosis of an ovarian cancer.Figure 1


Can multiple SNP testing in BRCA2 and BRCA1 female carriers be used to improve risk prediction models in conjunction with clinical assessment?

Prosperi MC, Ingham SL, Howell A, Lalloo F, Buchan IE, Evans DG - BMC Med Inform Decis Mak (2014)

Kaplan-Meier estimates of being cancer-free for BRCA1 (upper panels) and BRCA2 (lower panels) carriers: overall, stratified by menopausal stage, and by oophorectomy.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197237&req=5

Fig1: Kaplan-Meier estimates of being cancer-free for BRCA1 (upper panels) and BRCA2 (lower panels) carriers: overall, stratified by menopausal stage, and by oophorectomy.
Mentions: Incidence of cancer for all BRCA2 carriers was 323 events per 23,796 person-years of follow-up (PYFY), i.e. 0.014 (95% confidence interval, CI 0.012 0.015). It was 105/10,120 (0.010, 95% CI 0.008-0.012) and 72/3,265 (0.022, 95% CI 0.017- 0.028) for menopause and ovulating strata, respectively. The median (95% CI) Kaplan-Meier estimate of survival time was 48.9 (47.3-50.4) years in the whole BRCA2 population, 56.3 (52.3-58.7) for menopause stratum, and 36.8 (34.9-41.4) for the ovulating population (p > 0.0001, log-rank test). Women who underwent an oophorectomy had a higher survival probability than those who did not (p > 0.0001, log-rank test). At age 50 years, probability (95% CI) of survival was 0.88 (0.82-0.95) for those who had oophorectomy (102 women, 23 breast cancer events), versus 0.34 (0.30-0.40) for the others. At age 60 it was 0.70 (0.59-0.83) versus 0.11 (0.07-0.15). As in the BRCA1 population, there was only one case of breast cancer after risk reducing mastectomy (out of 17 women operated). Figure 1 shows Kaplan-Meier graphs for the whole BRCA1/2 population, for the menopausal stage strata, and for those who had/had not oophorectomy after the diagnosis of an ovarian cancer.Figure 1

Bottom Line: Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables.Random survival forests did not yield higher performance compared to Cox proportional hazards.We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation.

View Article: PubMed Central - PubMed

Affiliation: Institute of Population Health, Centre for Health Informatics, University of Manchester, Manchester, UK. mattia.prosperi@manchester.ac.uk.

ABSTRACT

Background: Several single nucleotide polymorphisms (SNPs) at different loci have been associated with breast cancer susceptibility, accounting for around 10% of the familial component. Recent studies have found direct associations between specific SNPs and breast cancer in BRCA1/2 mutation carriers. Our aim was to determine whether validated susceptibility SNP scores improve the predictive ability of risk models in comparison/conjunction to other clinical/demographic information.

Methods: Female BRCA1/2 carriers were identified from the Manchester genetic database, and included in the study regardless of breast cancer status or age. DNA was extracted from blood samples provided by these women and used for gene and SNP profiling. Estimates of survival were examined with Kaplan-Meier curves. Multivariable Cox proportional hazards models were fit in the separate BRCA datasets and in menopausal stages screening different combinations of clinical/demographic/genetic variables. Nonlinear random survival forests were also fit to identify relevant interactions. Models were compared using Harrell's concordance index (1 - c-index).

Results: 548 female BRCA1 mutation carriers and 523 BRCA2 carriers were identified from the database. Median Kaplan-Meier estimate of survival was 46.0 years (44.9-48.1) for BRCA1 carriers and 48.9 (47.3-50.4) for BRCA2. By fitting Cox models and random survival forests, including both a genetic SNP score and clinical/demographic variables, average 1 - c-index values were 0.221 (st.dev. 0.019) for BRCA1 carriers and 0.215 (st.dev. 0.018) for BRCA2 carriers.

Conclusions: Random survival forests did not yield higher performance compared to Cox proportional hazards. We found improvement in prediction performance when coupling the genetic SNP score with clinical/demographic markers, which warrants further investigation.

Show MeSH
Related in: MedlinePlus