Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.

Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer. Advances in high-throughput sequencing technologies have accelerated the identification of somatic and germline single nucleotide mutations in non-coding genomic regions. This review provides an overview of somatic and germline non-coding single nucleotide alterations affecting transcription factor binding sites in GREs, specifically involved in cancer biology. It also summarizes the technologies available for exploring GREs and the challenges associated with studying and characterizing non-coding single nucleotide mutations. Understanding the role of GRE alterations in cancer is essential for improving diagnostic and prognostic capabilities in the precision medicine era, leading to enhanced patient-centered clinical outcomes.

Comparing Costs: Does Extreme Oncoplastic Breast-Conserving Surgery Confer a Cost Benefit When Compared with Mastectomy and Reconstruction?

INTRODUCTION: Extreme oncoplastic breast-conserving surgery (eOBCS) describes the application of OBCS to patients who would otherwise need a mastectomy, and its safety has been previously described. OBJECTIVE: We aimed to compare the costs of eOBCS and mastectomy. METHODS: We reviewed our institutional database to identify breast cancer patients treated surgically from 2018 to 2023. We included patients with a large disease span (≥5 cm) and multifocal/multicentric disease. Patients were grouped by their surgical approach, i.e. eOBCS or mastectomy. The direct costs of care were determined and compared; however, indirect costs were not included. RESULTS: Eighty-six patients met the inclusion criteria, 10 (11.6%) of whom underwent mastectomy and 76 (88.4%) who underwent eOBCS. Six mastectomy patients (60%) had reconstruction and 6 (60%) underwent external beam radiation therapy (EBRT). Reconstructions were completed in a staged fashion, and the mean cost of the index operation (mastectomy and tissue expander) was $17,816. These patients had one to three subsequent surgeries to complete their reconstruction, at a mean cost of $45,904. The mean cost of EBRT was $5542. Thirty-four eOBCS patients (44.7%) underwent 44 margin re-excisions, including 6 (7.9%) who underwent mastectomy. Sixty (78.9%) of the eOBCS patients had EBRT. The mean cost of their index operation was $6345; the mean cost of a re-excision was $3615; the mean cost of their mastectomies with reconstruction was $49,400; and the mean cost of EBRT was $6807. The cost of care for eOBCS patients remained lower than that for mastectomy patients, i.e. $17,318 versus $57,416. CONCLUSION: eOBCS is associated with a lower cost than mastectomy and had a low conversion rate to mastectomy.

Breast Conservation Project: Clinical Outcomes of Extreme Oncoplastic Breast-Conserving Therapy Versus Mastectomy for Large and Multiple Lesions.

INTRODUCTION: Patients with multiple or large malignant breast lesions are classically considered mastectomy candidates, but extreme oncoplastic breast-conservation surgery (eOBCS) has become an alternative approach. There is a paucity of outcomes data comparing eOBCS with mastectomy. METHODS: We reviewed our prospectively maintained, single-institution database. We included patients with non-metastatic breast cancer with multiple ipsilateral or single large (≥ 5 cm) malignant breast lesions identified preoperatively who underwent either eOBCS or mastectomy. Patient demographics, clinicopathologic features, and surgical, oncologic, and cosmetic outcomes were evaluated. RESULTS: Seventy-six (88%) patients underwent eOBCS and 10 (12%) underwent mastectomy. Median follow-up was 24.8 months. Mastectomy patients had larger lesions than eOBCS patients (median 70 mm vs. 32.5 mm; p = 0.06). Six (60%) index mastectomy patients underwent at least one additional surgery. For eOBCS patients, 34 (44%) required re-excision, 7 of whom underwent more than one subsequent surgery to obtain negative margins, and 6 (7.9%) ultimately underwent mastectomy. For patients undergoing additional surgery (n = 40), median time between index and final operation was 315 days for mastectomy versus 21 days for eOBCS patients (p < 0.001). Mastectomy patients more frequently experienced complications (p = 0.001) and underwent cosmetic revision (p < 0.001). There was no difference in cosmetic scores, and eOBCS patients reported less pain (p = 0.009). There were two local and three distant recurrences in the eOBCS cohort and one distant recurrence in the mastectomy group. CONCLUSION: Breast conservation was attainable in over 90% of eOBCS patients. Increased postoperative complications and discomfort and longer duration of surgical treatment in mastectomy patients without oncologic superiority should drive informed patient discussions.

Chromatin insulation orchestrates matrix metalloproteinase gene cluster expression reprogramming in aggressive breast cancer tumors.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype that exhibits a high incidence of distant metastases and lacks targeted therapeutic options. Here we explored how the epigenome contributes to matrix metalloprotease (MMP) dysregulation impacting tumor invasion, which is the first step of the metastatic process. METHODS: We combined RNA expression and chromatin interaction data to identify insulator elements potentially associated with MMP gene expression and invasion. We employed CRISPR/Cas9 to disrupt the CCCTC-Binding Factor (CTCF) binding site on an insulator element downstream of the MMP8 gene (IE8) in two TNBC cellular models. We characterized these models by combining Hi-C, ATAC-seq, and RNA-seq with functional experiments to determine invasive ability. The potential of our findings to predict the progression of ductal carcinoma in situ (DCIS), was tested in data from clinical specimens. RESULTS: We explored the clinical relevance of an insulator element located within the Chr11q22.2 locus, downstream of the MMP8 gene (IE8). This regulatory element resulted in a topologically associating domain (TAD) boundary that isolated nine MMP genes into two anti-correlated expression clusters. This expression pattern was associated with worse relapse-free (HR = 1.57 [1.06 - 2.33]; p = 0.023) and overall (HR = 2.65 [1.31 - 5.37], p = 0.005) survival of TNBC patients. After CRISPR/Cas9-mediated disruption of IE8, cancer cells showed a switch in the MMP expression signature, specifically downregulating the pro-invasive MMP1 gene and upregulating the antitumorigenic MMP8 gene, resulting in reduced invasive ability and collagen degradation. We observed that the MMP expression pattern predicts DCIS that eventually progresses into invasive ductal carcinomas (AUC = 0.77, p < 0.01). CONCLUSION: Our study demonstrates how the activation of an IE near the MMP8 gene determines the regional transcriptional regulation of MMP genes with opposing functional activity, ultimately influencing the invasive properties of aggressive forms of breast cancer.

Simultaneous Symmetry Procedure in Patients Undergoing Oncoplastic Breast-Conserving Surgery: An Evaluation of Patient Desire and Revision Rates.

INTRODUCTION: In the era of oncoplastic breast conserving-surgery (OBCS), cosmetic outcomes and the desire for symmetry have become essential elements of the surgical management of breast cancer (BC). The timing of contralateral symmetry procedures remains a controversial topic. Simultaneous symmetry procedures (SSP) in OBCS have not been routinely offered due to the perceived risk of delayed asymmetry, potentially increasing the need for delayed cosmetic revision. This study evaluates the rate of revision after SSP in patients undergoing OBCS. METHODS: We reviewed our institutional prospectively maintained database identifying all BC patients treated surgically since our introduction of oncoplastic surgery in 2018. We routinely offer SSP when appropriate. Descriptive statistics evaluated oncoplastic surgical techniques, SSP offerings and procedures, perioperative complications, and revision rates after treatment completion. RESULTS: Between 2018 and 2022, 485 breast cancer patients underwent partial mastectomy, and 396 (82%) underwent OBCS. Of the 313 patients offered SSP, 272 (87%) accepted. The margin reexcision rate of this cohort was 20%. Of the 272 patients with SSP, 152 (56%) underwent intraoperative radiation therapy (IORT), and 105 (39%) had adjuvant external beam radiation therapy. Three patients (1%) experienced complications involving the symmetry side. No patients with complications experienced a delay in adjuvant therapies or requested cosmetic revisions. Three patients (1%) desired surgical revisions due to asymmetry. CONCLUSIONS: Symmetry procedures at the time of OBCS are widely accepted by patients and rarely require delayed cosmetic revision. Simultaneous symmetry procedures should be routinely discussed with patients during the surgical planning of OBCS.

A Look at the Other Side: High-Risk Lesions and Occult Contralateral Malignancy in Symmetry Procedures for Patients Undergoing Oncoplastic Breast-Conserving Surgery.

BACKGROUND: The incidence of occult breast cancer among patients undergoing reduction mammoplasty or risk-reducing mastectomies ranges from 1% to approximately 10%, respectively. Identification of incidental cancer often mandates subsequent mastectomy due to ambiguous margins. This study aimed to determine the incidence of contralateral malignancy among patients undergoing oncoplastic breast-conserving surgery (OBCS) with concurrent symmetry procedures. METHODS: The authors reviewed their prospectively maintained institutional database of patients with unilateral breast cancer who underwent OBCS. Patients who underwent excisional biopsy on the contralateral breast were analyzed separately. Patient demographics, pathologic features, and subsequent disease management were evaluated. RESULTS: Between March 2018 and July 2022, 289 patients underwent OBCS with a symmetry procedure, and 100 patients yielded contralateral breast tissue specimens. For 14 patients, a planned excisional biopsy was performed with their symmetry procedure, and five lesions (36%) were found to be malignant. Of the remaining 86 patients, 92% underwent preoperative breast magnetic resonance imaging (MRI). Four patients (4.7%) had occult malignancies identified on the contralateral breast pathology; three patients with ductal carcinoma in situ and one patient with invasive lobular carcinoma. Three patients had undergone preoperative MRI without suspicious findings. No patients required mastectomy for treatment of the contralateral breast cancer. CONCLUSION: The incidence of occult malignancy among OBCS symmetry procedures approaches 5%. The final pathology of excisional biopsies had a higher upgrade rate than previously reported. All identified malignancies were early-stage disease. The higher incidence of occult breast cancer in this population warrants the routine orientation of all specimens, which allows patients with incidental early-stage cancer the option of breast preservation.

Impact of Locoregional Treatment on Survival in Young Patients with Early-Stage Breast Cancer undergoing Upfront Surgery.

BACKGROUND: Randomized, controlled trials comparing breast-conserving therapy (BCT) with mastectomy have demonstrated equivalent overall survival (OS), but recent observational studies have shown improved OS in patients undergoing BCT. These studies provide limited data on young patients who are traditionally offered mastectomy due to perceived higher disease risk. This study examines the OS in a contemporary series of young women with breast cancer undergoing upfront BCT compared with mastectomy. METHODS: Women ≤40 years old with primary invasive T1-T2, N0-N1 breast cancer were identified from the National Cancer Database between 2006 and 2016. Patient cohorts were based according to locoregional treatment: BCT, mastectomy alone (Mx), and mastectomy with radiotherapy (Mx/RT). Kaplan-Meier method followed by Cox proportional-hazards regression with inverse probability of treatment weighting (IPTW) were performed to account for treatment selection bias effects in OS. RESULTS: A total of 15,611 patients met the study criteria; 9,509 patients (60.9%) had BCT, 4,020 (25.8%) had Mx/RT, and 2,082 (13.3%) had Mx alone. The median follow-up was 4.6 years (interquartile range [IQR] 3.0-6.4). After IPTW-adjustment, the 5-year OS was similar for BCT (95%), Mx (95%), and Mx/RT (94%), and there was no significant difference in OS in Mx (hazard ratio [HR] = 1.16, 95% confidence interval [CI] 0.90-1.51) and Mx/RT (HR = 1.08, 95% CI 0.88-1.34) compared with BCT. Mx/RT was associated with decreased survival in patients with pT2N0 (HR = 1.78, 95% CI 1.12-2.84). CONCLUSIONS: Among young patients with early-stage breast cancer, overall survival was equivalent regardless of surgical approach. Breast-conserving therapy remains a safe option in young women despite the clinical tendency to offer upfront mastectomy in young patients.

Machine Learning-Based Epigenetic Classifiers for Axillary Staging of Patients with ER-Positive Early-Stage Breast Cancer.

BACKGROUND: In the era of molecular stratification and effective multimodality therapies, surgical staging of the axilla is becoming less relevant for patients with estrogen receptor (ER)-positive early-stage breast cancer (EBC). Therefore, a nonsurgical method for accurately predicting lymph node disease is the next step in the de-escalation of axillary surgery. This study sought to identify epigenetic signatures in the primary tumor that accurately predict lymph node status. PATIENTS AND METHODS: We selected a cohort of patients in The Cancer Genome Atlas (TCGA) with ER-positive, HER2-negative invasive ductal carcinomas, and clinically-negative axillae (n = 127). Clinicopathological nomograms from the Memorial Sloan Kettering Cancer Center (MSKCC) and the MD Anderson Cancer Center (MDACC) were calculated. DNA methylation (DNAm) patterns from primary tumor specimens were compared between patients with pN0 and those with > pN0. The cohort was divided into training (n = 85) and validation (n = 42) sets. Random forest was employed to obtain the combinations of DNAm features with the highest accuracy for stratifying patients with > pN0. The most efficient combinations were selected according to the area under the curve (AUC). RESULTS: Clinicopathological models displayed a modest predictive potential for identifying > pN0 disease (MSKCC AUC 0.76, MDACC AUC 0.69, p = 0.15). Differentially methylated sites (DMS) between patients with pN0 and those with > pN0 were identified (n = 1656). DMS showed a similar performance to the MSKCC model (AUC = 0.76, p = 0.83). Machine learning approaches generated five epigenetic classifiers, which showed higher discriminative potential than the clinicopathological variables tested (AUC > 0.88, p < 0.05). CONCLUSIONS: Epigenetic classifiers based on primary tumor characteristics can efficiently stratify patients with no lymph node involvement from those with axillary lymph node disease, thereby providing an accurate method of staging the axilla.

Epigenetic Signatures Predict Pathologic Nodal Stage in Breast Cancer Patients with Estrogen Receptor-Positive, Clinically Node-Positive Disease.

BACKGROUND: Breast cancer patients with clinically positive nodes who undergo upfront surgery are often recommended for axillary lymph node dissection (ALND), yet more than half are found to have limited nodal disease (≤ 3 positive nodes, pN1) at surgery. In this study, we examined the efficiency of molecular classifiers in stratifying patients with clinically positive nodes to pN1 versus > pN1 disease. METHODS: We evaluated the clinical and epigenetic data of patients in The Cancer Genome Atlas with estrogen receptor-positive, human epidermal growth factor receptor 2-negative invasive ductal carcinoma who underwent ALND for node-positive disease. Patients were divided into control (pN1, ≤ 3 positive nodes) and case (> pN1, > 3 positive nodes) groups. Machine learning algorithms were trained on 50% of the cohort and validated on the remaining 50% to identify DNA methylation signatures that predict > pN1 disease. Clinical variables and epigenetic signatures were compared. RESULTS: Controls (n = 34) and case (n = 24) cohorts showed similar mean age (56.4 ± 12.2 vs. 57.6 ± 16.7 years; p = 0.77), number of nodes removed (16.1 ± 7.3 vs. 17.5 ± 6.2; p = 0.45), tumor grade (p = 0.76), presence of lymphovascular invasion (p = 0.18), extranodal extension (p = 0.17), tumor laterality (p = 0.89), and tumor location (p = 0.42). The mean number of positive nodes was significantly different (1.76 ± 0.82, pN1; 8.83 ± 5.36, > pN1; p < 0.001). Three epigenetic signatures (EpiSig14, EpiSig13, EpiSig10) based on DNA methylation patterns of the primary tumors demonstrated high accuracy in predicting > pN1 disease (area under the curve 0.98). CONCLUSIONS: Epigenetic signatures have an excellent diagnostic accuracy for stratifying nodal disease in patients with clinically positive nodes. Validation of this tool is warranted and may provide an accurate and cost-effective method of identifying patients with predicted low nodal burden who could be spared the morbidity of ALND.

Establishing Novel Molecular Subtypes of Appendiceal Cancer.

PURPOSE: Appendiceal cancer is a rare disease process with complex treatment strategies. The objective of this study was to identify mutation-based genetic subtypes that may differ from the current histological classification, compare the genetic make-up of primaries and metastases, and find novel targetable alterations. METHODS: The analyses involved the curation and normalization of gene mutation panels from appendiceal adenocarcinoma and mucinous adenocarcinoma (n = 196) stored in the AACR GENIE Database v6.0. Genes mutated in less than one patient and tumors profiled with incomplete mutation panels were excluded from the study. The optimal number of AC subtypes was established using the Nonnegative Matrix Factorization algorithm. Statistical comparisons of mutation frequencies were performed using Pearson's χ2 test. RESULTS: AC patients were stratified into five mutation subtypes, based on a final set of 41 cancer-related genes. AC0 had no mutations. The most frequently mutated genes varied between the subtypes were: AC1: KRAS (91.9%) and GNAS (77.4%); AC2: KRAS (52.5%), APC (32.5%), and GNAS (30%); AC3: KMT2D (38.7%), TP53 (38.7%), KRAS (35.5%), EP300 (22.6%); and AC4: TP53 (97.2%), KRAS (77.8%), and SMAD4 (36.1%). Additionally, AC3 was less likely to be mucinous (22.6% vs. 50.0-74.2%, p < 0.001) and had a higher mutation frequency (3.6 vs. 0-3.1, p < 0.001). There were no significant differences between primary tumors and metastases in the 41 assessed genes (p = 0.35). CONCLUSIONS: The characterization of these subtypes suggests a need for molecular approaches to complement anatomical and histopathological staging for AC. A prospective comparison of subtype prognosis and response to surgery and adjuvant treatment is needed to identify the clinical applications of the novel molecular subtypes.

Is the 21-Gene Recurrence Score on Core Needle Biopsy Equivalent to Surgical Specimen in Early-Stage Breast Cancer? A Comparison of Gene Expression Between Paired Core Needle Biopsy and Surgical Specimens.

BACKGROUND: Molecular testing on surgical specimens predicts disease recurrence and benefit of adjuvant chemotherapy in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer (EBC). Testing on core biopsies has become common practice despite limited evidence of concordance between core/surgical samples. In this study, we compared the gene expression of the 21 genes and the recurrence score (RS) between paired core/surgical specimens. METHODS: Eighty patients with HR+/HER2- EBC were evaluated from two publicly available gene expression datasets (GSE73235, GSE76728) with paired core/surgical specimens without neoadjuvant systemic therapy. The expression of the 21 genes was compared in paired samples. A microarray-based RS was calculated and a value ≥ 26 was defined as high-RS. The concordance rate and kappa statistic were used to evaluate the agreement between the RS of paired samples. RESULTS: Overall, there was no significant difference and a high correlation in the gene expression levels of the 21 genes between paired samples. However, CD68 and RPLP0 in GSE73235, AURKA, BAG1, and TFRC in GSE76728, and MYLBL2 and ACTB in both datasets exhibited weak to moderate correlation (r < 0.5). There was a high correlation of the microarray-based RS between paired samples in GSE76728 (r = 0.91, 95% confidence interval [CI] 0.81-0.96) and GSE73235 (r = 0.82, 95% CI 0.71-0.89). There were no changes in RS category in GSE76728, whereas 82% of patients remained in the same RS category in GSE73235 (κ = 0.64). CONCLUSIONS: Gene expression levels of the 21-gene RS showed a high correlation between paired specimens. Potential sampling and biological variability on a set of genes need to be considered to better estimate the RS from core needle biopsy.

The metastatic microenvironment: Melanoma-microglia cross-talk promotes the malignant phenotype of melanoma cells.

Melanoma has the highest propensity to metastasize to the brain compared to other cancers, as brain metastases are found frequently high in patients who have prolonged survival with visceral metastasis. Once disseminated in the brain, melanoma cells communicate with brain resident cells that include astrocytes and microglia. Microglia cells are the resident macrophages of the brain and are the main immunological cells in the CNS involved in neuroinflammation. Data on the interactions between brain metastatic melanoma cells and microglia and on the role of microglia-mediated neuroinflammation in facilitating melanoma brain metastasis are lacking. To elucidate the role of microglia in melanoma brain metastasis progression, we examined the bidirectional interactions between microglia and melanoma cells in the tumor microenvironment. We identified the molecular and functional modifications occurring in brain-metastasizing melanoma cells and microglia cells after the treatment of each cell type with supernatants of the counter cell type. Both cells induced alteration in gene expression programs, cell signaling, and cytokine secretion in the counter cell type. Moreover, melanoma cells exerted significant morphological changes on microglia cells, enhanced proliferation, induced matrix metalloproteinase-2 (MMP-2) activation, and cell migration. Microglia cells induced phenotypic changes in melanoma cells increasing their malignant phenotype: increased melanoma proliferation, MMP-2 activity, cell migration, brain endothelial penetration, and tumor cells ability to grow as spheroids in 3D cultures. Our work provides a novel insight into the bidirectional interactions between melanoma and micoglia cells, suggesting the contribution of microglia to melanoma brain metastasis formation.

Clinical Implications of Transcriptomic Changes After Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer.

BACKGROUND: Pathological response to neoadjuvant chemotherapy (NAC) is critical in prognosis and selection of systemic treatments for patients with triple-negative breast cancer (TNBC). The aim of this study is to identify gene expression-based markers to predict response to NAC. PATIENTS AND METHODS: A survey of 43 publicly available gene expression datasets was performed. We identified a cohort of TNBC patients treated with NAC (n = 708). Gene expression data from different studies were renormalized, and the differences between pretreatment (pre-NAC), on-treatment (post-C1), and surgical (Sx) specimens were evaluated. Euclidean statistical distances were calculated to estimate changes in gene expression patterns induced by NAC. Hierarchical clustering and pathway enrichment analyses were used to characterize relationships between differentially expressed genes and affected gene pathways. Machine learning was employed to refine a gene expression signature with the potential to predict response to NAC. RESULTS: Forty nine genes consistently affected by NAC were involved in enhanced regulation of wound response, chemokine release, cell division, and decreased programmed cell death in residual invasive disease. The statistical distances between pre-NAC and post-C1 significantly predicted pathological complete response [area under the curve (AUC) = 0.75; p = 0.003; 95% confidence interval (CI) 0.58-0.92]. Finally, the expression of CCND1, a cyclin that forms complexes with CDK4/6 to promote the cell cycle, was the most informative feature in pre-NAC biopsies to predict response to NAC. CONCLUSIONS: The results of this study reveal significant transcriptomic changes induced by NAC and suggest that chemotherapy-induced gene expression changes observed early in therapy may be good predictors of response to NAC.

Clinicopathological Features of Triple-Negative Breast Cancer Epigenetic Subtypes.

BACKGROUND/OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous collection of breast tumors with numerous differences including morphological characteristics, genetic makeup, immune-cell infiltration, and response to systemic therapy. DNA methylation profiling is a robust tool to accurately identify disease-specific subtypes. We aimed to generate an epigenetic subclassification of TNBC tumors (epitypes) with utility for clinical decision-making. METHODS: Genome-wide DNA methylation profiles from TNBC patients generated in the Cancer Genome Atlas project were used to build machine learning-based epigenetic classifiers. Clinical and demographic variables, as well as gene expression and gene mutation data from the same cohort, were integrated to further refine the TNBC epitypes. RESULTS: This analysis indicated the existence of four TNBC epitypes, named as Epi-CL-A, Epi-CL-B, Epi-CL-C, and Epi-CL-D. Patients with Epi-CL-B tumors showed significantly shorter disease-free survival and overall survival [log rank; P = 0.01; hazard ratio (HR) 3.89, 95% confidence interval (CI) 1.3-11.63 and P = 0.003; HR 5.29, 95% CI 1.55-18.18, respectively]. Significant gene expression and mutation differences among the TNBC epitypes suggested alternative pathway activation that could be used as ancillary therapeutic targets. These epigenetic subtypes showed complementarity with the recently described TNBC transcriptomic subtypes. CONCLUSIONS: TNBC epigenetic subtypes exhibit significant clinical and molecular differences. The links between genetic make-up, gene expression programs, and epigenetic subtypes open new avenues in the development of laboratory tests to more efficiently stratify TNBC patients, helping optimize tailored treatment approaches.

A Role-Based Software Architecture to Support Mobile Service Computing in IoT Scenarios.

The interaction among components of an IoT-based system usually requires using low latency or real time for message delivery, depending on the application needs and the quality of the communication links among the components. Moreover, in some cases, this interaction should consider the use of communication links with poor or uncertain Quality of Service (QoS). Research efforts in communication support for IoT scenarios have overlooked the challenge of providing real-time interaction support in unstable links, making these systems use dedicated networks that are expensive and usually limited in terms of physical coverage and robustness. This paper presents an alternative to address such a communication challenge, through the use of a model that allows soft real-time interaction among components of an IoT-based system. The behavior of the proposed model was validated using state machine theory, opening an opportunity to explore a whole new branch of smart distributed solutions and to extend the state-of-the-art and the-state-of-the-practice in this particular IoT study scenario.

Epigenomic and Transcriptomic Characterization of Secondary Breast Cancers.

BACKGROUND: Molecular alterations impact tumor prognosis and response to treatment. This study was designed to identify transcriptomic and epigenomic signatures of breast cancer (BC) tumors from patients with any prior malignancy. METHODS: RNA-sequencing and genome-wide DNA methylation profiles from BCs were generated in the Cancer Genome Atlas project. Patients with secondary breast cancer (SBC) were separated by histological subtype and matched to primary breast cancer controls to create two independent cohorts of invasive ductal (IDC, n = 36) and invasive lobular (ILC, n = 40) carcinoma. Differentially expressed genes, as well as differentially methylated genomic regions, were integrated to identify epigenetically regulated abnormal gene pathways in SBCs. RESULTS: Differentially expressed genes were identified in IDC SBCs (n = 727) and in ILC SBCs (n = 261; Wilcoxon's test; P < 0.05). In IDC SBCs, 105 genes were upregulated and hypomethylated, including an estrogen receptor gene, and 73 genes were downregulated and hypermethylated, including genes involved in antigen presentation and interferon response pathways (HLA-E, IRF8, and RELA). In ILC SBCs, however, only 17 genes were synchronously hypomethylated and upregulated, whereas 46 genes hypermethylated and downregulated. Interestingly, the SBC gene expression signatures closely corresponded with each histological subtype with only 1.51% of genes overlapping between the two histological subtypes. CONCLUSIONS: Differential gene expression and DNA methylation signatures are seen in both IDC and ILC SBCs, including genes that are relevant to tumor growth and proliferation. Differences in gene expression signatures corresponding with each histological subtype emphasize the importance of disease subtype-specific evaluations of molecular alterations.

Detection of Minimal Residual Disease and Its Clinical Applications in Melanoma and Breast Cancer Patients.

Melanoma and breast cancer (BC) patients face a high risk of recurrence and disease progression after curative surgery and/or therapeutic treatment. Monitoring for minimal residual disease (MRD) during a disease-free follow-up period would greatly improve patient outcomes through earlier detection of relapse or treatment resistance. However, MRD monitoring in solid tumors such as melanoma and BC are not well established. Here, we discuss the clinical applications of MRD monitoring in melanoma and BC patients and highlight the current approaches for detecting MRD in these solid tumors.