Dataset Information

Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases.

ABSTRACT:

Purpose

High activity of the intracellular phosphatidylinositol-3 kinase (PI3K) pathway is common in breast cancer. Here, we explore differences in expression of important PI3K pathway regulators: the activator, phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA), and the tumour suppressor, phosphatase and tensin homolog (PTEN), in breast carcinoma tissue and normal breast tissue. Furthermore, we examine whether expression of PIK3CA and PTEN mRNA and occurrence of PIK3CA mutations are associated with lymph node metastases in patients with primary breast cancer.

Methods

Paired tissue samples of breast carcinoma and normal breast tissue were obtained from 175 breast cancer patients at the time of primary surgery, of these 105 patients were lymph node positive. Expression of PIK3CA and PTEN mRNA was quantified with Quantitative Real Time PCR. Somatic mutations in exon 9 and exon 20 of the PIK3CA gene were identified by genotyping.

Results

Both PIK3CA and PTEN mRNA expression was significantly increased in breast carcinoma tissue compared to normal breast tissue (p = 2 × 10(-11)) and (p < 0.001), respectively. PIK3CA mutations were present in 68 out of 175 patients (39%), but were not associated with PIK3CA expression (p = 0.59). Expression of PIK3CA and PTEN mRNA, and PIK3CA mutations in breast carcinomas were not associated with presence of lymph node metastases.

Conclusions

The expression of PTEN and PIK3CA mRNA is increased in breast carcinoma tissue compared to normal breast tissue, and PIK3CA mutations are frequent in primary breast carcinoma, however these factors were not associated with lymph node metastases.

SUBMITTER: Palimaru I

PROVIDER: S-EPMC3786083 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases.

Palimaru Irina I Brügmann Anja A Wium-Andersen Marie Kim MK Nexo Ebba E Sorensen Boe Sandahl BS

SpringerPlus 20130916

<h4>Purpose</h4>High activity of the intracellular phosphatidylinositol-3 kinase (PI3K) pathway is common in breast cancer. Here, we explore differences in expression of important PI3K pathway regulators: the activator, phosphatidylinositol-3-kinase catalytic subunit alpha (PIK3CA), and the tumour suppressor, phosphatase and tensin homolog (PTEN), in breast carcinoma tissue and normal breast tissue. Furthermore, we examine whether expression of PIK3CA and PTEN mRNA and occurrence of PIK3CA mutat ...[more]

PMID: 24083111

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Project description:BackgroundPatients with breast cancer presenting with single lymph node metastasis (from a sentinel node) experience prolonged survival compared to patients with multiple lymph node metastases (≥3). However, little information is available on the genetic and immunological characteristics of breast cancer metastases within the regional lymph nodes as they progress from the sentinel lymph node (SLN) downstream to multiple regional lymph nodes (MLNs).MethodsGenomic profiling was performed using a next-generation sequencing panel covering 520 cancer-related genes in the primary tumour and metastatic lymph nodes of 157 female patients with breast cancer. We included primary tumours, metastatic lymph nodes and adjacent clinically normal lymph nodes (20 patients from the SLN group and 28 patients from the MLNs group) in the whole transcriptome analysis.FindingsThe downstream metastatic lymph nodes (P = 0.029) and the primary breast tumours (P = 0.011) had a higher frequency of PIK3CA mutations compared to the SLN metastasis. We identified a distinct group of 14 mutations from single sentinel node metastasis and a different group of 15 mutations from multiple nodal metastases. Only 4 distinct mutations (PIK3CA, CDK4, NFKBIA and CDKN1B) were conserved in metastases from both lymph node settings. The tumour mutational burden (TMB) was significantly lower in single nodal metastasis compared to the paired primary breast cancer (P = 0.0021), while the decline in TMB did not reach statistical significance in the MLNs group (P = 0.083). In the gene set enrichment analysis, we identified 4 upregulated signatures in both primary tumour and nodal metastases from the MLNs group, including 3 Epithelial-mesenchymal transition(EMT) signatures and 1 angiogenesis signature. Both the CD8/Treg ratio and the CD8/EMT ratio were significantly higher in adjacent normal lymph nodes from patients with a single metastasis in the SLN compared with samples from the MLNs group (P = 0.045 and P = 0.023, respectively). This suggests that the immune defence from the MLNs patients might have a less favourable microenvironment, thus permitting multiple lymph nodes metastasis.InterpretationSingle lymph node metastases and multiple lymph node metastases have significant differences in their molecular profiles and immune profiles. The findings are associated with more aggressive tumour characteristics and less favourable immune charactoristics in patients with multiple nodal metastases compared to those with a single metastasis in the sentinel node.FundingThis work was supported by funds from High-level Hospital Construction Project (DFJH201921), the National Natural Science Foundation of China (81902828 and 82002928), the Fundamental Research Funds for the Central Universities (y2syD2192230), and the Medical Scientific Research Foundation of Guangdong Province (B2019039).

Project description:Whether the expression status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) receptor and Ki-67 show concordance between the primary tumors and the synchronous axillary lymph node (ALN) metastases has been discussed in numerous studies. However, to date, the results of these studies remain controversial. Therefore, the present study aimed to investigate whether the expression of ER, PR, HER-2 and Ki-67 was in concordance between the primary tumors and synchronous ALN metastases in patients with operable breast cancer (BC). A total of 60 tissue samples were collected from patients with primary operable BC diagnosed with primary tumors and synchronous ALN metastases. The expression levels of the four biomarkers, ER, PR, HER-2 and Ki-67, were assessed in primary lesions and synchronous ALN metastases samples using immunohistochemistry. The cut-off values were set to 10% for ER and PR, while the labeling index of Ki-67 was set to 14%. The immunostaining intensity of ER and PR was scored as negative (?), 1+, 2+ and 3+. The criteria for HER-2 testing in BC were implemented according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines. The concordance rates for ER, PR and HER-2 were 96.7 (58/60), 96.7 (58/60) and 90% (54/60), respectively. In addition, the kappa values of consistency in the primary lesions and the synchronous ALN metastases were 0.773 for ER, 0.654 for PR and 0.785 for HER-2. Furthermore, the P-values of ER, PR and Ki-67 numerical variables between the two groups were 0.393, 0.400 and 0.331, respectively, as demonstrated using a non-parametric Wilcoxon signed rank test. The findings of the present study demonstrated a high degree of concordance between the expression of ER, PR, HER-2 and Ki-67 in the primary tumors and that in the synchronous ALN metastases, suggesting that the BC primary tumor biomarkers may be used for the prognosis of synchronous ALN metastases in patients with operable BC.

Project description:BackgroundBreast cancer is a very heterogeneous disease and some patients are cured by the surgical removal of the primary tumour whilst other patients suffer from metastasis and spreading of the disease, despite adjuvant therapy. A number of prognostic and treatment predictive factors have been identified such as tumour size, oestrogen (ER) and progesterone (PgR) receptor status, human epidermal growth factor receptor type 2 (HER2) status, histological grade, Ki67 and age. Lymph node involvement is also assessed during surgery to determine if the tumour has spread which requires dissection of the axilla and adjuvant treatment. The prognostic and treatment predictive factors assessing the nature of the tumour are all routinely based on the status of the primary tumour.ResultsWe have analysed a unique tumour set of fourteen primary breast cancer tumours with matched synchronous axillary lymph node metastases and a set of nine primary tumours with, later developed, matched distant metastases from different sites in the body. We used a pairwise tumour analysis (from the same individual) since the difference between the same tumour-type in different patients was greater. Glycopeptide capture was used in this study to selectively isolate and quantify N-linked glycopeptides from tumours mixtures and the captured glycopeptides were subjected to label-free quantitative tandem mass spectrometry analysis. Differentially expressed proteins between primary tumours and matched lymph node metastasis and distant metastasis were identified. Two of the top hits, ATPIF1 and tubulin β-chain were validated by immunohistochemistry to be differentially regulated.ConclusionsWe show that the expression of a large number of glycosylated proteins change between primary tumours and matched lymph node metastases and distant metastases, confirming that cancer cells undergo a molecular transformation during the spread to a secondary site. The proteins are part of important pathways such as cell adhesion, migration pathways and immune response giving insight into molecular changes needed for the tumour to spread. The large difference between primary tumours and lymph node and distant metastases also suggest that treatment should be based on the phenotype of the lymph node and distant metastases.

Project description:Approximately 59 % of patients with breast cancer with one or two sentinel lymph nodes (1-2 SLN) macrometastases do not benefit from axillary lymph node dissection (ALND), which may also incur morbidities. It is necessary to evaluate the association between various clinicopathological characteristics and non-sentinel lymph node metastases (non-SLNM) in patients with breast cancer with 1-2 SLN macrometastases, and determine whether they 1-2 should avoid ALND. Eight electronic literature databases (PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Chinese Scientific Journal, Wanfang, and Chinese Biomedical Literature) were searched from their inception to June 30, 2023, and two reviewers independently extracted the data and assessed the risk of bias. Association strength was summarized using odds ratios (OR) and 95 % confidence intervals (CI). Heterogeneity was accounted for using a subgroup analysis. Publication bias was evaluated using funnel plots and Egger's test. There were 25 studies with 8021 participants, and 27 potential risk factors were evaluated. The risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer include the following: factors of primary tumor: multifocality (OR (95 % CI (2.63 (1.96, 3.54))), tumor size ≥ T2 (2.64 (2.22, 3.14)), tumor localization (upper outer quad) (2.06 (1.23, 3.43)), histopathological grade (G3) (2.45 (1.70, 3.52)), vascular invasion (VI) (2.60 (1.35, 4.98)), lymphovascular invasion (LVI) (2.87 (1.80, 4.56)), perineural invasion (PNI) (3.16 (1.18,8.43)). Factors of lymph nodes: method of SLNs detected (blue dye) (3.85 (1.54, 9.60)), SLN metastasis ratio ≥0.5 (2.79 (2.24, 3.48)), two positive SLNs (3.55, (2.08, 6.07)), zero negative SLN (3.72 (CI 2.50, 4.29)), extranodal extension (ENE) (4.69 (2.16, 10.18)). Molecular typing: Her-2 positive (2.08 (1.26, 3.43)), Her-2 over-expressing subtype (1.83 (1.22, 2.73)). Factors of examination/inspection: axillary lymph nodes (ALNs) positive on imaging (3.18 (1.68, 6.00)), cancer antigen 15-3 (CA15-3) (4.01 (2.33,6.89)), carcinoembryonic antigen (CEA) (2.13 (1.32-3.43)). This review identified the risk factors for non-SLNM in patients with 1-2 SLN macrometastatic breast cancer. However, additional studies are needed to confirm the above findings owing to the limited number and types of studies included.

Dataset Information

Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases.

Purpose

Methods

Results

Conclusions

Publications

Expression of PIK3CA, PTEN mRNA and PIK3CA mutations in primary breast cancer: association with lymph node metastases.

Similar Datasets

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