Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldINTRODUCTION: Germline mutations in the BRCA1 and BRCA2 genes account for a considerable fraction of familial predisposition to breast cancer. Somatic mutations in BRCA1 and BRCA2 have not been found and the involvement of these genes in sporadic tumour development therefore remains unclear. METHODS: The study group consisted of 67 primary breast tumours with and without BRCA1 or BRCA2 abnormalities. Genomic alterations were profiled by high-resolution (~7 kbp) comparative genome hybridisation (CGH) microarrays. Tumour phenotypes were analysed by immunohistochemistry on tissue microarrays using selected biomarkers (ER, PR, HER-2, EGFR, CK5/6, CK8, CK18). RESULTS: Classification of genomic profiles through cluster analysis revealed four subgroups, three of which displayed high genomic instability indices (GII). Two of these GII-high subgroups were enriched with either BRCA1- or BRCA2-related tumours whereas the third was not BRCA-related. The BRCA1-related subgroup mostly displayed non-luminal phenotypes, of which basal-like were most prominent, whereas the other two genomic instability subgroups BRCA2- and GII-high-III (non-BRCA), were almost entirely of luminal phenotype. Analysis of genome architecture patterns revealed similarities between the BRCA1- and BRCA2 subgroups, with long deletions being prominent. This contrasts with the third instability subgroup, not BRCA-related, where small gains were more prominent. CONCLUSIONS: The results suggest that BRCA1- and BRCA2-related tumours develop largely through distinct genetic pathways in terms of the regions altered while also displaying distinct phenotypes. Importantly, we show that the development of a subset of sporadic tumours is similar to that of either familial BRCA1- or BRCA2 tumours. Despite their differences, we observed clear similarities between the BRCA1- and BRCA2-related subgroups reflected in the type of genomic alterations acquired with deletions of long DNA segments being prominent. This suggests similarities in the mechanisms promoting genomic instability for BRCA1- and BRCA2-associated tumours, possibly relating to deficiency in DNA repair through homologous recombination. Indeed, this feature characterized both familial and sporadic tumours displaying BRCA1- or BRCA2-like spectrums of genomic alterations. The importance of these findings lies in the potential benefit from targeted therapy, through the use of agents leading to DNA double-strand breaks such as PARP inhibitors (olaparib) and cisplatin, for a much larger group of patients than the few BRCA1 and BRCA2 germline mutation carriers

CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesDNA repair of alkylation damage is defective in various cancers. This occurs through somatically acquired inactivation of the MGMT gene in various cancer types, including breast cancers. In addition to MGMT, the two E. coli AlkB homologs ALKBH2 and ALKBH3 have also been linked to direct reversal of alkylation damage. However, it is currently unknown whether ALKBH2 or ALKBH3 are found inactivated in cancer.Methylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation. TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3. DNA methylation analysis for the ALKBH3 promoter region was carried out by pyrosequencing (PyroMark Q24) in 265 primary breast tumours and 30 proximal normal breast tissue samples along with 8 breast-derived cell lines. ALKBH3 mRNA and protein expression were analysed in cell lines using RT-PCR and Western blotting, respectively. DNA alkylation damage assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical parameters and survival outcomes in patients were obtained and assessed in relation to ALKBH3 promoter methylation.The ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer. We developed a quantitative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels of alkylation damage in association with epigenetic inactivation of the ALKBH3 gene (P = 0.029). In our cohort of 265 primary breast cancer, we found 72 cases showing aberrantly high CpG promoter methylation over the ALKBH3 promoter (27%; 72 out of 265). We further show that increasingly higher degree of ALKBH3 promoter methylation is associated with reduced breast-cancer specific survival times in patients. In this analysis, ALKBH3 promoter methylation at >20% CpG methylation was found to be statistically significantly associated with reduced survival (HR = 2.3; P = 0.012). By thresholding at the clinically relevant CpG methylation level (>20%), we find the incidence of ALKBH3 promoter methylation to be 5% (13 out of 265).ALKBH3 is a novel addition to the catalogue of DNA repair genes found inactivated in breast cancer. Our results underscore a link between defective alkylation repair and breast cancer which, additionally, is found in association with poor disease outcome.Icelandic Centre for Researc

Automated Cancer Diagnostics via Analysis of Optical and Chemical Images by Deep and Shallow Learning

Funding Information: The Icelandic Centre for Research, grant no. 174566051 & 207301. The Icelandic Breast Cancer Research Fund, Göngum Saman. CRUK GC, NIHR/Imperial BRC. Dr Jean Alero Thomas Scholarship. Funding Information: Funding: The Icelandic Centre for Research, grant no. 174566051 & 207301. The Icelandic Breast Cancer Research Fund, Göngum Saman. CRUK GC, NIHR/Imperial BRC. Dr Jean Alero Thomas Scholarship. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Optical microscopy has long been the gold standard to analyse tissue samples for the diagnostics of various diseases, such as cancer. The current diagnostic workflow is time-consuming and labour-intensive, and manual annotation by a qualified pathologist is needed. With the ever-increasing number of tissue blocks and the complexity of molecular diagnostics, new approaches have been developed as complimentary or alternative solutions for the current workflow, such as digital pathology and mass spectrometry imaging (MSI). This study compares the performance of a digital pathology workflow using deep learning for tissue recognition and an MSI approach utilising shallow learning to annotate formalin-fixed and paraffin-embedded (FFPE) breast cancer tissue microarrays (TMAs). Results show that both deep learning algorithms based on conventional optical images and MSI-based shallow learning can provide automated diagnostics with F1-scores higher than 90%, with the latter intrinsically built on biochemical information that can be used for further analysis.Peer reviewe

CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer

Triple-negative breast cancer (TNBC) occurs in approximately 15% of all breast cancer patients, and the incidence of TNBC is greatly increased in BRCA1 mutation carriers. This study aimed to assess the impact of BRCA1 promoter methylation with respect to breast cancer subtypes in sporadic disease. Tissue microarrays (TMAs) were constructed representing tumors from 303 patients previously screened for BRCA1 germline mutations, of which a subset of 111 sporadic tumors had previously been analyzed with respect to BRCA1 methylation. Additionally, a set of eight tumors from BRCA1 mutation carriers were included on the TMAs. Expression analysis was performed on TMAs by immunohistochemistry (IHC) for BRCA1, pRb, p16, p53, PTEN, ER, PR, HER2, CK5/6, CK8, CK18, EGFR, MUC1, and Ki-67. Data on BRCA1 aberrations and IHC expression was examined with respect to breast cancer-specific survival. The results demonstrate that CpG island hypermethylation of BRCA1 significantly associates with the basal/triple-negative subtype. Low expression of pRb, and high/intense p16, were associated with BRCA1 promoter hypermethylation, and the same effects were seen in BRCA1 mutated tumors. The expression patterns of BRCA1, pRb, p16 and PTEN were highly correlated, and define a subgroup of TNBCs characterized by BRCA1 aberrations, high Ki-67 (≥ 40%) and favorable disease outcome. In conclusion, our findings demonstrate that epigenetic inactivation of the BRCA1 gene associates with RB/p16 dysfunction in promoting TNBCs. The clinical implications relate to the potential use of targeted treatment based on PARP inhibitors in sporadic TNBCs, wherein CpG island hypermethylation of BRCA1 represents a potential marker of therapeutic response

Idiosyncratic drug-induced liver injury associated with bile duct loss and vanishing bile duct syndrome: Rare but has severe consequences.

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Etiology and management of esophageal food impaction: a population based study.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageEsophageal food impaction (FI) is a common clinical problem with limited information on incidence. Previous population based studies are lacking. The incidence, main etiological factors, recurrence and outcome of FI was determined in the present study in a population based setting.This was a study of consecutive adult patients who presented with FI from 2008 to 2013 at the National University Hospital of Iceland. The mean crude incidence rate of FI was calculated. Retrospective analysis was undertaken on relevant clinical data such as type of bolus, management, complications, recurrence rate, risk factors for recurrence, and outcome.Overall 308 patients had endoscopically confirmed FI, males 199/308 (65%), median age 62 years. The mean crude incidence was 25 per 100,000 inhabitants per year. The types of FI was meat (68%), fish (12%), vegetable (4%) and other food/objects (16%). Causes for the FI included: esophageal strictures (45%), hiatal hernia (22%), eosinophilic esophagitis (EoE) (16%) and esophageal carcinoma (2%). Recurrence appeared in 21%, in which 24/48 (50%) had EoE vs. 40/260 (15%) in others (p = 0.0001). The removal of the foreign body was successful in 98% of the cases during the first endoscopy. Endoscopic associated complications included four (1.3%) aspirations, one (0.3%) esophageal perforation and one Boerhaave syndrome at presentation (both had EoE).The incidence of FI is the highest reported to date. EoE was strongly associated with recurrence of FI. In a population based setting endoscopy is a safe and effective procedure for removing FI

Salivary gland tumours in Iceland 1986-2015: a nationwide epidemiological analysis over a 30-year time period.

To access publisher's full text version of this article click on the hyperlink belowSalivary gland tumours (SGT) are a vast and heterogenous group of neoplasms. There is a relative lack of comprehensive nationwide epidemiological studies on the subject. The aim of this nationwide analysis was to gain insight into epidemiological traits, such as site, incidence and histological subtypes of SGT in general. Patients diagnosed with a primary SGT between 1986 and 2015 were identified from The Icelandic Cancer Registry and registries from all pathology departments in Iceland. Information on age, sex, tumour location and histology was retrieved from pathology reports. A total of 687 patients were diagnosed with a SGT, 609 (89%) were benign and 78 (11%) malignant. 9% of parotid gland tumours, 22% of submandibular gland tumours and 26% of minor SGT were malignant. The most common malignant tumours were mucoepidermoid carcinoma, acinic cell carcinoma and adenoid cystic carcinoma. The incidence of benign SGT was 4.9 per 100 000 among men and 7.0 per 100 000 among women. The incidence of malignant tumours was 0.59 per 100 000 for men and 0.79 per 100 000 for women. The proportion of malignant SGT is lower than most often reported. Only 10% of parotid gland tumours, 20% of submandibular gland tumours and 25% of minor salivary gland tumours are malignant. Keywords: Salivary gland; epidemiology; histology; oncology; tumour