Neuroblastomas are characterized by 1p deletions, suggesting that a tumor suppressor gene (TSG) resides in this region. We have mapped the smallest region of deletion (SRD) to a 2 Mb region of 1p36.31 using microsatellite and single nucleotide polymorphisms. We have identified 23 genes in this region, and we have analysed these genes for mutations and RNA expression patterns to identify candidate TSGs. We sequenced the coding exons of these genes in 30 neuroblastoma cell lines. Although rare mutations were found in 10 of the 23 genes, none showed a pattern of genetic change consistent with homozygous inactivation. We examined the expression of these 23 genes in 20 neuroblastoma cell lines, and most showed readily detectable expression, and no correlation with 1p deletion. However, 7 genes showed uniformly low expression in the lines, and 2 genes (CHD5, RNF207) had virtually absent expression, consistent with the expected pattern for a TSG. Our mutation and expression analysis in neuroblastoma cell lines, combined with expression analysis in normal tissues, putative function and prior implication in neuroblastoma pathogenesis, suggests that the most promising TSG deleted from the 1p36 SRD is CHD5, but TNFRSF25, CAMTA1 and AJAP1 are also viable candidates.

Min (Multiple intestinal neoplasia) mice carry a dominant mutation in the adenomatous polyposis coli (Apc) gene and develop multiple adenomas throughout their intestinal tract (Moser et al. 1990; Su et al. 1992). Polyp multiplicity in Min mice is greatly influenced by genetic background. A modifier locus, Mom1 (Modifier of Min 1), was identified and localized to distal mouse chromosome 4 (Moser et al. 1992; Dietrich et al. 1993), and accounts for some of the genetic variance in polyp multiplicity. Mom1 is a semidominant modifier of polyp size and multiplicity in Min mice (Gould and Dove 1997), and encodes the secretory type II nonpancreatic phospholipase A2 (Pla2g2a) gene (MacPhee et al. 1995; Cormier et al. 1997, 2000). We now report the identification of a second Modifier of Min 2 (Mom2) locus that is the result of a spontaneous mutation. One resistant Mom2 allele can suppress 88%–95% of polyps detected in ApcMin/+ mice, indicating that Mom2 acts in a dominant fashion. Linkage analysis has localized Mom2 to distal mouse chromosome 18. The effects of the Mom2 locus on reducing polyp multiplicity are stronger than the effects of the Mom1 locus, in both the small and large intestines. Some ApcMin/+ mice that carried one resistant Mom2 allele were tumor-free at 21 weeks of age, even in the absence of a resistant Mom1 allele. Thus, the resistant Mom2 allele can, in some cases, completely suppress the penetrance of the ApcMin mutation

Inactivation of the APC gene is considered the initiating event in human colorectal cancer. Modifier genes that influence the penetrance of mutations in tumor-suppressor genes hold great potential for preventing the development of cancer. The mechanism by which modifier genes alter adenoma incidence can be readily studied in mice that inherit mutations in the Apc gene. R encodes a recessive embryonic lethal mutation. We devised an exclusion strategy for mapping the Mom2 locus using embryonic lethality as a method of selection. Expression and sequence analyses of candidate genes identified a duplication of four nucleotides within exon 3 of the ␣ subunit of the ATP synthase (Atp5a1) gene. Tumor analyses revealed a novel mechanism of polyp suppression by Mom2 R in Min mice. Furthermore, we show that more adenomas progress to carcinomas in Min mice that carry the Mom2 R mutation. The absence of loss of heterozygosity (LOH) at the Apc locus, combined with the tendency of adenomas to progress to carcinomas, indicates that the sequence of events leading to tumors in Apc Min/+ Mom2 R/+ mice is consistent with the features of human tumor initiation and progression.[Supplemental material is available online at www.genome.org.]Colorectal cancer is one of the leading causes of cancer deaths in the United States (www.cancer.org). The dysregulation of normal colonic epithelium leads to the formation of adenomas, which are considered a prerequisite to progression to carcinoma (Fodde et al. 2003). This multistep process involves interactions between the genome and the gut environment, leading to mutations and epigenetic changes in oncogenes and/or tumor suppressor genes (Kinzler and Vogelstein 1996;Ilyas et al. 1999;Gregorieff and Clevers 2005). However, the variation in penetrance of hereditary forms of cancer has emphasized the impact of tumormodifier genes that can influence individual susceptibility to cancer by either enhancing or suppressing the initiation, growth, and/or progression of tumor cells. Due to environmental and genetic heterogeneity in the human population, it has been difficult to identify tumor modifier loci in humans. Therefore, complex trait analysis in experimental mouse crosses is a powerful approach to genetically dissect multigenic diseases (Moore and Nagle 2000;Threadgill et al. 2002;Siracusa et al. 2004).The mapping, identification, and characterization of genes influencing tumor susceptibility has been facilitated by the use of mammalian models (Mao and Balmain 2003). Inbred strains of mice that differ in their susceptibility to various types of solid tumors and leukemias have been instrumental in uncovering loci that affect tumor risk (Dragani 2003;Mao and Balmain 2003). Tumor susceptibility genes may act cell autonomously within the tumor lineage, or may act in a non-cell autonomous fashion within the microenvironment leading to tumor formation (Demant 2003). Genomic differences among inbred strains of mice are being exploited to limit the regions containing the causative allelic variants and ul...

Residential Treatment Centres (RTCs) provide 24‐hour care and mental health services to young people, many of whom are referred from county departments that oversee services to young people involved with child welfare services, mental health services and corrections. While RTCs are required to provide mental health services to young people, the regulations governing these programmes have few specific requirements about the process, content or duration of treatment. Therefore, many questions have arisen about what a typical RTC day looks like and whether it differs among providers or differs based on the severity or type of the young person's mental‐health related behaviours and symptoms. This study conducted interviews with RTC providers in the State of Colorado on this topic. Most RTC services were relatively uniform across case types within each RTC. It appears that with a few exceptions, a similar set of services is provided to all young people, regardless of their problems.