Supervision and culture: Meetings at thresholds

Counsellors are required to engage in supervision in order to reflect on, reflexively review, and extend their practice. Supervision, then, might be understood as a partnership in which the focus of practitioners and supervisors is on ethical and effective practice with all clients. In Aotearoa/New Zealand, there has recently been interest in the implications for supervision of cultural difference, particularly in terms of the Treaty of Waitangi as a practice metaphor, and when non-Māori practitioners counsel Māori clients. This article offers an account of a qualitative investigation by a group of counsellors/supervisors into their experiences of supervision as cultural partnership. Based on interviews and then using writing-as-research, the article explores the playing out of supervision’s contribution to practitioners’ effective and ethical practice in the context of Aotearoa/New Zealand, showing a range of possible accounts and strategies and discussing their effects. Employing the metaphor of threshold, the article includes a series of reflections and considerations for supervision practice when attention is drawn to difference

Should we consider introducing systematic screening for Lynch Syndrome?

Lynch Syndrome is characterised by the development of colorectal, endometrial and other cancers, often at a young age. It is caused by constitutional mutations of DNA mismatch repair genes and cancers that arise in this setting are mismatch repair deficient, as demonstrated by loss of the relevant mismatch repair protein and microsatellite instability. In theory, universal screening of all index colorectal cancers for mismatch repair deficient should identify individuals who are at higher than population risk of carrying a constitutional mutation in the mismatch repair genes. A health economic evaluation in the UK found that this type of screening strategy applied to individuals under the age of 51 years was highly cost effective. In Australia, some centres routinely test all colorectal cancer for mismatch repair deficient, however there is currently no systematic national approach to screening. Given the cost effectiveness of universal screening is dependent on uptake of constitutional testing by the index case and their relatives, we suggest that research into the determinants and barriers to uptake of constitutional testing is a high priority. Further, given that the health care context can influence the assessment of cost-effectiveness, we propose that the UK economic evaluation also needs to be undertaken in an Australian context

How can histopathologists help clinical genetics in the investigation of suspected hereditary gastrointestinal cancer?

Histopathologists are critical in the diagnosis of hereditary gastrointestinal tumours. This is increasingly important as genetic testing becomes more available and the benefits of anti-cancer surveillance in those at increased risk are realised. Cancer genetics services should include pathologists and be organised on multidisciplinary team lines. Hereditary cancer syndromes predispose to tumours throughout the GI tract. Lynch syndrome is the most prevalent hereditary GI cancer condition, responsible for ∼3.3% of all colorectal as well as other GI and extra-intestinal cancers. Tumour tests to diagnose Lynch syndrome are important in guiding genetic testing, and can be used systematically to screen cancers for the condition. Familial adenomatous polyposis and all the other forms of hereditary polyposis put together account for <1% of all colorectal cancer. However, the histological distinction of the various polyposes, including type, site and numbers of polyps is crucial in informing genetic testing

The NF1 somatic mutational landscape in sporadic human cancers

Abstract Background Neurofibromatosis type 1 (NF1: Online Mendelian Inheritance in Man (OMIM) #162200) is an autosomal dominantly inherited tumour predisposition syndrome. Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1. The major known function of the NF1 gene product neurofibromin is to downregulate RAS. NF1 exhibits variable clinical expression and is characterized by benign cutaneous lesions including neurofibromas and café-au-lait macules, as well as a predisposition to various types of malignancy, such as breast cancer and leukaemia. However, acquired somatic mutations in NF1 are also found in a wide variety of malignant neoplasms that are not associated with NF1. Main body Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context. Conclusion As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma. Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1. Somatic NF1 mutations may be critical drivers in multiple cancers. The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer. The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1

Consensus for genes to be included on cancer panel tests offered by UK genetics services: guidelines of the UK Cancer Genetics Group.

Genetic testing for hereditary cancer predisposition has evolved rapidly in recent years with the discovery of new genes, but there is much debate over the clinical utility of testing genes for which there are currently limited data regarding the degree of associated cancer risk. To address the discrepancies that have arisen in the provision of these tests across the UK, the UK Cancer Genetics Group facilitated a 1-day workshop with representation from the majority of National Health Service (NHS) clinical genetics services. Using a preworkshop survey followed by focused discussion of genes without prior majority agreement for inclusion, we achieved consensus for panels of cancer genes with sufficient evidence for clinical utility, to be adopted by all NHS genetics services. To support consistency in the delivery of these tests and advice given to families across the country, we also developed management proposals for individuals who are found to have pathogenic mutations in these genes. However, we fully acknowledge that the decision regarding what test is most appropriate for an individual family rests with the clinician, and will depend on factors including specific phenotypic features and the family structure

Position statement of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) on APC I1307K and cancer risk

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on the APC I1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of the APC I1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals

A genome-wide association study identifies protein quantitative trait loci (pQTLs)

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10 -57), CCL4L1 (p = 3.9×10-21), IL18 (p = 6.8×10-13), LPA (p = 4.4×10-10), GGT1 (p = 1.5×10-7), SHBG (p = 3.1×10-7), CRP (p = 6.4×10-6) and IL1RN (p = 7.3×10-6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10-40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways. © 2008 Melzer et al