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

Aims Increased expression of senescence markers p14ARF and p16INK4a in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome

Breast cancer is a hormonally driven disease. Cellular senescence is an age‐related irreversible cell cycle arrest at the G1 phase upon induction. The aim of this study was to characterize the expression patterns of the senescence markers p14ARF, p16INK4a and p21WAF1/Cip1 during breast cancer progression in a large patient cohort. Methods and results: We conducted a retrospective study of 1080 patients with invasive ductal carcinoma, no special type, over an 11‐year period. We performed immunohistochemical staining on tissue microarrays that included normal, benign hyperplasia, ductal carcinoma in situand invasive ductal carcinoma tissue from each patient. Invasive ductal carcinomas showed higher expression of p14ARF and p16INK4a but lower expression of p21WAF1/Cip1than non‐malignant tissues. There were significant correlations of normal, benign, preinvasive and malignant tissues with p14ARF, p16INK4a and p21WAF1/Cip1 expression (P < 0.05). Univariate comparison showed a correlation between high p16INK4a expression and poor survival (P = 0.000) and an increased risk of relapse (P = 0.000), whereas high p14ARF expression correlated only with an increased risk of relapse (P = 0.038). Multivariate analysis showed p16INK4a to be an important prognostic factor for overall survival (P = 0.011) and disease‐free survival (P = 0.004), with p14ARF also being a significant prognostic factor for disease‐free survival (P = 0.043). Moreover, patients showing both high p16INK4a expression and and high p14ARF expression had an adjusted three‐fold increased risk of disease recurrence (P < 0.05) and a two‐fold increased risk of all‐cause‐related death (P < 0.05). Conclusions: These finding suggest p16INK4a expression and p14ARF expression may play an important role in the progression of proliferative breast tissue to invasive cancer, and may be useful as prognostic factor

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

Ultra-high field MRI for evaluation of rectal cancer stroma ex vivo : correlation with histopathology

Purpose or Objective: Current clinical MRI techniques in rectal cancer are unable to differentiate Stage T1 from T2 (invasion of muscularis propria) tumours, and the differentiation of tumour from desmoplastic reaction or fibrous tissue remains a challenge1. Diffusion tensor imaging (DTI) MRI has potential to assess collagen structure and organisation (anisotropy). To our knowledge, there have been no MRI studies assessing DTI MRI for rectal cancer ex vivo. The purpose of this study was to examine DTI MRI derived biomarkers of rectal cancer stromal heterogeneity at high field strength ex vivo

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

Prognostic impact of TP53 mutations and tumor mutational load in colorectal cancer

The DNA damage response (DDR) is critical for maintaining genome stability, and abnormal DDR—resulting from mutations in DNA damage-sensing and repair proteins—is a hallmark of cancer. Here, we aimed to investigate the predictive power of DDR gene mutations and the tumor mutational load (TML) for survival outcomes in a cohort of 22 rectal cancer patients who received pre-operative neoadjuvant therapy. Univariate analysis revealed that TML-high and TP53 mutations were significantly associated with worse overall survival (OS) with TML-high retaining significance in multivariate analyses. Kaplan–Meier survival analyses further showed TML-high was associated with worse disease-free (p = 0.036) and OS (p = 0.024) results in our patient cohort. A total of 53 somatic mutations were identified in 22 samples with eight (36%) containing mutations in DDR genes, including ATM, ATR, CHEK2, MRE11A, RAD50, NBN, ERCC2 and TP53. TP53 was the most frequently mutated gene, and TP53 mutations were significantly associated with worse OS (p = 0.023) in Kaplan–Meier survival analyses. Thus, our data indicate that TML and TP53 mutations have prognostic value for rectal cancer patients and may be important independent biomarkers for patient management. This suggests that prognostic determination for rectal cancer patients receiving pre-operative neoadjuvant therapy should include consideration of the initial TML and tumor genetic status

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Breast cancer pathology

Focuses on breast cancer pathology. Progress made by the biologists in the field of tumor biology; Elucidation of cell signaling pathways that has improved the understanding of the stromal epithelial interaction in some types of breast cancers; View that clarification of the concept of flat epithelial atypia has contributed further to the understanding of the early development of ductal carcinoma

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

Gastrointestinal pathology : recent developments and concepts

Editorial: This issue of the Journal of Clinical Pathology comprises a series of review articles on some of the latest developments in gastrointestinal pathology