Linkage to chromosome 2q32.2-q33.3 in familial serrated neoplasia (Jass syndrome)

Abstract Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.

CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb. Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC and MCC, we wished to determine if this was also the case in MCC. Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and 1 on 9q. No loss of heterozygosity (LOH) was seen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p. Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined. Half of all informative cases had LOH at D9S168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168. A second region (IFNA-D9S126) showed LOH in 10 (44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all 11 tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p14(ARF) antibody. These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus.

Evidence for three tumor suppressor loci on chromosome 9p involved in melanoma development

Cytogenetic and loss of heterozygosity (LOH) studies have long indicated the presence of a tumor suppressor gene (TSG) on 9p involved in the development of melanoma. Although LOH at 9p has been reported in approximately 60% of melanoma tumors, only 5-10% of these tumors have been shown to carry CDKN2A mutations, raising the possibility that another TSG involved in melanoma maps to chromosome 9p. To investigate this possibility, a panel of 37 melanomas derived from 35 individuals was analyzed for CDKN2A mutations by single-strand conformation polymorphism analysis and sequencing. The melanoma samples were then typed for 15 markers that map to 9p13-24 to investigate LOH trends in this region. In those tumors demonstrating retention of heterozygosity at markers flanking CDKN2A and LOH on one or both sides of the gene, multiplex microsatellite PCR was performed to rule out homozygous deletion of the region encompassing CDKN2A. CDKN2A mutations were found in tumors from 5 patients [5 (14%) of 35], 4 of which demonstrated LOH across the entire region examined. The remaining tumor with no observed LOH carried two point mutations, one on each allele. Although LOH was identified at one or more markers in 22 (59%) of 37 melanoma tumors corresponding to 20 (57%) of 35 individuals, only 11 tumors from 9 individuals [9 (26%) of 35] demonstrated LOH at D9S942 and D9S1748 the markers closest to CDKN2A. Of the remaining 11 tumors with LOH 9 demonstrated LOH at two or more contiguous markers either centromeric and/or telomeric to CDKN2A while retaining heterozygosity at several markers adjacent to CDKN2A. Multiplex PCR revealed one tumor carried a homozygous deletion extending from D9S1748 to the IFN-alpha locus. In the remaining eight tumors, multiplex PCR demonstrated that the observed heterozygosity was not attributable to homozygous deletion and stromal contamination at D9S1748, D9S942, or D9S974, as measured by comparative amplification strengths, which indicates that retention of heterozygosity with flanking LOH does not always indicate a homozygous deletion. This report supports the conclusions of previous studies that a least two TSGs involved in melanoma development in addition to CDKN2A may reside on chromosome 9p.

Mathematics funds of knowledge : sotmaute and sermaute fish in a Torres Strait Islander community

The purpose of this article is to describe a project with one Torres Strait Islander Community. It provides some insights into parents’ funds of knowledge that are mathematical in nature, such as sorting shells and giving fish. The idea of funds of knowledge is based on the premise that people are competent and have knowledge that has been historically and culturally accumulated into a body of knowledge and skills essential for their functioning and well-being. This knowledge is then practised throughout their lives and passed onto the next generation of children. Through adopting a community research approach, funds of knowledge that can be used to validate the community’s identities as knowledgeable people, can also be used as foundations for future learnings for teachers, parents and children in the early years of school. They can be the bridge that joins a community’s funds of knowledge with schools validating that knowledge.

Statistical phylogeographic tests of competing 'Lake Carpentaria hypotheses' in the mouth-brooding freshwater fish, Glossamia aprion (Apogonidae)

Glacial cycles during the Pleistocene reduced sea levels and created new land connections in northern Australia, where many currently isolated rivers also became connected via an extensive paleo-lake system, 'Lake Carpentaria'. However, the most recent period during which populations of freshwater species were connected by gene flow across Lake Carpentaria is debated: various 'Lake Carpentaria hypotheses' have been proposed. Here, we used a statistical phylogeographic approach to assess the timing of past population connectivity across the Carpentaria region in the obligate freshwater fish, Glossamia aprion. Results for this species indicate that the most recent period of genetic exchange across the Carpentaria region coincided with the mid- to late Pleistocene, a result shown previously for other freshwater and diadromous species. Based on these findings and published studies for various freshwater, diadromous and marine species, we propose a set of 'Lake Carpentaria' hypotheses to explain past population connectivity in aquatic species: (1) strictly freshwater species had widespread gene flow in the mid- to late Pleistocene before the last glacial maximum; (2) marine species were subdivided into eastern and western populations by land during Pleistocene glacial phases; and (3) past connectivity in diadromous species reflects the relative strength of their marine affinity.

The developmental consequences of rare chromosome disorders : two case reports

Aim: As molecular and cytogenetic testing becomes increasingly sophisticated, more individuals are being diagnosed with rare chromosome disorders. Yet despite a burgeoning knowledge about biomedical aspects, little is known about implications for psychosocial development. The scant literature gives a general impression of deficits and adverse developmental outcomes. Method: Developmental data were obtained from two 16 year olds diagnosed with a rare chromosome disorder – a girl with 8p23.1 and a boy with 16q11.2q12.1. Measures of intellectual ability, academic achievement, and other aspects of functioning were administered at multiple time points from early childhood to adolescence. Results: Both adolescents experienced initial delays in motor and language development. Although the girl’s intelligence is assessed as being in the average range, she experiences difficulties with motor planning, spelling and writing. The boy has been diagnosed with a mild intellectual disability and demonstrates mild autistic features. Conclusions: The two case descriptions are in marked contrast to the published literature about these two chromosome anomalies. Both adolescents are developing much more positively than would be expected on the basis of the grim predictions of their paediatricians and the negative reports in the literature. It is concluded that, for most rare chromosome disorders, the range of possible developmental outcomes is currently unknown.

Supporting siblings of children with a rare chromosome disorder

Siblings play an important role in children’s learning and development. Interactions with brothers and sisters provide opportunities to learn about sharing and emotional reciprocity, to develop social skills, to express thoughts and feelings, and to practise resolving conflict. But for children whose brother or sister has a disability, such as a rare chromosome disorder, some of these sibling experiences may be different. Many parents worry about how their non-disabled child will be affected by the experience of living with a brother or sister with a disability, and a great deal of research has explored both the possible negative consequences and also the potential benefits for siblings. In this article, we summarise the research findings and provide suggestions for ways that parents can support the positive development and well-being of all their children.

Insights into historical drainage evolution based on the phylogeography of the chevron snakehead fish (Channa striata) in the Mekong Basin

1. The phylogeography of freshwater taxa is often integrally linked with landscape changes such as drainage re-alignments that may present the only avenue for historical dispersal for these taxa. Classical models of gene flow do not account for landscape changes and so are of little use in predicting phylogeography in geologically young freshwater landscapes. When the history of drainage formation is unknown, phylogeographical predictions can be based on current freshwater landscape structure, proposed historical drainage geomorphology, or from phylogeographical patterns of co-distributed taxa. 2. This study describes the population structure of a sedentary freshwater fish, the chevron snakehead (Channa striata), across two river drainages on the Indochinese Peninsula. The phylogeographical pattern recovered for C. striata was tested against seven hypotheses based on contemporary landscape structure, proposed history and phylogeographical patterns of codistributed taxa. 3. Consistent with the species ecology, analysis of mitochondrial and microsatellite loci revealed very high differentiation among all sampled sites. A strong signature of historical population subdivision was also revealed within the contemporary Mekong River Basin (MRB). Of the seven phylogeographical hypotheses tested, patterns of co-distributed taxa proved to be the most adequate for describing the phylogeography of C. striata. 4. Results shed new light on SE Asian drainage evolution, indicating that the Middle MRB probably evolved via amalgamation of at least three historically independent drainage sections and in particular that the Mekong River section centred around the northern Khorat Plateau in NE Thailand was probably isolated from the greater Mekong for an extensive period of evolutionary time. In contrast, C. striata populations in the Lower MRB do not show a phylogeographical signature of evolution in historically isolated drainage lines, suggesting drainage amalgamation has been less important for river landscape formation in this region.

The effects of dietary fish oil on inflammation, fibrosis and oxidative stress associated with obstructive renal injury in rats.

Scope: We examined whether dietary supplementation with fish oil modulates inflammation, fibrosis and oxidative stress following obstructive renal injury. Methods and results: Three groups of Sprague-Dawley rats (n = 16 per group) were fed for 4 wk on normal rat chow (oleic acid), chow containing fish oil (33 g eicosapentaenoic acid and 26 g docosahexaenoic acid per kg diet), or chow containing safflower oil (60 g linoleic acid per kg diet). All diets contained 7% fat. After 4 wk, the rats were further subdivided into four smaller groups (n = 4 per group). Unilateral ureteral obstruction was induced in three groups (for 4, 7 and 14 days). The fourth group for each diet did not undergo surgery, and was sacrificed as controls at 14 days. When rats were sacrificed, plasma and portions of the kidneys were removed and frozen; other portions of kidney tissue were fixed and prepared for histology. Compared with normal chow and safflower oil, fish oil attenuated collagen deposition, macrophage infiltration, TGF-beta expression, apoptosis, and tissue levels of arachidonic acid, MIP-1 alpha, IL-1 beta, MCP-1 and leukotriene B(4). Compared with normal chow, fish oil increased the expression of HO-1 protein in kidney tissue. Conclusions: Fish oil intake reduced inflammation, fibrosis and oxidative stress following obstructive renal injury.

Fish out of water : refugee and international students in mainstream Australian schools

In this paper, the authors combine Pierre Bourdieu’s concept of hysteresis (the ‘fish out of water’ experience) with the discourse historical approach to critical discourse analysis (CDA) as a theoretical and analytical framework through which they examine specific moments in the schooling experiences of one refugee student and one international student, both enrolled in post-compulsory education in Australian mainstream secondary schools. We examine specific moments – as narrated by these students during interviews – in which these students can be described as ‘fish out of water’. As such, this paper takes up the concerns of researchers who call for an examination of the lived geographies and the everyday lives of individual students in mainstream schools. We find that our students’ habitus, conditioned by their previous schooling experiences in their home countries, did not match their new Australian schools, resulting in frustration with, and alienation from, their mainstream schools. However, we also note that schools, too, need to adapt and adjust their habitus to the new multicultural world, in which there are international and refugee students among their usual cohort of mainstream students.