The magnitude and scope of intrinsic age-correlated and host endocrine age-correlated gene expression in breast cancer is not well understood. From age-correlated gene expression in 3,071 breast cancer transcriptomes and epithelial protein expression of 42 markers in 5,001 breast cancers and 537 normal breast tissues, we identified a majority of age-correlated genes as putatively regulated by age-dependent estrogen signaling. Surprisingly, these included genes encoding the chromatin modifier EZH2 (which had a negative age correlation) and associated H3K27me3 (which had an inverse, positive age correlation). Among The Cancer Genome Atlas lung, thyroid, kidney and prostate transcriptomes, the largest overlap with breast cancer in age-correlated transcripts was lung cancer, for which about one-third of overlapping age-correlated transcripts appeared to be estrogen regulated. Age-quartile-stratified outcomes analysis of 3,500 breast cancers using EZH2, H3K27me3, FOXA1 and BCL2 proteins revealed distinct age-related prognostic significance. Age correlation in gene expression may thus be an important factor in ER, EZH2, H3K27me3 and other biomarker assessment and treatment strategies.
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TCGA data (-BRCA, -PRAD, -KIRC, -LUAD and -THCA) are available at https://portal.gdc.cancer.gov/projects/. METABRIC data are available at https://ega-archive.org/studies/EGAS00000000083. The raw data and the Vancouver Big Series 3,991-case TMA and normal breast 537-case TMA data used to generate all of the results are available from the GitHub (https://github.com/BCCRCMO/BrCa_AgeAssociations) and Zenodo repositories (https://doi.org/10.5281/zenodo.3715548)62. The raw images from IHC that were applied to TMAs are available on the BC Cancer Research Institute servers described in the supplementary information63,64,65,66,67,68,69. All of the ChIP-Seq data generated in the Zwart et al.42 study and the RNA-Seq data are available from the Gene Expression Omnibus repository (accession codes GSE104399 and GSE104730, respectively). Methodology information is available in the associated publication25. Expression data fold-change estimates and age-associated P values for the 18,950 protein-coding genes for the 60 years age group, as well as all of the cases of the METABRIC and TCGA cancer datasets, are available as Supplementary Data 1.
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S.A. and C.J.E. are supported by the BC Cancer Foundation, Canadian Cancer Research Society (S.A. 705617), Terry Fox Research Institute (S.A. 1082) and Canadian Institutes for Health Research (S.A. 148429). S.A. is also supported by Canada Research Chairs and Breast Cancer Resesarch Foundation (BCRF-19-180). T.O. is supported by a Molecular Oncologic Pathology Fellowship from the Canadian Institute of Health Research and the Terry Fox Foundation, and by awards from the Sumitomo Life Welfare and Culture Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research and Takashi Tsuruo Memorial Fund. H.L. is supported by the Severance Research Initiative Scholarship from Yonsei University.
S.A. is a founder and consultant for Contextual Genomics. S.A. advises Sangamo Therapeutics and Repare Therapeutics.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 Age-correlated transcripts among different cancer types and biphasic age-correlated transcripts.
a, Venn sets bar plot of intersection sizes (upper panel) and histogram of age-correlated gene counts by cancer site (left panel). Vertical connectors below the Intersection Size bar plot show the corresponding set intersections. The breast cancer cohorts showed the most age-correlated gene counts (left three bars, thousands of age-associated genes). Lung and thyroid cohorts also showed hundreds of age-correlated genes, with considerable overlap with breast cancer cohorts. Kidney and prostate cohorts showed very few age-correlated genes. b, Biphasic age-correlated transcripts from TCGA Breast expression dataset (N = 1079 cases per graph). c, Biphasic age-correlated transcripts from the METABRIC expression dataset (N = 1992 cases per graph). The red curves are loess smoother curves indicating the mean expression for any given age, yielding a semi-parametric age-correlated expression pattern for the indicated biomarker. The tan coloured interval represents a 99% confidence interval for the smoother curve. The Benjamini-Hochberg multiple comparison adjusted p-values were obtained from linear model ANOVA (2-sided F-test) of cases with age < 60 (METABRIC N = 991 cases, TCGA N = 595 cases), age > 60 (METABRIC N = 1001 cases, TCGA N = 484 cases), and across all ages (METABRIC N = 1992 cases, TCGA N = 1079 cases). Genes with absolute fold change > 1.25 and adjusted p-value < 0.01 for cases age < 60 or cases age > 60 or all cases were declared as age-associated.
Extended Data Fig. 2 Age dependent transcript volcano plots for estrogen receptor (ER) and human epidermal growth factor receptor (HER2) subgroups for the TCGA dataset.
Horizontal axis displays the maximum fold change measured from the three regression line fits to expression data from the TCGA Breast expression dataset (N = 1079 cases) for cases < 60 years of age, cases > 60, and all cases. Fold changes to the right (Up) indicate genes exhibiting an increase in expression levels from younger to older cases. Fold changes to the left (Down) indicate genes exhibiting a decrease in expression levels from younger to older cases. Genes exhibiting a large absolute fold change and strong statistical evidence of association (small p-values) appear in the upper left and right areas of the volcano plots. P-values from linear model ANOVA (2-sided F-test) based on the sample sizes shown above each plot. Genes with absolute fold change > 1.25 and adjusted p-value < 0.01 for cases age < 60 or cases age > 60 or all cases are coloured according to the legend categories for ER binding.
Immunohistochemistry (IHC) of tissue microarrays (TMAs) from a, Vancouver Big series, and b, METABRIC series. Even though pathologists score TMA staining patterns with a variety of schemas, e.g. percent of tumour cells positively stained, staining intensity, or a combination thereof, biphasic and other age-associated patterns are still revealed via supersmoother fits to the data. The age at which biphasic inflection occurs varies by biomarker, e.g. near 60 years of age for EZH2 and p16, near 70 years for ER. The red curves are supersmoother curves fitted to the IHC data. The tan coloured intervals are randomization test confidence bands under the null hypothesis of no age association (see Methods) at one of the four confidence levels indicated by the associated p-value bound in each graph. Red curves that extend beyond the (1-α) confidence bounds at any location indicate age-association at the given confidence level with a two-sided p-value p < α (95%, 99%, 99.9% and 99.99% confidence levels assessed via randomization tests yielding p < 0.05, 0.01, 0.001 and 1e-04 respectively, exact p-values not available, see Methods).
Extended Data Fig. 4 Age-correlated protein expression in normal breast epithelium and age-correlated distribution of estrogen receptor (ER) in breast cancer.
a, Age-correlated protein expression in a tissue microarray (TMA) from normal breast epithelium (Normal Breast 13 TMA, N = 537 cases). The red curves and tan confidence bands are described above in Extended Data Fig. 3. Since breast reduction mammoplasty is not performed as often for women over 65 years of age, trends in older cases are more variable, indicated by the wide confidence bands around age 70-80. b, Distribution of percent of tumour cells positively stained for ER proteins in immunohistochemistry tissue samples (Big Series TMA, N = 3991 cases). The youngest cases showed the lowest rates of percentages above 50%. The distribution of percent tumour cells positively stained was strongly associated with age (Pearson 𝜒2 (15) = 348.3, p = 4.8×10−65). c, Distribution of percent of tumour cells positively stained for ER proteins in immunohistochemistry tissue samples for ER positive cases only (from Big Series TMA, N = 3991 total cases, N = 2760 ER positive cases). Though all these cases were designated ER positive because they had 1% or more of tumour cells positively stained, the younger cases showed much fewer instances of 50% or more of tumour cells positively stained (Pearson 𝜒2 (10) =215.7, p = 8.3×10−41). Younger ER positive cases had a much higher rate of individual tumour cells that did not show ER staining, which presumably would not be responsive to ER targeting therapies such as tamoxifen.
Extended Data Fig. 5 Kaplan-Meier survival curves and unadjusted two-sided logrank test p-values for EZH2 and H3K27me3 scored by immunohistochemistry within age (rows) and ER (columns) strata.
The two left columns show survival curves for EZH2 and H3K27me3 for ER+ cases (Big Series TMA, N = 3991 total cases). The two right columns show survival curves for EZH2 and H3K27me3 for ER- cases. Age group and sample sizes for the solid and dashed line survival curves are shown above each graph.
Extended Data Fig. 6 Kaplan-Meier survival curves and unadjusted two-sided logrank test p-values for H3K27me3 within age and EZH2 strata, and EZH2 within age and H3K27me3 strata.
The two left columns show survival curves for H3K27me3 low (< 60% tumour cells positively stained) versus H3K27me3 high (60% or more tumour cells positively stained) within age (rows) and EZH2 (columns) strata (Big Series TMA, N = 3991 total cases). The cohort sizes N for H3K27me3 low, and H3K27me3 high respectively are shown above the curves. The two right columns show survival curves for EZH2 negative (< 10% tumour cells positively stained) versus EZH2 positive (10% or more tumour cells positively stained) within age (rows) and H3K27me3 (columns) strata. The cohort sizes N for EZH2 negative, and EZH2 positive respectively are shown above the curves. The youngest cases show a marked difference in survival between H3K27me3 low and high cohorts within the EZH2 negative strata, while the oldest cases show a marked difference in the EZH2 positive strata.
Extended Data Fig. 7 Kaplan-Meier survival curves and unadjusted two-sided logrank test p-values for H3K27me3 within age and EZH2 strata, and EZH2 within age and H3K27me3 strata, scored by immunohistochemistry, for ER+ cases.
The two left columns show ER positive cases’ survival curves for H3K27me3 low (< 60% tumour cells positively stained) versus H3K27me3 high (60% or more tumour cells positively stained) within age (rows) and EZH2 (columns) strata (Big Series TMA, N = 3991 total cases). The cohort sizes N for H3K27me3 low, and H3K27me3 high respectively are shown above the curves. The two right columns show ER positive cases’ survival curves for EZH2 negative (< 10% tumour cells positively stained) versus EZH2 positive (10% or more tumour cells positively stained) within age (rows) and H3K27me3 (columns) strata. The cohort sizes N for EZH2 negative, and EZH2 positive respectively are shown above the curves. The youngest cases show a marked difference in survival between H3K27me3 low and high cohorts within the EZH2 negative strata, while the oldest cases do not show a marked difference in the EZH2 positive strata. (See Extended Data Fig. 8 for ER- cases).
Extended Data Fig. 8 Kaplan-Meier survival curves and unadjusted two-sided logrank test p-values for H3K27me3 within age and EZH2 strata (left two columns), and EZH2 within age and H3K27me3 strata (right two columns), for ER- cases.
The two left columns show ER negative cases’ survival curves for H3K27me3 low (< 60% tumour cells positively stained) versus H3K27me3 high (60% or more tumour cells positively stained) within age (rows) and EZH2 (columns) strata (Big Series TMA, N = 3991 total cases). The cohort sizes N for H3K27me3 low, and H3K27me3 high respectively are shown above the curves. The two right columns show ER negative cases’ survival curves for EZH2 negative (< 10% tumour cells positively stained) versus EZH2 positive (10% or more tumour cells positively stained) within age (rows) and H3K27me3 (columns) strata. The cohort sizes N for EZH2 negative, and EZH2 positive respectively are shown above the curves. The youngest cases do not show a marked difference in survival between H3K27me3 low and high cohorts within the EZH2 negative strata, while the oldest cases show a marked difference in the EZH2 positive strata. (See Extended Data figure 7 for ER+ cases).
Extended Data Fig. 9 Kaplan-Meier survival curves and unadjusted two-sided logrank test p-values for FOXA1 and BCL2 within age strata for ER positive cases (left two columns) and ER negative cases (right two columns).
Big Series TMA data (N = 3991 cases) survival patterns within ER and age group strata for FOXA1 and BCL2 protein staining levels. The cohort sizes N for low and high protein staining rates within each ER and age group strata are shown above the curves. For FOXA1, all survival differences occur in cases under age 55 years, specifically for 40-55 year old cases in the ER positive strata, and for 20-40 year old cases in the ER negative strata. For BCL2, survival differences are seen in the three youngest age strata for ER positive cases, but in the oldest three age strata for ER negative cases.
A random sample with replacement of size N was taken from the METABRIC expression set (1992 cases in total) in each of the ten IntClust groups to yield equally sized IntClust groups, so as to avoid the issue of smaller p-values in larger IntClust groups as seen in Fig. 4 where IntClust groups 3, 4 and 8 appear to show more age-correlated gene targets. Age-association status was reassessed for all gene targets with the bootstrapped sample and the proportion of age-correlated targets within each IntClust group recalculated, as shown by the red points plotted. Proportion of age-associated genes from each of the 20 bootstrap analyses are shown along with their associated boxplot, suggesting that IntClust groups 1, 2, 6 and 9 also contain sizable proportions of gene targets with age-correlated expression. The bootstrap sample size N per IntClust group is shown at the top of each graph. Boxplot elements show median (centre line), first and third quartiles (box top and bottom “hinges”), and whiskers extending from the hinge to the largest value no further than 1.5 * IQR from the hinge (where IQR is the inter-quartile range, or distance between the first and third quartiles).
Supplementary Discussion and Supplementary Tables 1–7.
Expression data fold-change estimates and age-associated P values for 18,950 protein-coding genes for the ages <60 years and >60 years and all cases combined, for the METABRIC and TCGA cancer datasets.
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Osako, T., Lee, H., Turashvili, G. et al. Age-correlated protein and transcript expression in breast cancer and normal breast tissues is dominated by host endocrine effects. Nat Cancer 1, 518–532 (2020). https://doi.org/10.1038/s43018-020-0060-4
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