Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma

Aims: Microglandular adenosis (MGA) is a rare breast lesion, which has long been considered to be hyperplastic. However, atypical forms of MGA (AMGA) and invasive carcinomas arising in the background of MGA are recorded. Recent studies have suggested that MGA may be a non‐obligate precursor of invasive carcinomas that are negative for hormone receptors and lack HER‐2 overexpression (triple‐negative phenotype). The aim of this study was to determine whether MGA is clonal and whether it harbours chromosomal aberrations similar to those found in matched invasive ductal carcinoma of no special type (IDC‐NST). Methods and results: We report on a case comprising MGA, AMGA and a high‐grade IDC‐NST. The three components were separately microdissected and subjected to genetic analysis with high‐resolution microarray comparative genomic hybridisation. Identical genetic changes were detected in all components with subsequent acquisition of additional genetic aberrations in the invasive component, suggesting that MGA was the substrate for the development of the invasive carcinoma. Immunohistochemistry revealed concordant profiles across all components, characterized by triple‐negative phenotype and variable positivity for basal markers. Conclusions: Similar to adenomas, MGA is, at least in some cases, a clonal lesion and may be a non‐obligate precursor of a subgroup of high‐grade triple‐negative and basal‐like breast carcinomas.     

Integrated Functional, Gene Expression and Genomic Analysis for the Identification of Cancer Targets

The majority of new drug approvals for cancer are based on existing therapeutic targets. One approach to the identification of novel targets is to perform high-throughput RNA interference (RNAi) cellular viability screens. We describe a novel approach combining RNAi screening in multiple cell lines with gene expression and genomic profiling to identify novel cancer targets. We performed parallel RNAi screens in multiple cancer cell lines to identify genes that are essential for viability in some cell lines but not others, suggesting that these genes constitute key drivers of cellular survival in specific cancer cells. This approach was verified by the identification of PIK3CA, silencing of which was selectively lethal to the MCF7 cell line, which harbours an activating oncogenic PIK3CA mutation. We combined our functional RNAi approach with gene expression and genomic analysis, allowing the identification of several novel kinases, including WEE1, that are essential for viability only in cell lines that have an elevated level of expression of this kinase. Furthermore, we identified a subset of breast tumours that highly express WEE1 suggesting that WEE1 could be a novel therapeutic target in breast cancer. In conclusion, this strategy represents a novel and effective strategy for the identification of functionally important therapeutic targets in cancer.     

A Clinicopathological Study of Adenocarcinoma in Situ of the Cervix. The Influence of Cervical HPV Infection and Other Factors, and the Role of Conservative Surgery

Adenocarcinoma in situ (ACIS) of the uterine cervix is an increasingly recognized disease. Thirty-seven cases were reviewed to determine the effect of HPV, marital status, parity, smoking habit and age on the topography and behaviour of this lesion. Using a commercial probe, 25% of 28 lesions tested were positive for HPV 16/18. The presence of HPV and a history of smoking appeared to exert no significant influence upon the topography and behaviour of ACIS. Nulliparity and a history of never being married was associated with a significant reduction in the incidence of coexisting CIN lesions. Age less than 36 years was associated with a significant reduction in the proximal linear extent of ACIS. While hysterectomy is probably the definitive treatment for ACIS of the cervix, there is an important place for conservative management by conization alone. Patients younger than 36 years are most likely to be desirous of retained fertility and appear to have the lesions most amenable to conservative surgery.     

A recurrent mutation in the loricrin gene underlies the ichthyotic variant of Vohwinkel syndrome

Vohwinkel syndrome (VS) is a family of genodermatoses which exhibits extensive clinical and genetic heterogeneity. Here, we studied a pedigree originating from the UK with typical features of the ichthyotic variant of VS and identified a recurrent insertion mutation in the loricrin gene resulting in a mutant polypeptide with an unusual C terminus. Functional studies in transgenic mice have shown that the accumulation of mutant loricrin in the nucleus appears to interfere with the later stages of epidermal differentiation, thereby explaining the clinical manifestations of ichthyosis, keratoderma and pseudoainhum. Our findings extend the body of evidence implicating mutations in the loricrin gene as the underlying cause of VS.     

Antioxidants and vitamins to reduce cardiovascular disease

Cardiovascular disease is the leading cause of morbidity and mortality in Western populations. Several lines of evidence support the role of oxidative stress in atherogenesis. Dietary micronutrients with antioxidant properties and vitamins have also been shown to have a benefit with regards to cardiovascular disease. The most persuasive evidence relates to alpha tocopherol and folate and vitamin B₁₂. Although the evidence is mounting for supplementation with alpha tocopherol and folate and B₁₂ for secondary prevention of cardiovascular disease, no clear consensus can be reached for primary prevention of cardiovascular disease. This will have to await results of ongoing clinical trials.