Microsatellite Instability Testing and Prognostic Implications in Colorectal Cancer.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

Detailed DNA methylation characterisation of phyllodes tumours identifies a signature of malignancy and distinguishes phyllodes from metaplastic breast carcinoma.

Phyllodes tumours (PTs) are rare fibroepithelial lesions of the breast that are classified as benign, borderline, or malignant. As little is known about the molecular underpinnings of PTs, current diagnosis relies on histological examination. However, accurate classification is often difficult, particularly for distinguishing borderline from malignant PTs. Furthermore, PTs can be misdiagnosed as other tumour types with shared histological features, such as fibroadenoma and metaplastic breast cancers. As DNA methylation is a recognised hallmark of many cancers, we hypothesised that DNA methylation could provide novel biomarkers for diagnosis and tumour stratification in PTs, whilst also allowing insight into the molecular aetiology of this otherwise understudied tumour. We generated whole-genome methylation data using the Illumina EPIC microarray in a novel PT cohort (n = 33) and curated methylation microarray data from published datasets including PTs and other potentially histopathologically similar tumours (total n = 817 samples). Analyses revealed that PTs have a unique methylome compared to normal breast tissue and to potentially histopathologically similar tumours (metaplastic breast cancer, fibroadenoma and sarcomas), with PT-specific methylation changes enriched in gene sets involved in KRAS signalling and epithelial-mesenchymal transition. Next, we identified 53 differentially methylated regions (DMRs) (false discovery rate < 0.05) that specifically delineated malignant from non-malignant PTs. The top DMR in both discovery and validation cohorts was hypermethylation at the HSD17B8 CpG island promoter. Matched PT single-cell expression data showed that HSD17B8 had minimal expression in fibroblast (putative tumour) cells. Finally, we created a methylation classifier to distinguish PTs from metaplastic breast cancer samples, where we revealed a likely misdiagnosis for two TCGA metaplastic breast cancer samples. In conclusion, DNA methylation alterations are associated with PT histopathology and hold the potential to improve our understanding of PT molecular aetiology, diagnostics, and risk stratification. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells' behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

INTRODUCTION: Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. METHODS: Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. RESULTS: Characteristics of patients receiving FOLFOX (n = 195) and CAPOX (n = 62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p < 0.01) and oxaliplatin (72% vs. 66%, p = 0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR = 0.53, p = 0.068) and similar OS (89% vs. 89%, HR = 0.53, p = 0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR = 0.41, p = 0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p = 0.017) and hand-foot syndrome (p < 0.001) but not peripheral neuropathy or myelosuppression. CONCLUSION: In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Epithelial Carcinomas Arising within Phyllodes Tumours of the Breast: A Review of Their Pathological Characteristics.

Epithelial proliferation is a common feature of phyllodes tumours (PTs), but epithelial malignancy is rare. This review seeks to further our understanding of epithelial malignancy within PTs by analysing their histopathological characteristics in previously reported cases and providing an overview of studies on their pathological features. PubMed and DeepDyve were searched for case reports, case series, and literature reviews of in situ and invasive carcinoma within PTs. Only cases where the carcinoma was within the PT were included. Cases of synchronous carcinoma in the ipsilateral or contralateral breast were excluded. Ninety-eight cases of in situ or invasive carcinoma within a PT were identified. Across the grades of PTs, there was a similar proportion of invasive carcinomas compared to in situ lesions. Malignant PT correlates with a higher likelihood of epithelial malignancy, and molecular studies support a possible causal pathophysiological relationship. This higher likelihood may suggest interactions between malignant stroma and the transforming epithelium that could potentially play a significant role in the phenomenon, which remains to be elucidated. Encasement within a PT likely improves the prognosis of breast carcinoma due to earlier detection. The presence of carcinoma within a malignant PT has uncertain prognostic implications. Thorough sampling of all PTs is recommended for appropriate prognostication and management.

KRAS and BRAF Mutation Rates and Survival Outcomes in Colorectal Cancer in an Ethnically Diverse Patient Cohort.

KRAS and BRAF mutation rates in colorectal cancer (CRC) reported from various mono-ethnic studies vary amongst different ethnic groups. However, these differences in mutation rates may not be statistically significant or may be due to differences in environmental and/or laboratory factors across countries rather than racial genetic differences. Here, we compare the KRAS/BRAF mutation rates and survival outcomes in CRC between ethnic groups at a single institution. We also investigate the contributions of genetic, environmental, and laboratory factors to the variations in KRAS/BRAF mutation rates reported from different countries. Clinicopathological data from 453 ethnically diverse patients with CRC were retrospectively analyzed at Liverpool Hospital, NSW Australia (2014-2016). KRAS/BRAF mutations were detected using real-time PCR (Therascreen kits from Qiagen). Mismatch repair (MMR) status was determined using immunohistochemical staining. Four ethnic groups were analyzed: Caucasian, Middle Eastern, Asian, and South American. Overall survival data were available for 406 patients. There was no significant difference in KRAS mutation rates between Caucasians (41.1%), Middle Easterners (47.9%), Asians (44.8%), and South Americans (25%) (p = 0.34). BRAF mutation rates differed significantly between races (p = 0.025), with Caucasians having the highest rates (13.5%) and Middle Easterners the lowest (0%). A secondary analysis in which Caucasians were divided into three subgroups showed that ethnic grouping correlated significantly with KRAS mutation rate (p = 0.009), with central and eastern Europeans having the highest rates (58.3%). There were no significant differences in overall survival (OS) or disease-free survival (DFS) between the four races. The similarity in KRAS mutation rates across races raises the possibility that the differences in KRAS mutation rates reported from various countries may either not be statistically significant or may be due to environmental and/or laboratory factors rather than underlying racial genetic differences. In contrast, we verified that BRAF mutation rates differ significantly between races, suggesting racial genetic differences may be responsible for the discrepant BRAF mutation rates reported from different countries.

Prognostic Significance of MRE11 Overexpression in Colorectal Cancer Patients.

Meiotic recombination 11 (MRE11) plays a critical role in the DNA damage response and maintenance of genome stability and is associated with the prognosis for numerous malignancies. Here, we explored the clinicopathological significance and prognostic value of MRE11 expression in colorectal cancer (CRC), a leading cause of cancer-related deaths worldwide. Samples from 408 patients who underwent surgery for colon and rectal cancer between 2006 and 2011, including a sub-cohort of 127 (31%) patients treated with adjuvant therapy, were analyzed. In Kaplan-Meier survival analyses, we found that high MRE11 expression in the tumor center (TC) was significantly associated with poor disease-free survival (DFS; p = 0.045) and overall survival (OS; p = 0.039). Intriguingly, high MRE11 expression in the TC was also significantly correlated with reduced DFS (p = 0.005) and OS (p = 0.010) in the subgroup with right-sided primary CRC. In multivariate analyses, high MRE11 expression (hazard ratio [HR] = 1.697, 95% confidence interval [CI]: 1.034-2.785; p = 0.036) and lymphovascular/perineural invasion (LVI/PNI; HR = 1.922, 95% CI 1.122-3.293; p = 0.017) showed significant association with worse OS in patients with right-sided tumors but not those with left-sided tumors. Moreover, in patients with right-sided tumors, high MRE11 was associated with worse OS for those with lymph node involvement (p = 0.006) and LVI/PNI (p = 0.049). Collectively, our results suggest that MRE11 may serve as an independent prognostic marker in those with right-sided severe CRC, with clinical value in the management of these patients.

The Role of the AT-Rich Interaction Domain 1A Gene (ARID1A) in Human Carcinogenesis.

The switch/sucrose non-fermentable (SWI/SNF) (SWI/SNF) complex uses energy from ATP hydrolysis to mobilise nucleosomes on chromatin. Components of SWI/SNF are mutated in 20% of all human cancers, of which mutations in AT-rich binding domain protein 1A (ARID1A) are the most common. ARID1A is mutated in nearly half of ovarian clear cell carcinoma and around one-third of endometrial and ovarian carcinomas of the endometrioid type. This review will examine in detail the molecular functions of ARID1A, including its role in cell cycle control, enhancer regulation, and the prevention of telomerase activity. ARID1A has key roles in the maintenance of genomic integrity, including DNA double-stranded break repair, DNA decatenation, integrity of the cohesin complex, and reduction in replication stress, and is also involved in mismatch repair. The role of ARID1A loss in the pathogenesis of some of the most common human cancers is discussed, with a particular emphasis on gynaecological cancers. Finally, several promising synthetic lethal strategies, which exploit the specific vulnerabilities of ARID1A-deficient cancer cells, are briefly mentioned.

The Role of Chaperone-Mediated Autophagy in Bortezomib Resistant Multiple Myeloma.

Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell viability and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensitises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cytotoxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM.

Rectal cancer treatment and outcomes in elderly patients treated with curative intent.

The elderly population comprises a significant proportion of patients diagnosed with rectal cancer. However, there is a lack of evidence to guide treatment decisions in this group. Thus, this multicentre study compares the histopathology, treatment patterns and outcomes between the elderly and young populations with non-metastatic rectal cancer. The present study reported on the clinicopathological variables, treatment modalities and survival outcomes in 736 patients diagnosed with non-metastatic rectal cancer between 2006 and 2015. Patients were divided into the following two groups, <70 and ≥70 years of age, which were compared using Chi-square and survival outcome analysis using Kaplan-Meier. Elderly patients made up nearly half of the cohort and were less likely to undergo trimodality therapy or be discussed in a multidisciplinary meeting. Surgery in the elderly patients was associated with increased mortality. Elderly patients had worse cancer-specific survival (75 vs. 85%), which was particularly evident in stage III disease (hazard ratio, 2.1). Elderly patients in this subgroup treated with trimodality therapy had similar survival outcomes to younger patients. Elderly patients with locally advanced rectal cancer comprise a large proportion of the patient cohort. Consideration should be given for trimodality therapy in this group, taking into account biological age, especially in the context of increasing life expectancy and improvement in the management of age-related comorbidities.

Campylobacter concisus upregulates PD-L1 mRNA expression in IFN-γ sensitized intestinal epithelial cells and induces cell death in esophageal epithelial cells.

Introduction: Campylobacter concisus is an oral bacterium that is associated with inflammatory bowel disease (IBD) and Barrett's esophagus (BE). Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that is used by tumor cells for immune evasion and has increased expression in patients with IBD and BE. We examined whether C. concisus upregulates PD-L1 expression in intestinal and esophageal epithelial cells. Methods: Human intestinal epithelial HT-29 cells and esophageal epithelial FLO-1 cells with and without interferon (IFN)-γ sensitization were incubated with C. concisus strains. The level of PD-L1 mRNA was quantified using quantitative real-time PCR. Cytokines were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Apoptosis of HT-29 and FLO-1 cells were measured using caspase 3/7 assay. Results: We found that intestinal epithelial cells with IFN-γ sensitization incubated with C. concisus significantly upregulated PD-L1 expression and significantly increased the production of interleukin (IL)-8. Whereas, PD-L1 expression was significantly inhibited in IFN-γ sensitized FLO-1 cells incubated with C. concisus strains. Furthermore, FLO-1 cells with and without IFN-γ sensitization incubated with C. concisus strains both had significantly higher levels of cell death. Conclusion: C. concisushas the potential to cause damage to both intestinal and esophageal epithelial cells, however, with different pathogenic effects.

The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy.

Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.

Tumour immune microenvironment biomarkers predicting cytotoxic chemotherapy efficacy in colorectal cancer.

The role of the local tumour and stromal immune landscape is increasingly recognised to be important in cancer development, progression and response to therapy. The composition, function, spatial orientation and gene expression profile of the infiltrate of the innate and adaptive immune system at the tumour and surrounding tissue has an established prognostic role in colorectal cancer (CRC). Multiple studies have confirmed that a tumour immune microenvironment (TIME) reflective of a type 1 adaptive immune response is associated with improved prognosis. There have been significant efforts to evolve these observations into validated, histopathology-based prognostic biomarkers, such as the Immunoscore. However, the clinical need lies much more in the development of predictive, not prognostic, biomarkers which have the potential to improve patient outcomes. This is particularly pertinent to help guide cytotoxic chemotherapy use in CRC, which remains the standard of care. Cytotoxic chemotherapy has recognised immunomodulatory activity distinct from its antimitotic effects, including mechanisms such as immunogenic cell death (ICD) and induction/inhibition of key immune players. Response to chemotherapy may differ with regard to molecular subtype of CRC, which are strongly associated with immune phenotypes. Thus, immune markers are potentially useful, though under-reported, predictive biomarkers. In this review, we discuss the impact of the TIME on response to cytotoxic chemotherapy in CRC, with a focus on baseline immune markers, and associated genomic and transcriptomic signatures.

Cancer-associated fibroblasts (CAFs) in thyroid papillary carcinoma: molecular networks and interactions.

In 1989, Stephen Paget proposed the 'seed and soil' theory of cancer metastasis. This theory has led to previous researchers focusing on the role of a tumour as a cancer seed and antiangiogenesis agents as cancer soil fumigant; for the latter to be effective, it is important for them to be able to distinguish cancer cells from stromal cells. However, antiangiogenesis agents have not produced dramatic survival benefits in vivo. This may be related to their inability to destroy the supporting stroma that promote cancer cell growth. Therefore, in order to effectively arrest cancer cell growth for therapeutic purposes, a paradigm shift is required in our fundamental approach to decipher the molecular events and networks in the stromal environment that cancer cells can thrive and proliferate. The pathogenesis of cancer is a multidimensional process of pathological molecular and cellular pathways, influencing different stromal properties and achieving a mutually negotiated crosstalk between cancer cells and stromal cells. This review summarises the clinical presentation of current knowledge of classical papillary thyroid carcinoma (PTC), emerging molecular diagnostics and future directions of classical PTC research.

Aberrant Expression of RAD52, Its Prognostic Impact in Rectal Cancer and Association with Poor Survival of Patients.

The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and cancer survival and response to preoperative radiotherapy. RAD52 expression was examined in tumour samples from 179 patients who underwent surgery for rectal cancer, including a sub-cohort of 40 patients who were treated with neoadjuvant therapy. A high score for RAD52 expression in the tumour centre was significantly associated with worse disease-free survival (DFS; p = 0.045). In contrast, reduced RAD52 expression in tumour centre samples from patients treated with neoadjuvant therapy (n = 40) significantly correlated with poor DFS (p = 0.025) and overall survival (OS; p = 0.048). Our results suggested that RAD52 may have clinical value as a prognostic marker of tumour response to neoadjuvant radiation and both disease-free status and overall survival in patients with rectal cancer.

SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress.

Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated (ATM) are members of the PI3-kinase like-kinase (PIKK) family of proteins. ATM is a well-established tumour suppressor. Loss of one or both alleles of ATM results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm-/- Smg1gt/+ mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm-/- Smg1gt/+ mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.

Correlation of ultra-high field MRI with histopathology for evaluation of rectal cancer heterogeneity.

Current clinical MRI techniques in rectal cancer have limited ability to examine cancer stroma. The differentiation of tumour from desmoplasia or fibrous tissue remains a challenge. Standard MRI cannot differentiate stage T1 from T2 (invasion of muscularis propria) tumours. Diffusion tensor imaging (DTI) can probe tissue structure and organisation (anisotropy). The purpose of this study was to examine DTI-MRI derived imaging markers of rectal cancer stromal heterogeneity and tumour extent ex vivo. DTI-MRI at ultra-high magnetic field (11.7 tesla) was used to examine the stromal microstructure of malignant and normal rectal tissue ex vivo, and the findings were correlated with histopathology. Images obtained from DTI-MRI (A0, apparent diffusion coefficient and fractional anisotropy (FA)) were used to probe rectal cancer stromal heterogeneity. FA provided the best discrimination between cancer and desmoplasia, fibrous tissue and muscularis propria. Cancer had relatively isotropic diffusion (mean FA 0.14), whereas desmoplasia (FA 0.31) and fibrous tissue (FA 0.34) had anisotropic diffusion with significantly higher FA than cancer (p < 0.001). Tumour was distinguished from muscularis propria (FA 0.61) which was highly anisotropic with higher FA than cancer (p < 0.001). This study showed that DTI-MRI can assist in more accurately defining tumour extent in rectal cancer.

Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients.

Breast cancer is a heterogeneous disease displaying different histopathological characteristics, molecular profiling and clinical behavior. This study describes the expression patterns of senescence markers P53, DEC1 and DCR2 and assesses their significance on patient survival as a single or combined marker with P16 or P14 using breast cancer progression series. One thousand and eighty (1080) patients with primary invasive ductal carcinoma, no special type, were recruited through an 11-year retrospective study period. We constructed tissue microarrays of normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma from each patient and performed immunohistochemical staining to study the protein expression. Statistical analysis includes Pearson chi-square, Kaplan-Meier log ran test and Cox proportional hazard regression were undertaken to determine the associations and predict the survival outcomes. P53, DEC1 and DCR2 expression correlated significantly with normal, benign, premalignant and malignant tissues with (p<0.05). The expression profile of these genes increases from normal to benign to premalignant and plateaued from premalignant to malignant phenotype. There is a significant association between P53 protein expression and age, grade, staging, lymphovascular invasion, estrogen receptor, progesterone receptor and HER2 whereas DCR2 protein expression significantly correlated with tumour grade, hormone receptors status and HER2 (p<0.05 respectively). P53 overexpression correlated with increased risk of relapse (p = 0.002) specifically in patients who did not receive hormone therapy (p = 0.005) or chemotherapy (p<0.0001). The combination of P53+/P16+ is significantly correlated with poor overall and disease-free survival, whereas a combination of P53+/P14+ is associated with worse outcome in disease-free survival (p<0.05 respectively). P53 overexpression appears to be a univariate predictor of poor disease-free survival. The expression profiles of DEC1 and DCR2 do not appear to correlate with patient survival outcomes. The combination of P53 with P16, rather P53 expression alone, appears to provide more useful clinical information on patient survival outcomes in breast cancer.

MRN (MRE11-RAD50-NBS1) Complex in Human Cancer and Prognostic Implications in Colorectal Cancer.

The MRE11-RAD50-NBS1 (MRN) complex has been studied in multiple cancers. The identification of MRN complex mutations in mismatch repair (MMR)-defective cancers has sparked interest in its role in colorectal cancer (CRC). To date, there is evidence indicating a relationship of MRN expression with reduced progression-free survival, although the significance of the MRN complex in the clinical setting remains controversial. In this review, we present an overview of the function of the MRN complex, its role in cancer progression, and current evidence in colorectal cancer. The evidence indicates that the MRN complex has potential utilisation as a biomarker and as a putative treatment target to improve outcomes of colorectal cancer.

Overexpression of the MRE11-RAD50-NBS1 (MRN) complex in rectal cancer correlates with poor response to neoadjuvant radiotherapy and prognosis.

BACKGROUND: The MRE11/RAD50/NBS1 (MRN) complex plays an essential role in detecting and repairing double-stranded breaks, and thus the potential roles of MRE11, RAD50 and NBS1 proteins in the pathogenesis of various cancers is the subject of investigation. This study was aimed at assessing the three-protein panel of MRN complex subunits as a potential radiosensitivity marker and evaluating the prognostic and clinicopathological implications of MRN expression in rectal cancer. METHODS: Samples from 265 rectal cancer patients treated with surgery and adjuvant chemoradiotherapy, including samples from 55 patients who were treated with neoadjuvant radiotherapy between 2000 and 2011, were analyzed. Expression of MRN complex proteins in tissue samples was determined by immunohistochemistry. Univariate and multivariate analyses were carried out to identify clinicopathological characteristics that are associated with the MRN three-protein panel expression in rectal cancer samples. RESULTS: In Kaplan-Meier survival analyses, we found that high level expression of MRN complex proteins in postoperative samples was associated with poor disease-free (p = 0.021) and overall (P = 0.002) survival. Interestingly, high MRN expression also correlated with poor disease-free (P = 0.047) and overall (P = 0.024) survival in the neoadjuvant radiotherapy subgroup. In multivariate analysis, combined MRN expression (hazard ratio = 2.114, 95% confidence interval 1.096-4.078, P = 0.026) and perineural invasion (hazard ratio = 2.160, 95% confidence interval 1.209-3.859, P = 0.009) were significantly associated with a worse disease-free survival. CONCLUSIONS: Expression levels of MRN complex proteins significantly predict disease-free survival in rectal cancer patients, including those treated with neoadjuvant radiotherapy, and may have value in the management of these patients.