KPNA2 protein expression in invasive breast carcinoma and matched peritumoral ductal carcinoma in situ

The aim of this study was to evaluate protein expression of Karyopherin alpha 2 (KPNA2) in invasive breast cancer and matched ductal carcinoma in situ (DCIS) and to correlate it with clinicopathological data, including patient survival. KPNA2 protein expression was assessed by immunohistochemistry in breast tissue samples, containing invasive carcinomas, DCIS, and adjacent histologically benign breast tissues. A polyclonal goat KPNA2 antibody was used for immunostaining of 83 clinicopathologically characterized cases. For statistical analysis, staining of at least 10% of nuclei was considered KPNA2 positive. Immunohistochemical detection of KPNA2 in invasive carcinoma showed a significant correlation with higher tumor stage, positive lymph node status, higher tumor grade, and negative ER status. Concordantly, KPNA2-positive tumors (31.3%) showed significantly shorter disease-free survival times (69months vs 118months; p = 0.007). KPNA2 protein expression was also detected in DCIS (21.3%) adjacent to invasive tumor and correlated with nuclear grade (p = 0.013). Expression of KPNA2 in invasive breast cancer correlates with conventional prognostic parameters and shorter disease-free survival. Additionally, KPNA2 is overexpressed in DCIS, particularly high grade lesions, which emphasizes its potential role in carcinogenesis of invasive breast carcinoma

KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer

Background: It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin a-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC.Methods: A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry.Results: KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, gammaH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P less than 0.0001), but this effect was not independent of other prognostic variables.Conclusions: This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers

Background: Although distant metastasis (DM) in breast cancer (BC) is the most lethal form of recurrence and the most commonunderlying cause of cancer related deaths, the outcome following the development of DM is related to the site of metastasis.Triple negative BC (TNBC) is an aggressive form of BC characterised by early recurrences and high mortality. Athough multiplevariables can be used to predict the risk of metastasis, few markers can predict the specific site of metastasis. This study aimed atidentifying a biomarker signature to predict particular sites of DM in TNBC.Methods: A clinically annotated series of 322 TNBC were immunohistochemically stained with 133 biomarkers relevant to BC, todevelop multibiomarker models for predicting metastasis to the bone, liver, lung and brain. Patients who experienced metastasisto each site were compared with those who did not, by gradually filtering the biomarker set via a two-tailed t-test and Coxunivariate analyses. Biomarker combinations were finally ranked based on statistical significance, and evaluated in multivariableanalyses.Results: Our final models were able to stratify TNBC patients into high risk groups that showed over 5, 6, 7 and 8 times higher riskof developing metastasis to the bone, liver, lung and brain, respectively, than low-risk subgroups. These models for predictingsite-specific metastasis retained significance following adjustment for tumour size, patient age and chemotherapy status.Conclusions: Our novel IHC-based biomarkers signatures, when assessed in primary TNBC tumours, enable prediction of specificsites of metastasis, and potentially unravel biomarkers previously unknown in site tropism

2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included