Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations

Kreike, Bas; Hart, Guus; Bartelink, Harry; Vijver, Marc J. van de

doi:10.1007/s10549-009-0588-6

Cited by 23 publications

(23 citation statements)

References 34 publications

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“…RNA of sufficient quantity and quality was available for 48 cases and the gene expression profiles were reported in Natrajan et al [29]. Immunohistochemistry for ER, progesterone receptor (PR) and HER2 was performed as previously described [9,31]. Histological grade was determined by two pathologists (FCG and JSR-F) using the modified Scarff-Bloom-Richardson system [32].…”

Section: Methodsmentioning

confidence: 99%

Functional characterization of the 19q12 amplicon in grade III breast cancers

et al. 2012

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IntroductionThe 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification.MethodsWe investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification.Results19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly over-expressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival.ConclusionsThe 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancers.

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Section: Methodsmentioning

confidence: 99%

Functional characterization of the 19q12 amplicon in grade III breast cancers

et al. 2012

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“…Most of these studies have used immunohistochemical expression of the cyclin D1 expression [7, 10, 12, 13, 16–22, 25, 26, 28, 29, 31–42, 44, 45, 47–49], some mRNA expression [5, 23, 29, 30, 46], some amplification of the CCND1 gene [10, 11, 13, 14, 16, 24, 27, 43], and several methods [10, 13, 16, 29]. There is still no consensus about which method of assessment of cyclin D1 signaling aberrations is optimal.…”

Section: Introductionmentioning

confidence: 99%

High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers

Ahlin

Lundgren

Embretsen-Varro

et al. 2017

Breast Cancer Res Treat

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PurposeCyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case–control study.MethodsImmunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression.ResultsExpression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5–6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (ρ 0.19, p = 0.006) and B (ρ 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4–4.4).ConclusionWe confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

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“…Furthermore, a few more recent methods allow the user to simultaneously account for the violations of both assumptions in a single model . Applications of these flexible models demonstrated that many risk/prognostic factors investigated in epidemiological and clinical research have nonlinear or time‐dependent (i.e., non‐PH) effects . Furthermore, for some continuous covariates, both the linearity and PH assumptions may be violated .…”

Section: Introductionmentioning

confidence: 99%

Impact of the model‐building strategy on inference about nonlinear and time‐dependent covariate effects in survival analysis

Wynant

Abrahamowicz

2014

Statistics in Medicine

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Cox's proportional hazards (PH) model assumes constant-over-time covariate effects. Furthermore, most applications assume linear effects of continuous covariates on the logarithm of the hazard. Yet, many prognostic factors have time-dependent (TD) and/or nonlinear (NL) effects, that is, violate these conventional assumptions. Detection of such complex effects could affect prognosis and clinical decisions. However, assessing the effects of each of the multiple, often correlated, covariates in flexible multivariable analyses is challenging. In simulations, we investigated the impact of the approach used to build the flexible multivariable model on inference about the TD and NL covariate effects. Results demonstrate that the conclusions regarding the statistical significance of the TD/NL effects depend heavily on the strategy used to decide which effects of the other covariates should be adjusted for. Both a failure to adjust for true TD and NL effects of relevant covariates and inclusion of spurious effects of covariates that conform to the PH and linearity assumptions increase the risk of incorrect conclusions regarding other covariates. In this context, iterative backward elimination of nonsignificant NL and TD effects from the multivariable model, which initially includes all these effects, may help discriminate between true and spurious effects. The practical importance of these issues was illustrated in an example that reassessed the predictive ability of selected biomarkers for survival in advanced non-small-cell lung cancer. In conclusion, a careful model-building strategy and flexible modeling of multivariable survival data can yield new insights about predictors' roles and improve the validity of analyses.

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Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations

Cited by 23 publications

References 34 publications

Functional characterization of the 19q12 amplicon in grade III breast cancers

Functional characterization of the 19q12 amplicon in grade III breast cancers

High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers

Impact of the model‐building strategy on inference about nonlinear and time‐dependent covariate effects in survival analysis

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