Genetic renal abnormalities

Inherited disorders of renal structure and function are relatively common causes of end-stage renal disease requiring renal replacement therapy. A family history of haematuria, urinary tract infection or renal failure can alert the clinician to the possible diagnosis of underlying renal genetic abnormalities. In practice, the commonest inherited renal disorder is autosomal dominant polycystic kidney disease (ADPKD), characterized by multiple kidney cysts associated with hypertension and renal failure. Insights into the cell biology of ADPKD are informing new therapeutic approaches to limit cyst growth and prevent progressive renal failure. Non-visible haematuria is a clinical finding that presents a diagnostic challenge because it has so many possible causes. Mutations in the genes encoding collagen proteins within the glomerular basement membrane (GBM) can disrupt its normal barrier function. Thin basement membrane nephropathy, caused by GBM collagen gene mutations, is a relatively common cause of familial haematuria that normally has a good long-term prognosis. Alport syndrome is a rare and genetically heterogeneous condition leading to renal failure in men inheriting the X-linked gene defect. Single-gene defects may cause diverse renal tubular disorders, such as predisposition to renal calculi, diabetes insipidus, renal tubular acidosis or hypertension with associated electrolyte imbalance. Gene mutations responsible for familial renal cancer syndromes, such as tuberous sclerosis complex and von Hippel–Lindau disease, have also been identified

What do men understand about lifetime risk following genetic testing?:The effect of context and numeracy.

Genetic testing for gene mutations associated with specific cancers provides an opportunity for early detection, surveillance, and intervention (Smith, Cokkinides, & Brawley, 2008). Lifetime risk estimates provided by genetic testing refer to the risk of developing a specific disease within one's lifetime, and evidence suggests that this is important for the medical choices people make, as well as their future family and financial plans. The present studies tested whether adult men understand the lifetime risks of prostate cancer informed by genetic testing. In 2 experiments, adult men were asked to interpret the lifetime risk information provided in statements about risks of prostate cancer. Statement format was manipulated such that the most appropriate interpretation of risk statements referred to an absolute risk of cancer in experiment 1 and a relative risk in experiment 2. Experiment 1 revealed that few men correctly interpreted the lifetime risks of cancer when these refer to an absolute risk of cancer, and numeracy levels positively predicted correct responding. The proportion of correct responses was greatly improved in experiment 2 when the most appropriate interpretation of risk statements referred instead to a relative rather than an absolute risk, and numeracy levels were less involved. Understanding of lifetime risk information is often poor because individuals incorrectly believe that these refer to relative rather than absolute risks of cancer.

Infection systems biology:from reactive to proactive (P4) medicine

This short review establishes the conceptual bases and discusses the principal aspects of P4-shorthand for predictive, preventive, personalized and participatory medicine-medicine, in the framework of infectious diseases. P4 medicine is a new way to approach medical care; instead of acting when the patient is sick, physicians will be able to detect early warnings of disease to take early action. Furthermore, people might even be able to adjust their lifestyles to prevent disease. P4 medicine is fuelled by systems approaches to disease, including methods for personalized genome sequencing and new computational techniques for building dynamic disease predictive networks from massive amounts of data from a variety of OMICs. An excellent example of the effectiveness of the P4 medicine approach is the change in cancer treatments. Emphasis is placed on early detection, followed by genotyping of the patient to use the most adequate treatment according to the genetic background. Cardiovascular diseases and perhaps even neurodegenerative disorders will be the next targets for P4 medicine. The application of P4 medicine to infectious diseases is still in its infancy, but is a promising field that will provide much benefit to both the patients and the health-care system.

Genetic association suggests that SMOC1 mediates between prenatal sex hormones and digit ratio

Men and women differ statistically in the relative lengths of their index and ring fingers; and the ratio of these lengths has been used as a biomarker for prenatal testosterone. The ratio has been correlated with a wide range of traits and conditions including prostate cancer, obesity, autism, ADHD, and sexual orientation. In a genome-wide association study of 979 healthy adults, we find that digit ratio is strongly associated with variation upstream of SMOC1 (rs4902759: P = 1.41 × 10(-8)) and a meta-analysis of this and an independent study shows a probability of P = 1.5 × 10(-11). The protein encoded by SMOC1 has recently been shown to play a critical role in limb development; its expression in prostate tissue is dependent on sex hormones, and it has been implicated in the sexually dimorphic development of the gonads. We put forward the hypothesis that SMOC1 provides a link between prenatal hormone exposure and digit ratio.

Positive aspects and challenges associated with caring for a dying relative at home

Research has consistently shown that family caregivers have a variety of unmet needs, despite comprehensive professional support for caregivers being a central aim of palliative care. This sub-study of a larger randomized controlled trial sought feedback from 47 primary family caregivers of advanced cancer patients who had recently commenced home palliative care. During semi-structured interviews in their homes, family caregivers were asked to comment on the key challenges associated with their role and whether they could identify challenges. These were associated with their own ill health, family circumstances, insufficient skills to manage patient symptoms, limited time for themselves and inadequate support from health professionals. Despite these challenges, 60% of family caregivers were readily able to identify positive aspects of the role. Previous research has tended to focus on the negative impact of caregiving. The extent to which the positive aspects buffer the negative aspects of the role warrants further exploration, as does the long-term impact of the caregiver role on those who are unable to recognize positive elements.

The experience of research participation for family caregivers of palliative care cancer patients

There have been concerns raised regarding the ethical merit of involving dying patients and family caregivers as research participants. This study sought feedback from 103 primary family caregivers who had participated in a longitudinal research project. Caregivers were sent a questionnaire regarding the benefits and negative aspects associated with participating in research while also supporting or having supported a relative dying of cancer. The study identified that almost three quarters (71.1%) of the 45 respondents reported benefits of being involved in research and the majority (88.9%) cited no negative aspects associated with research participation. Findings of the study suggest that it is pertinent to invite family caregivers to be involved in palliative care research. Moreover, this study demonstrated that not only is it probably safe for family caregivers to be involved in research but also that many participants actually derive benefits.

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk.

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10(-10)), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10(-10)) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10(-10)) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α

Transcription factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female Runx3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERa-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERa-dependent transactivation by reducing the stability of ERa. Consistent with its ability to regulate the levels of ERa, expression of RUNX3 inversely correlates with the expression of ERa in breast cancer cell lines, human breast cancer tissues and Runx3(+/-) mouse mammary tumors. By destabilizing ERa, RUNX3 acts as a novel tumor suppressor in breast cancer.

Combined genomic and phenotype screening reveals secretory factor SPINK1 as an invasion and survival factor associated with patient prognosis in breast cancer

Secretory factors that drive cancer progression are attractive immunotherapeutic targets. We used a whole-genome data-mining approach on multiple cohorts of breast tumours annotated for clinical outcomes to discover such factors. We identified Serine protease inhibitor Kazal-type 1 (SPINK1) to be associated with poor survival in estrogen receptor-positive (ER+) cases. Immunohistochemistry showed that SPINK1 was absent in normal breast, present in early and advanced tumours, and its expression correlated with poor survival in ER+ tumours. In ER- cases, the prognostic effect did not reach statistical significance. Forced expression and/or exposure to recombinant SPINK1 induced invasiveness without affecting cell proliferation. However, down-regulation of SPINK1 resulted in cell death. Further, SPINK1 overexpressing cells were resistant to drug-induced apoptosis due to reduced caspase-3 levels and high expression of Bcl2 and phospho-Bcl2 proteins. Intriguingly, these anti-apoptotic effects of SPINK1 were abrogated by mutations of its protease inhibition domain. Thus, SPINK1 affects multiple aggressive properties in breast cancer: survival, invasiveness and chemoresistance. Because SPINK1 effects are abrogated by neutralizing antibodies, we suggest that SPINK1 is a viable potential therapeutic target in breast cancer.

How does involvement of a hospice nurse specialist impact on the experience on informal caring in palliative care? Perspectives of middle-aged partners bereaved through cancer

The aim of this study was to retrospectively explore partners' understandings and experiences in relation to caring for a loved one with a terminal illness, with a particular focus on the role of the hospice nurse specialist (HNS). Participants were purposively sampled and recruited through HNS gatekeepers. Seven middle-aged, bereaved partners participated in semi-structured, qualitative interviews. The interviews were audio recorded and transcribed verbatim and data were analysed using thematic content analysis. Five main themes emerged regarding the impact of the HNS on informal caring: ‘the ambivalence of caring’, ‘the HNS as a “confidante” in caring’, ‘the HNS as a “champion” in support’, ‘the work of the HNS – an unseen benefit’ and ‘being prepared for death and bereavement’. Findings from this study offer new insights into how involvement of a HNS impacts on the ability of carers to perform their role as an informal caregiver. Results highlight a crucial need for carers to have a clear understanding of all aspects of the HNS role so that full benefit is derived from their input. Recruitment of experienced and knowledgeable nurses is paramount, but equally important for carers is the supportive aspect of the role for which nurses need to demonstrate excellent communication skills and an intuitive, caring approach.

Interfacing cellular networks of S. cerevisiae and E. coli: Connecting dynamic and genetic information

Background: In recent years, various types of cellular networks have penetrated biology and are nowadays used omnipresently for studying eukaryote and prokaryote organisms. Still, the relation and the biological overlap among phenomenological and inferential gene networks, e.g., between the protein interaction network and the gene regulatory network inferred from large-scale transcriptomic data, is largely unexplored.

Results: We provide in this study an in-depth analysis of the structural, functional and chromosomal relationship between a protein-protein network, a transcriptional regulatory network and an inferred gene regulatory network, for S. cerevisiae and E. coli. Further, we study global and local aspects of these networks and their biological information overlap by comparing, e.g., the functional co-occurrence of Gene Ontology terms by exploiting the available interaction structure among the genes.

Conclusions: Although the individual networks represent different levels of cellular interactions with global structural and functional dissimilarities, we observe crucial functions of their network interfaces for the assembly of protein complexes, proteolysis, transcription, translation, metabolic and regulatory interactions. Overall, our results shed light on the integrability of these networks and their interfacing biological processes.

Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells

Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy.

Description and predictors of hospital costs of oesophageal cancer during the first year following diagnosis in Northern Ireland

The cost-effectiveness of novel interventions in the treatment of cancer is well researched; however, relatively little attention is paid to the cost of many aspects of routine care. Oesophageal cancer is the ninth most common cancer in the UK and sixth most common cause of cancer death. It usually presents late and has a poor prognosis. The hospital costs incurred by oesophageal cancer patients diagnosed in Northern Ireland in 2005 (n = 198) were determined by review of medical records. The average cost of hospital care per patient in the 12 months from presentation was £7847. Variations in total hospital costs by age at diagnosis, gender, cancer stage, histological type, mortality at 1 year, co-morbidity count and socio-economic status were analysed using multiple regression analyses. Higher costs were associated with earlier stages of cancer and cancer stage remained a significant predictor of costs after controlling for cancer type, patient age and mortality at 1 year. Thus, although early detection of cancer usually improves survival, this would mean increased costs in the first year. Deprivation achieved borderline significance with those from more deprived areas having lower resource consumption relative to the more affluent. © 2013 John Wiley & Sons Ltd.

Identification and Validation of an Anthracycline/Cyclophosphamide–Based Chemotherapy Response Assay in Breast Cancer

Background: There is no method routinely used to predict response to anthracycline and cyclophosphamide–based chemotherapy in the clinic; therefore patients often receive treatment for breast cancer with no benefit. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA damage response (DDR) pathway occurs in approximately 25% of breast cancer patients through several mechanisms and results in sensitization to DNA-damaging agents. The aim of this study was to develop an assay to detect DDR-deficient tumors associated with loss of the FA/BRCA pathway, for the purpose of treatment selection.

Methods: DNA microarray data from 21 FA patients and 11 control subjects were analyzed to identify genetic processes associated with a deficiency in DDR. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples, and a molecular subgroup was identified that was defined by the molecular processes represented within FA patients. A 44-gene microarray-based assay (the DDR deficiency assay) was developed to prospectively identify this subgroup from formalin-fixed, paraffin-embedded samples. All statistical tests were two-sided.

Results: In a publicly available independent cohort of 203 patients, the assay predicted complete pathologic response vs residual disease after neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline, and cyclophosphamide) with an odds ratio of 3.96 (95% confidence interval [Cl] =1.67 to 9.41; P = .002). In a new independent cohort of 191 breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, a positive assay result predicted 5-year relapse-free survival with a hazard ratio of 0.37 (95% Cl = 0.15 to 0.88; P = .03) compared with the assay negative population.

Conclusions: A formalin-fixed, paraffin-embedded tissue-based assay has been developed and independently validated as a predictor of response and prognosis after anthracycline/cyclophosphamide–based chemotherapy in the neoadjuvant and adjuvant settings. These findings warrant further validation in a prospective clinical study.