A Sleeping Beauty transposon-mediated screen identifies murine susceptibility genes for adenomatous polyposis coli (Apc)-dependent intestinal tumorigenesis.

It is proposed that a progressive series of mutations and epigenetic events leads to human colorectal cancer (CRC) and metastasis. Furthermore, data from resequencing of the coding regions of human CRC suggests that a relatively large number of mutations occur in individual human CRC, most at low frequency. The functional role of these low-frequency mutations in CRC, and specifically how they may cooperate with high-frequency mutations, is not well understood. One of the most common rate-limiting mutations in human CRC occurs in the adenomatous polyposis coli (APC) gene. To identify mutations that cooperate with mutant APC, we performed a forward genetic screen in mice carrying a mutant allele of Apc (Apc(Min)) using Sleeping Beauty (SB) transposon-mediated mutagenesis. Apc(Min) SB-mutagenized mice developed three times as many polyps as mice with the Apc(Min) allele alone. Analysis of transposon common insertion sites (CIS) identified the Apc locus as a major target of SB-induced mutagenesis, suggesting that SB insertions provide an efficient route to biallelic Apc inactivation. We also identified an additional 32 CIS genes/loci that may represent modifiers of the Apc(Min) phenotype. Five CIS genes tested for their role in proliferation caused a significant change in cell viability when message levels were reduced in human CRC cells. These findings demonstrate the utility of using transposon mutagenesis to identify low-frequency and cooperating cancer genes; this approach will aid in the development of combinatorial therapies targeting this deadly disease.

Public Perceptions on the Influence of Diet and Kidney Stone Formation.

Introduction: Public awareness regarding the influence of diet on kidney stones is unknown. We sought to evaluate such perceptions among an unselected community cohort. Materials and Methods: A survey was created to assess perception of beverages/foods on risk of kidney stone formation. Surveys were distributed to attendees of a State Fair. Participants were categorized to determine the effect of stone history on prevention knowledge (no prior stone vs prior stone). Results: Seven hundred fifty-three participants completed the survey, including 264 (35%) with a prior stone. Participants with prior stones were less likely to believe stones were preventable compared to those without (56% vs 65%, p = 0.01). Appropriate perceptions regarding influence of diet on stones were highest for water (>90% of participants) and cola/salt/red meat (>50%). Fewer than half of respondents correctly identified the influence of the remaining 14 substances. On multivariable analysis, stone formers were more likely to correctly identify the influence of lemonade (odds ratio [OR] 2.09; 95% confidence interval [CI] 1.32-3.31), nuts (OR 2.60; 95% CI 1.60-4.23), and spinach (OR 5.06; 95% CI 2.89-8.86), but less likely to identify the influence of coffee (OR 0.43; 95% CI 0.23-0.82) and red meat (OR 0.52; 95% CI 0.23-0.59). Conclusion: Patients with prior stones hold different attitudes regarding the influence of certain foods and drinks on stone formation relative to the public. Such attitudes are not always correct, and as a group they are less likely to believe in dietary stone prevention. Such findings may indicate confusion among stone formers and highlight an opportunity for improved dietary counseling.