DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. We evaluated Affymetrix gene expression profiles for 145 ...DNA repair genes in untreated breast cancer (BC) patients (n = 684) and BC patients treated with regimens containing neoadjuvant taxane/anthracycline (n = 294) or anthracycline (n = 210). We independently assessed estrogen receptor (ER)‐positive/HER2‐negative, HER2‐positive, and ER‐negative/HER2‐negative subgroups for differential expression, bimodal distribution, and the prognostic and predictive value of DNA repair gene expression. Twenty‐two genes were consistently overexpressed in ER‐negative tumors, and five genes were overexpressed in ER‐positive tumors, but no differences in expression were associated with HER2 status. In ER‐positive/HER2‐negative tumors, the expression of nine genes (BUB1, FANCI, MNAT1, PARP2, PCNA, POLQ, RPA3, TOP2A, and UBE2V2) was associated with poor prognosis, and the expression of one gene (ATM) was associated with good prognosis. Furthermore, the prognostic value of specific genes did not correlate with proliferation. A few genes were associated with chemotherapy response in BC subtypes and treatment‐specific manner. In ER‐negative/HER2‐negative tumors, the MSH2, MSH6, and FAN1 (previously MTMR15) genes were associated with pathological complete response and residual invasive cancer in taxane/anthracycline‐treated patients. Conversely, PMS2 expression was associated with residual invasive cancer in treatments using anthracycline as a single agent. In HER2‐positive tumors, TOP2A was associated with patient response to anthracyclines but not to taxane/anthracycline regimens. In genes expressed in a bimodal fashion, RECQL4 was significantly associated with clinical outcome. In vitro studies showed that defects in RECQL4 impair homologous recombination, sensitizing BC cells to DNA‐damaging agents.
摘要
DNA 修复通路可使肿瘤细胞幸免于化疗所引起的 DNA 损害，因而具有重要的预后和/或预测价值。我们在未经治疗的乳腺癌 (BC) 患者 (n =684) 和接受过新辅助化疗方案包含紫杉烷/蒽环类 (n =294) 或蒽环类 (n =210) 的 BC 患者中评估了 145 种 DNA 修复基因的 Affymetrix 基因表达谱。我们分别评估了雌激素受体 (ER)‐阳性/HER2‐阴性、HER2‐阳性以及 ER‐阴性/HER2‐阴性乳腺癌亚组的 DNA 修复基因差异表达情况、双峰分布情况以及预后和预测价值。ER‐阴性肿瘤有 22 个基因一致性过表达，ER‐阳性肿瘤有 5 个基因过表达，但是 HER2 的状态并未导致基因表达的差异。在 ER‐阳性/HER2‐阴性肿瘤中，有九个基因（BUB1、FANCI、MNAT1、PARP2、PCNA、POLQ、RPA3、TOP2A 和 UBE2V2）的表达提示预后不良，有 1 个基因 (ATM) 的表达提示预后良好。此外，特定基因的预后价值与增殖并不存在相互关联。有几个基因与化疗应答存在关联，而且该应答因 BC 亚型和化疗类型而异。在 ER‐阴性/HER2‐阴性肿瘤中，MSH2、MSH6 和 FAN1 基因（以前称作 MTMR15）的表达在接受紫杉烷/蒽环类治疗的患者中提示与病理完全缓解和残余侵袭性癌相关。相反，PMS2 的表达在接受蒽环类单剂治疗的患者中提示残余侵袭性癌。在 HER2‐阳性肿瘤中，TOP2A 的表达提示患者可对蒽环类产生应答，但对紫杉烷/蒽环类联合化疗方案无应答。在呈双峰表达的基因中，RECQL4 与临床预后存在显著关联。体外研究表明，RECQL4 的缺陷可影响同源重组，使得 BC 细胞更容易受到 DNA 损伤剂的破坏。The Oncologist 2013;18:1063–1073
DNA repair pathways can enable tumor cells to survive DNA damage induced by chemotherapy and thus provide prognostic and/or predictive value. In this study, the authors sought to assess the differential expression, bimodal distribution, and prognostic and predictive role of DNA repair genes in individual breast cancer molecular subtypes including estrogen receptor‐positive/ HER2‐negative, estrogen receptor‐negative/HER2‐negative, and HER2‐positive cancers. The predictive value of DNA repair gene expression was assessed in breast cancer patients treated with neoadjuvant taxane/anthracycline‐ or anthracycline‐containing regimens, and gene set analyses were performed by grouping DNA repair genes according to biological pathways.
The mutation pattern of breast cancer molecular subtypes is incompletely understood. The purpose of this study was to identify mutations in genes that may be targeted with currently available ...investigational drugs in the three major breast cancer subtypes (ER+/HER2−, HER2+, and Triple Negative). We extracted DNA from fine needle aspirations of 267 stage I–III breast cancers. These tumor specimens typically consisted of >80 % neoplastic cells. We examined 28 genes for 163 known cancer-related nucleic acid variations by Sequenom technology. We observed at least one mutation in 38 alleles corresponding to 15 genes in 108 (40 %) samples, including
PIK3CA
(16.1 % of all samples),
FBXW7
(8 %),
BRAF
(3.0 %),
EGFR
(2.6 %),
AKT1
and
CTNNB1
(1.9 % each),
KIT
and
KRAS
(1.5 % each), and
PDGFR
-
α
(1.1 %). We also checked for the polymorphism in
PHLPP2
that is known to activate
AKT
and it was found at 13.5 % of the patient samples.
PIK3CA
mutations were more frequent in estrogen receptor-positive cancers compared to triple negative breast cancer (TNBC) (19
vs.
8 %,
p
=
0.001
). High frequency of
PIK3CA
mutations (28 %) were also found in HER2+ breast tumors. In TNBC,
FBXW7
mutations were significantly more frequent compared to ER+ tumors (13
vs.
5 %,
p
=
0.037
). We performed validation for all mutated alleles with allele-specific PCR or direct sequencing; alleles analyzed by two different sequencing techniques showed 95–100 % concordance for mutation status. In conclusion, different breast cancer subtypes harbor different type of mutations and approximately 40 % of tumors contained individually rare mutations in signaling pathways that can be potentially targeted with drugs. Simultaneous testing of many different mutations in a single needle biopsy is feasible and allows the design of prospective clinical trials that could test the functional importance of these mutations in the future.
Parafollicular C-cell-derived medullary thyroid cancer (MTC) comprises 3% to 4% of all thyroid cancers. While cytotoxic treatments have been shown to have limited efficacy, targeted molecular ...therapies that inhibit rearranged during transfection (RET) and other tyrosine kinase receptors that are mainly involved in angiogenesis have shown great promise in the treatment of metastatic or locally advanced MTC. Multi-tyrosine kinase inhibitors such as vandetanib, which is already approved for the treatment of progressive MTC, and cabozantinib have shown distinct advantages with regard to rates of disease response and control. However, these types of tyrosine kinase inhibitor compounds are able to concurrently block several types of targets, which limits the understanding of RET as a specific target. Moreover, important resistances to tyrosine kinase inhibitors can occur, which limit the long-term efficacy of these treatments. Deregulated cellular signaling pathways and genetic alterations in MTC, particularly the activation of the RAS/mammalian target of rapamycin (mTOR) cascades and RET crosstalk signaling, are now emerging as novel and potentially promising therapeutic treatments for aggressive MTC.
MicroRNAs (miRNAs) simultaneously modulate different oncogenic networks, establishing a dynamic system of gene expression and pathway regulation. In this study, we analyzed global miRNA and messenger ...RNA (mRNA) expression profiles of 17 cell lines representing different molecular breast cancer subtypes. Spearman's rank correlation test was used to evaluate the correlation between miRNA and mRNA expression. Hierarchical clustering and pathway analysis were also performed. Publicly available gene expression profiles (
= 699) and tumor tissues (
= 80) were analyzed to assess the relevance of key miRNA-regulated pathways in human breast cancer. We identified 39 significantly deregulated miRNAs, and the integration between miRNA and mRNA data revealed the importance of immune-related pathways, particularly the Oncostatin M (OSM) signaling, associated with mesenchymal-like breast cancer cells. OSM levels correlated with genes involved in the inflammatory response, epithelial-to-mesenchymal transition (EMT), and epidermal growth factor (EGF) signaling in human estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Our results suggest that the deregulation of specific miRNAs may cooperatively impair immune and EMT pathways. The identification of the OSM inflammatory pathway as an important mediator of EMT in triple-negative breast cancer (TNBC) may provide a novel potential opportunity to improve therapeutic strategies.
► These data show that ATC cells produce CXCL10, under the influence of IFN-γ+TNF-α. ► The pattern of modulation and the response induced by cytokines or TZDs is variable. ► The intracellular ...pathways involved in ATC may have different types of dysregulation. ► TZDs show a variable effect on CXCL10 secretion and ATC proliferation.
Until now, no data are present in literature about the prototype Th1 chemokine (C–X–C motif) ligand 10 (CXCL10) in anaplastic thyroid cancer (ATC).
This study aimed to test in “primary human ATC cells” (ANA) vs “normal thyroid follicular cells” (TFC): (a) CXCL10 secretion basally and after interferon (IFN)-γ and/or tumor necrosis factor (TNF)-α stimulation; (b) peroxisome proliferator-activated receptor (PPAR)-γ activation by thiazolidinediones, rosiglitazone or pioglitazone, on CXCL10 secretion, on proliferation and apoptosis in ANA.
We demonstrate that: (a) ANA, but not TFC, produced basally CXCL10, and did so in half of cases; (b) IFN-γ stimulated dose-dependently CXCL10, in ANA and TFC; (c) TNF-α did not induce CXCL10 secretion, in ANA and TFC; (d) IFN-γ+TNF-α induced a synergistic but variable release of CXCL10 in the different ANA preparations, while it was more reproducible in TFC; (e) rosiglitazone action on CXCL10 in ANA was inhibitory in 2/6, stimulatory in 1/6 and nil in 3/6, whereas it was inhibitory in TFC; (f) rosiglitazone inhibition of proliferation in ANA was not associated with the effect on CXCL10; (g) nuclear factor-κB and ERK1/2 were basally activated in ANA, increased by IFN-γ+TNF-α, and rosiglitazone inhibited that activation.
On the whole, the present data first show that ANA cells are able to produce CXCL10, basally and under the influence of cytokines. However, the pattern of modulation by IFN-γ, TNF-α or thiazolidinediones is extremely variable, suggesting that the intracellular pathways involved in the chemokine modulation in ATC have different types of deregulation.
We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of ...adjuvant endocrine therapy.
Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years.
In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers 0 to 10 year, HR 3.36; p = 0.013. High-MKS/High-ERS cancers had low risk of early relapse 0-2.5 years HR 0.13; p = 0.0006, but high risk of late relapse which was higher than in the High-MKS/Low-ERS group after 5 years HR 3.86; p = 0.007. The High-MKS/Low-ERS subset had most of the early relapses 0 to 2.5 years, HR 6.53; p < 0.0001 especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.
Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.
Different kinases are expressed in different clinical subsets of breast cancer. In this study, we assessed kinase expression patterns in different clinical subtypes of breast cancer, evaluated the ...prognostic and predictive values of kinase metagenes, and investigated their functions in vitro. Four hundred twenty-eight protein kinases in gene expression data were examined from 684 cases of breast cancer and 51 breast cancer cell lines to identify kinase expression patterns. We tested the prognostic value of kinase metagenes in 684 node-negative patients who received no adjuvant therapy and the predictive value in 233 patients who received uniform neoadjuvant chemotherapy. Twelve kinases were overexpressed in estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 7 in HER2(+), and 28 in ER(-)/HER2(-) cancers, respectively. We examined the functional role of 22 kinases overexpressed in ER(-)/HER2(-) cancers using siRNA. Downregulation of these kinases caused significant subtype-specific inhibition of cell growth in vitro. Two robust kinase clusters, including an immune kinase cluster and a mitosis kinase cluster, were present in all clinical subgroups. High mitosis kinase score was associated with worse prognosis but higher pathologic complete response (pCR) in ER(+)/HER2(-) cancers, but not in ER(-)/HER2(-) or HER2(+) cancers, in univariate and multivariate analyses including other genomic predictors (MammaPrint, genomic grade index, and the 76-gene signature). Conversely, higher immune kinase score was associated with better survival in ER(+)/HER2(-) and HER2(+) tumors and also predicted higher probability of pCR in HER2(+) cancers. Taken together, our results indicate that kinases regulating mitosis and immune functions convey distinct prognostic information that varies by clinical subtype.
Context: Congenital hypothyroidism (CH) is a common endocrine disorder with an incidence of 1:3000–4000 at birth. In 80–85% of cases, CH is caused by defects in thyroid organogenesis, resulting in ...absent, ectopically located, and/or severely reduced gland thyroid dysgenesis (TD). Mutations in genes controlling thyroid development have demonstrated that in a few cases, TD is a Mendelian trait. However, accumulating evidence supports the view that the genetics of TD are complex, possibly with a polygenic/multifactorial basis. A higher prevalence of congenital heart disease has been documented in children with CH than in the general population. Such an association suggests a possible pathogenic role of genes involved in both heart and thyroid development. NKX2–5 encodes a homeodomain-containing transcription factor with a major role in heart development, and mutations affecting this gene have been reported in individuals with congenital heart disease.
Objective: In the present work we investigated the possible involvement of NKX2–5 mutations in TD.
Results: Our results indicate that Nkx2–5−/− embryos exhibit thyroid bud hypoplasia, providing evidence that NKX2–5 plays a role in thyroid organogenesis and that NKX2–5 mutations contribute to TD. NKX2–5 mutational screening in 241 patients with TD allowed the identification of three heterozygous missense changes (R25C, A119S, and R161P) in four patients with TD. Functional characterization of the three mutations demonstrated reduced DNA binding and/or transactivation properties, with a dominant-negative effect on wild-type NKX2–5.
Conclusion: Our results suggest a previously unknown role of NKX2–5 in the pathogenesis of TD.
Abstract Introduction: Patients with basal-like breast cancer (BLBC) predominantly represented by triple-negative breast cancer have shown a high recurrence rate and are characterized by poor ...prognosis. There is an urgent need to undercover reliable prognostic biomarkers that can help in the clinical management of such patients and identify additional therapeutic targets. The objective of this study was to create a comprehensive transcriptomic database on a large scale and leverage it to identify and prioritize cancer-related genes associated with BLBC patients’ outcomes. Methods: We identified breast cancer cohorts from public repositories that contained gene expression data at the transcriptome level, along with clinical follow-up information. BLBC were identified using the PAM50 signature. All samples were standardized using a standard array normalization coupled with scaling to have a mean expression across all genes of 1000 in each sample and incorporated into a unified database. Redundant samples were removed. For each gene, Cox univariate survival analysis was conducted, to account for multiple hypothesis testing, the false discovery rate was computed, and a significant cutoff of 1% was employed to determine the highest statistical significance. Association with RFS and OS was performed. Multivariate analysis was performed for selected genes involving clinical and pathological variables. To uncover higher-level functions related to altered RFS, gene ontology analysis was performed using the enrichGO function in the TNM plotter (http://www.tnmplot.com). Results: The complete integrated database comprises 1,899 samples from 52 breast cancer datasets. Altogether, 2,342 genes were correlated with relapse-free survival (RFS), and 1,149 genes were correlated with overall survival (OS). 619 genes were statistically significant for both RFS and OS. The most significant genes were ANGPTL4 (p=4.25E-08, HR=2.02), NHP2 (p=5.98E-10, HR=1.93), STK3 (p=4.86E-10, HR=1.93), GBE1 (p=2.77E-09, HR=1.86), and PMVK (p=3.65E-09, HR=1.85) for RFS and PINK1 (p=1.64E-05 , HR=3.31), CAMK2N1 (p=1.06E-07 , HR=2.93), CACFD1 (p=4.79E-04 , HR=2.61), SCAP (p=3.29E-04 , HR=2.6), SDC1 (p=2.81E-04 , HR=2.57), for OS. The most significant gene ontology biological processes upregulated in tumors with a worse prognosis include GO:0000184, nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (p=6.64E-18); GO:0045047 , protein targeting to ER (p=6.64E-18); GO:0006614, SRP-dependent cotranslational protein targeting to membrane (p=9.08E-18); GO:0072599, establishment of protein localization to endoplasmic reticulum (p=1.30E-17); and GO:0006613, cotranslational protein targeting to membrane (p=1.90E-17). Conclusions: Our results help to prioritize genes and to neglect those which are most likely to fail in studies aiming to establish new clinically useful biomarkers and therapeutic targets in BLBC. Citation Format: Balazs Gyorffy, Libero Santarpia. Uncovering Novel Potential Prognostic Biomarkers in Basal-Like Breast Cancer using Transcriptomic Data of 1,899 Patients abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-03-08.
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