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Genomic aberrations in young and elderly breast cancer patients.

ABSTRACT: Age at breast cancer diagnosis is a known prognostic factor. Previously, several groups including ours have shown that young age at diagnosis is associated with higher prevalence of basal-like tumors and aggressive tumor phenotypes. Yet the impact of age at diagnosis on the genomic landscape of breast cancer remains unclear. In this study, we examined the pattern of somatic mutations, chromosomal copy number variations (CNVs) and transcriptomic profiles in young and elderly breast cancer patients.Analyses were performed on The Cancer Genome Atlas (TCGA) dataset. Patients with metastatic disease at diagnosis, classified as normal-like by PAM50 or had missing clinical information were excluded. Young patients were defined as ?45 years of age, while elderly patients were those ?70 years of age at breast cancer diagnosis. The remaining patients were classified as "intermediate". We evaluated the association between age at diagnosis and somatic mutations, CNV and gene expression in a logistic regression model adjusting for tumor size, nodal status, histology and breast cancer subtype. All analyses were corrected for multiple testing using the Benjamini-Hochberg approach.In this study, 125, 486 and 169 patients were ?45, 46-69 and ?70 years of age, respectively. Older patients had more somatic mutations (n?=?44 versus 35 versus 31; P?=?0.0009) and more CNVs, especially in ductal tumors (P?=?0.02). Eleven mutations were independently associated with age at diagnosis, of which only GATA3 was associated with young age (15.2% versus 8.2% versus 9%; P?=?0.003). Only two CNV events were independently associated with age, with more chr18p losses in older patients and more chr6q27 deletions in younger ones. Younger age at diagnosis was associated with higher expression of gene signatures related to proliferation, stem cell features and endocrine resistance.Age adds a layer of biological complexity beyond breast cancer molecular subtypes, classic pathological and clinical variables, worthy of further consideration in future drug development as we seek to refine therapeutic strategies in the era of personalized medicine.

SUBMITTER: Azim HA

PROVIDER: S-EPMC4606505 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Genomic aberrations in young and elderly breast cancer patients.

Azim Hatem A HA Nguyen Bastien B Brohée Sylvain S Zoppoli Gabriele G Sotiriou Christos C

BMC medicine 20151015

<h4>Background</h4>Age at breast cancer diagnosis is a known prognostic factor. Previously, several groups including ours have shown that young age at diagnosis is associated with higher prevalence of basal-like tumors and aggressive tumor phenotypes. Yet the impact of age at diagnosis on the genomic landscape of breast cancer remains unclear. In this study, we examined the pattern of somatic mutations, chromosomal copy number variations (CNVs) and transcriptomic profiles in young and elderly br ...[more]

PMID: 26467651

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Project description:To compare the distribution and prognostic effect of the breast cancer molecular subtypes in young and elderly breast cancer patients.Our study population (n = 822) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1996. A total of 142/822 fresh frozen tissues were available with good quality RNA and analyzed by gene expression microarray. Gene expression molecular subtypes were determined by correlation to the expression centroids of 534 "intrinsic" genes. Sections of a tissue micro array containing formalin-fixed paraffin-embedded tumor tissue of 714/822 patients were immunohistochemically (IHC) stained for Ki67, EGFR, CK5/6. Tumor expression of ER, PR, HER2 was previously determined. IHC molecular subtypes were defined based on expression of these markers: Luminal A: ER+ and/or PR+, HER2- and Ki67-; Luminal B: ER+ and/or PR+ and ki67+; ERBB2: ER-, PR- and HER2+; Basal-like: ER-, PR-, HER2- and EGFR+ and/or CK5/6+; Unclassified: ER-, PR-, HER2-, EGFR- and CK5/6-. IHC molecular subtypes were validated against gene expression defined molecular subtypes. Assessment of distribution and prognostic effect of molecular subtypes was stratified to age (<65 versus ≥65 years).Validation of molecular subtypes determined by IHC against gene expression revealed a substantial agreement in classification (Cohen's kappa coefficient 0.75). A statistically significant association (p = 0.02) was found between molecular subtypes and age, where Luminal tumors were more often found in elderly patients, while ERBB2, basal-like and unclassified subtypes were more often found in young patients. Molecular subtypes showed a prognostic association with outcome in young patients concerning relapse-free period (RFP) (p = 0.01) and relative survival (RS) (p < 0.001). No statistically significant prognostic effect was found for molecular subtypes in elderly patients (RFP p = 0.5; RS p = 0.1). Additional analyses showed that no molecular subtypes showed a statistically significant difference in outcome for elderly compare to young patients.We have shown that molecular subtypes have a different distribution and prognostic effect in elderly compared to young breast cancer patients, emphasizing the fact that biomarkers may have different distributions and prognostic effects and therefore different implications in elderly compared to their younger counterparts. Our results support the premise that breast cancer clinical behavior is significantly affected by patient age. We suggest that competing risks of death in elderly patients, ER-driven differences and micro-environmental changes in biology are underlying these age-dependent variations in patient prognosis.

Project description:IntroductionIn breast cancer, the basal-like subtype has high levels of genomic instability relative to other breast cancer subtypes with many basal-like-specific regions of aberration. There is evidence that this genomic instability extends to smaller scale genomic aberrations, as shown by a previously described micro-deletion event in the PTEN gene in the Basal-like SUM149 breast cancer cell line.MethodsWe sought to identify if small regions of genomic DNA copy number changes exist by using a high density, gene-centric Comparative Genomic Hybridizations (CGH) array on cell lines and primary tumors. A custom tiling array for CGH (244,000 probes, 200 bp tiling resolution) was created to identify small regions of genomic change, which was focused on previously identified basal-like-specific, and general cancer genes. Tumor genomic DNA from 94 patients and 2 breast cancer cell lines was labeled and hybridized to these arrays. Aberrations were called using SWITCHdna and the smallest 25% of SWITCHdna-defined genomic segments were called micro-aberrations (<64 contiguous probes, ~ 15 kb).ResultsOur data showed that primary tumor breast cancer genomes frequently contained many small-scale copy number gains and losses, termed micro-aberrations, most of which are undetectable using typical-density genome-wide aCGH arrays. The basal-like subtype exhibited the highest incidence of these events. These micro-aberrations sometimes altered expression of the involved gene. We confirmed the presence of the PTEN micro-amplification in SUM149 and by mRNA-seq showed that this resulted in loss of expression of all exons downstream of this event. Micro-aberrations disproportionately affected the 5' regions of the affected genes, including the promoter region, and high frequency of micro-aberrations was associated with poor survival.ConclusionUsing a high-probe-density, gene-centric aCGH microarray, we present evidence of small-scale genomic aberrations that can contribute to gene inactivation. These events may contribute to tumor formation through mechanisms not detected using conventional DNA copy number analyses.

Project description:BackgroundBreast cancer in young adults has been implicated with a worse outcome. Analyses of genomic traits associated with age have been heterogenous, likely because of an incomplete accounting for underlying molecular subtypes. We aimed to resolve whether triple-negative breast cancer (TNBC) in younger versus older patients represent similar or different molecular diseases in the context of genetic and transcriptional subtypes and immune cell infiltration.Patients and methodsIn total, 237 patients from a reported population-based south Swedish TNBC cohort profiled by RNA sequencing and whole-genome sequencing (WGS) were included. Patients were binned in 10-year intervals. Complimentary PD-L1 and CD20 immunohistochemistry and estimation of tumor-infiltrating lymphocytes (TILs) were performed. Cases were analyzed for differences in patient outcome, genomic, transcriptional, and immune landscape features versus age at diagnosis. Additionally, 560 public WGS breast cancer profiles were used for validation.ResultsMedian age at diagnosis was 62 years (range 26-91). Age was not associated with invasive disease-free survival or overall survival after adjuvant chemotherapy. Among the BRCA1-deficient cases (82/237), 90% were diagnosed before the age of 70 and were predominantly of the basal-like subtype. In the full TNBC cohort, reported associations of patient age with changes in Ki67 expression, PIK3CA mutations, and a luminal androgen receptor subtype were confirmed. Within DNA repair deficiency or gene expression defined molecular subgroups, age-related alterations in, e.g., overall gene expression, immune cell marker gene expression, genetic mutational and rearrangement signatures, amount of copy number alterations, and tumor mutational burden did, however, not appear distinct. Similar non-significant associations for genetic alterations with age were obtained for other breast cancer subgroups in public WGS data. Consistent with age-related immunosenescence, TIL counts decreased linearly with patient age across different genetic TNBC subtypes.ConclusionsAge-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.

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Genomic aberrations in young and elderly breast cancer patients.

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Genomic aberrations in young and elderly breast cancer patients.

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