Prognostic Values of Gene Copy Number Alterations in Prostate Cancer.

Whilst risk prediction for individual prostate cancer (PCa) cases is of a high priority, the current risk stratification indices for PCa management have severe limitations. This study aimed to identify gene copy number alterations (CNAs) with prognostic values and to determine if any combination of gene CNAs could have risk stratification potentials. Clinical and genomic data of 500 PCa cases from the Cancer Genome Atlas stable were retrieved from the Genomic Data Commons and cBioPortal databases. The CNA statuses of a total of 52 genetic markers, including 21 novel markers and 31 previously identified potential prognostic markers, were tested for prognostic significance. The CNA statuses of a total of 51/52 genetic markers were significantly associated with advanced disease at an odds ratio threshold of ≥1.5 or ≤0.667. Moreover, a Kaplan-Meier test identified 27/52 marker CNAs which correlated with disease progression. A Cox Regression analysis showed that the amplification of MIR602 and deletions of MIR602, ZNF267, MROH1, PARP8, and HCN1 correlated with a progression-free survival independent of the disease stage and Gleason prognostic group grade. Furthermore, a binary logistic regression analysis identified twenty-two panels of markers with risk stratification potentials. The best model of 7/52 genetic CNAs, which included the SPOP alteration, SPP1 alteration, CCND1 amplification, PTEN deletion, CDKN1B deletion, PARP8 deletion, and NKX3.1 deletion, stratified the PCa cases into a localised and advanced disease with an accuracy of 70.0%, sensitivity of 85.4%, specificity of 44.9%, positive predictive value of 71.67%, and negative predictive value of 65.35%. This study validated prognostic gene level CNAs identified in previous studies, as well as identified new genetic markers with CNAs that could potentially impact risk stratification in PCa.

Chromosome-specific segment size alterations are determinants of prognosis in prostate cancer.

Currently, risk stratification is the most difficult problem in prostate cancer (PCa) management. Gleason grading cannot adequately predict cancer progression. This study aimed to identify chromosome-specific segment size alterations that could aid risk stratification and predict metastasis using a retrospective cohort-study strategy. A binary logistic regression model was generated using 16 chromosome-specific segments with size alterations (deletions and amplifications) that showed associations with disease stage (primary versus metastatic). The regression model was trained with the MSKCC PIK3R1 PCa cohort (n = 1417), and validated with the TCGA Firehose Legacy (n = 500), MSKCC Prostate Oncogenome Project (n = 218), and the SU2C/PCF Dream Team (n = 150) PCa cohorts. Furthermore, the capacity of the model to predict metastasis between primary tumours with metastasis (n = 54) and primary tumours without metastasis (n = 54) was tested. The accuracy, sensitivity, and specificity of the model at disease stage stratification ranged from 69.02% to 88.55%, 72.8% to 86.00% and 66.30% to 89.50%, respectively. The model also showed good performance at metastasis prediction with accuracy, sensitivity, and specificity of 57.41%, 62.96% and 51.85%, respectively. The study conclusion was that chromosome-specific segment size alterations can aid risk stratification and metastasis prediction. The significance of the study findings is that in combinations with clinical, biochemical, and histopathological variables, chromosome-specific alterations could improve current risk stratification and prediction models for PCa.

Targeted Next-Generation Sequencing Validates the Use of Diagnostic Biopsies as a Suitable Alternative to Resection Material for Mutation Screening in Colorectal Cancer.

BACKGROUND: Mutation testing in the context of neoadjuvant therapy must be performed on biopsy samples. Given the issue of tumour heterogeneity, this raises the question of whether the biopsies are representative of the whole tumour. Here we have compared the mutation profiles of colorectal biopsies with their matched resection specimens. METHODS: We performed next-generation sequencing (NGS) analysis on 25 paired formalin-fixed, paraffin-embedded colorectal cancer biopsy and primary resection samples. DNA was extracted and analysed using the TruSight tumour kit, allowing the interrogation of 26 cancer driver genes. Samples were run on an Illumina MiSeq. Mutations were validated using quick-multiplex-consensus (QMC)-polymerase chain reaction (PCR) in conjunction with high resolution melting (HRM). The paired biopsy and resection tumour samples were assessed for presence or absence of mutations, mutant allele frequency ratios, and allelic imbalance status. RESULTS: A total of 81 mutations were detected, in ten of the 26 genes in the TruSight kit. Two of the 25 paired cases were wild-type across all genes. The mutational profiles, allelic imbalance status, and mutant allele frequency ratios of the paired biopsy and resection samples were highly concordant (88.75-98.85%), with all but three (3.7%) of the mutations identified in the resection specimens also being present in the biopsy specimens. All 81 mutations were confirmed by QMC-PCR and HRM analysis, although four low-level mutations required a co-amplification at lower denaturation temperature (COLD)-PCR protocol to enrich for the mutant alleles. CONCLUSIONS: Diagnostic biopsies are adequate and reliable materials for molecular testing by NGS. The use of biopsies for molecular screening will enhance targeted neoadjuvant therapy.

Blood cellular markers of inflammation in Breast Cancer and response to Neoadjuvant Chemotherapy

Background:Breast cancer is the most common female malignancy in Nigeria. Neoadjuvant chemotherapy is the first line treatment for locally advanced breast cancer. The advancement of many cancers is accompanied by inflammation, and inflammatory cells play an essential role in the progression.Objective:To determine if haematological parameters can predict the responsiveness of breast cancer to neoadjuvant chemotherapy regime.Method:A prospective cohort study of all breast cancer patients who had neoadjuvant chemotherapy betweenJuly 2017 andDecember 2018was carried out. Haematological parameters of red cell count (RCC), white cell count(WCC), neutrophil count (NC), lymphocyte count (LC), platelet count (PC), red cell distribution width (RCDW), mean platelet volume (MPV), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were measured. Response to chemotherapy was assessed by measuring the longest diameter of the lump and largest lymph node and applying the UICC criteria.Results: Thirty-five females with breast cancer with the age range of 33-82 years and mean age of 48± 11yearswere studied. The overall clinical response rate was 80% consisting of 40% complete clinical response, 40% partial clinical response, 8.6% stable disease and 11.4% progressive disease. Eleven (78.6%) with PLR values below average had good clinical response while 21.4% of those with PLR value above average had a good clinical response(χ2= 8.4, p =0.006)Conclusion: The study showed that PLR is associated with complete clinical response to neoadjuvant chemotherapy and should be used as part of routine assessment before chemotherapy

N_LyST: a simple and rapid screening test for Lynch syndrome.

AIMS: We sought to use PCR followed by high-resolution melting analysis to develop a single closed-tube screening panel to screen for Lynch syndrome. This comprises tests for microsatellite instability (MSI), MLH1 methylation promoter and BRAF mutation. METHODS: For MSI testing, five mononucleotide markers (BAT25, BAT26, BCAT25, MYB, EWSR1) were developed. In addition, primers were designed to interrogate Region C of the MLH1 promoter for methylation (using bisulphite-modified DNA) and to test for mutations in codon 600 of BRAF. Two separate cohorts from Nottingham (n=99, 46 with MSI, 53 being microsatellite stable (MSS)) and Edinburgh (n=88, 45 MSI, 43 MSS) were tested. RESULTS: All the cases (n=187) were blind tested for MSI and all were correctly characterised by our panel. The MLH1 promoter and BRAF were tested only in the Nottingham cohort. Successful blinded analysis was performed on the MLH1 promoter in 97 cases. All MSS cases showed a pattern of non-methylation while 41/44 cases with MSI showed full methylation. The three cases with MSI and a non-methylated pattern had aberrations in MSH2 and MSH6 expression. BRAF mutation was detected in 61% of MSI cases and 11% of MSS cases.Finally, 12 cases were blind screened by using the whole panel as a single test. Of these, five were identified as MSS, four as MSI/non-LS and three as MSI/possible LS. These results were concordant with the previous data. CONCLUSION: We describe the Nottingham Lynch Syndrome Test (N_LyST). This is a quick, simple and cheap method for screening for Lynch syndrome.

Checkpoint Kinase 1 Expression Predicts Poor Prognosis in Nigerian Breast Cancer Patients.

BACKGROUND: Checkpoint kinase 1 (CHEK1), a DNA damage sensor and cell death pathway stimulator, is regarded as an oncogene in tumours, where its activities are considered essential for tumourigenesis and the survival of cancer cells treated with chemotherapy and radiotherapy. In breast cancer, CHEK1 expression has been associated with an aggressive tumour phenotype, the triple-negative breast cancer subtype, an aberrant response to tamoxifen, and poor prognosis. However, the relevance of CHEK1 expression has, hitherto, not been investigated in an indigenous African population. We therefore aimed to investigate the clinicopathological, biological, and prognostic significance of CHEK1 expression in a cohort of Nigerian breast cancer cases. MATERIAL AND METHODS: Tissue microarrays of 207 Nigerian breast cancer cases were tested for CHEK1 expression using immunohistochemistry. The clinicopathological, molecular, and prognostic characteristics of CHEK1-positive tumours were determined using the Chi-squared test and Kaplan-Meier and Cox regression analyses in SPSS Version 16. RESULTS: Nuclear expression of CHEK1 was present in 61% of breast tumours and was associated with tumour size, triple-negative cancer, basal-like phenotype, the epithelial-mesenchymal transition, p53 over-expression, DNA homologous repair pathway dysfunction, and poor prognosis. CONCLUSIONS: The rate expression of CHEK1 is high in Nigerian breast cancer cases and is associated with an aggressive phenotype and poor prognosis.

Spectrum and prevalence of thyroid diseases seen at a tertiary health facility in Sagamu, South-West Nigeria.

BACKGROUND: The prevalence of goitrous swelling has reduced in Nigeria since the introduction of salt iodisation programme. Thyroid disorders are the second most common endocrine disorder after diabetes mellitus worldwide. They present to general outpatient, medical and surgical clinics accompanied by great anxiety and poor health-related quality of life. OBJECTIVES: The study aimed to determine and describe the spectrum of thyroid disorders seen at Olabisi Onabanjo University Teaching Hospital over a 10-year period. MATERIALS AND METHODS: This was a retrospective analysis of records of patients who presented to the hospital with thyroid swellings over a 10-year period (June 2004 to June 2014). Clinicopathological and demographic data obtained from hospital records in 175 patients diagnosed by clinical examination, thyroid ultrasound, hormone profile and histological confirmation in cases that had surgery were analysed for this study. RESULTS: The records of 175 patients were obtained comprising 151 (86.3%) females and 24 (13.7%) males (female to male ratio of 6.3:1) with age range from 18 to 76 years and mean age of 42.3 years, standard deviation 13.5. With clinical diagnosis, distribution of thyroid diseases was simple goitre 103 (58.9%), toxic goitre 64 (36.6%), hypothyroidism 3 (1.7%), malignant goitre 4 (2.3%) and thyroiditis 1 (0.6%). The age group of 30-49 years had the highest prevalence of the thyroid diseases 100 (57.2%) while the extremes of age, below 20 and over 70 years had the least (5.1 and 2.9%, respectively). CONCLUSION: The prevalent form of thyroid diseases seen at Olabisi Onabanjo University Teaching Hospital was simple goitre and most common in females. Studies on autoimmunity and other goitrogens are required to further elucidate the cause of this high prevalence.

Clinicopathological features of gastric carcinoma in Ibadan, Nigeria, 2000-2011.

AIM: The most recent study on the clinicopathological features of gastric carcinoma from the University College Hospital (UCH), Ibadan, was done in 2000. The aim of this study is to update the knowledge on the clinicopathological features of gastric carcinoma diagnosed in the Pathology Department of the UCH Ibadan between 2000 and 2011. MATERIALS AND METHODS: This was a 12-year retrospective review of clinical and demographic data and the histopathological features of gastric cancers diagnosed at the Pathology Department of the UCH. The chi square test, Fisher's exact test, and the t-independent test were used as applicable in the statistical analyses. RESULTS: A total of 117 cases of gastric carcinoma were histologically diagnosed at the Pathology Department of UCH, Ibadan in this period giving a relative ratio frequency of 1.38% for all cancers. It represented 18.4% of all gastrointestinal tract malignancies diagnosed in the same period. There was a male preponderance with male:female ratio of 1.72:1; the middle-aged and elderly made up about 76.1% of cases. The disease was clinically and histologically advanced in 92.8% of cases. Gastric tumours were predominantly antral/ pyloric in 80% of cases and exophytic in 62.3% of cases. The intestinal histotype constituted 47.0% cases although a rise in the diffuse histological type was observed. CONCLUSION: There is a decline in the relative ratio frequency of gastric carcinoma in Ibadan; and a fall in the rate of the intestinal type of gastric carcinoma relative to the diffuse type when compared to previous studies from our centre.