The APC I1307K allele conveys a significant increased risk for cancer.

This study is the first attempt to evaluate the association between the APC I1307K variant and overall cancer risk. It is unique in both its large sample size and in the reliability of data in the control group. The findings described in this article have major implications in terms of identifying asymptomatic individuals who are at increased risk to harbor cancer and therefore targeted to be enrolled in specific early detection and prevention programs. The prevalence of the APC I1307K missense mutation among Ashkenazi Jews is ∼ 6%. Carriers are at an increased risk for colorectal neoplasia. In this study, we examined the association of this variant with non-colorectal cancers. Consecutive 13,013 healthy subjects who underwent screening at the Integrated Cancer Prevention Center between 2006 and 2014 were enrolled. This population was supplemented with 1,611 cancer patients from the same institution. Demographics, medical history, and pathological data were recorded. Mortality data were obtained from the Ministry of Health's registry. The prevalence of APC I1307K in cancer patients and healthy subjects was compared. The APC I1307K variant was detected in 189 (11.8%) cancer patients compared to 614 (4.7%) healthy subjects, reflecting an adjusted age and sex odds ratio (OR) of 2.53 (p < 0.0001). History of two or more cancer types was associated with a positive carrier prevalence (OR = 4.38 p < 0.0001). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers. The carrier prevalence among females was significantly higher only in breast and skin cancers. Female carriers developed cancer at a significantly older age compared to non-carriers (average 62.7 years vs. 57.8, respectively, p = 0.027), had better survival rates (HR = 0.58, p = 0.022) and overall increased longevity (average age of death 78.8 vs. 70.4 years, respectively, p = 0.003). In conclusion, the APC I1307K variant is a reliable marker for overall cancer risk (OR 2.53). Further studies are needed to evaluate its use for specific cancer types-particularly in males. Female carriers have better prognosis and increased lifespan.

CD24 knockout prevents colorectal cancer in chemically induced colon carcinogenesis and in APC(Min)/CD24 double knockout transgenic mice.

Increased expression of CD24 is seen in a large variety of solid tumors, including up to 90% of gastrointestinal (GI) tumors. Stable derivatives of SW480 colorectal cancer (CRC) cells that overexpress CD24 proliferate faster, and increase cell motility, saturation density, plating efficiency, and growth in soft agar. They also produce larger tumors in nude mice as compared to the parental SW480 cells. Most significantly, even depletion of one copy of the CD24 allele in the APC(Min/+) mice of a transgenic mouse model led to a dramatic reduction in tumor burden in all sections of the small intestine. Homozygous deletion of both CD24 alleles resulted in complete abolishment of tumor formation. Moreover, CD24 knockout mice exhibited resistance to chemically induced inflammation-associated CRC. Finally, a new signal transduction pathway is suggested: namely, CD24 expression downstream to COX2 and PGE2 synthesis, which is directly regulated by ß-catenin. CD24 is shown in vitro and in vivo as being an important oncogene in the gut, and one that plays a critical role in the initiation and progression of carcinogenesis.

Impaired bone healing at tooth extraction sites in CD24-deficient mice: A pilot study.

AIM: To use a micro-computed tomography (micro-CT) to quantify bone healing at maxillary first molar extraction sites, and test the hypothesis that bone healing is impaired in CD24-knockout mice as compared with wild-type C57BL/6J mice. MATERIALS AND METHODS: Under ketamine-xylazine general anaesthesia, mice had either extraction of the right maxillary first molar tooth or sham operation. Mice were sacrificed 1 (n = 12/group), 2 (n = 6/group) or 4 (n = 6/group) weeks postoperatively. The right maxillae was disected. Micro-CT was used to quantify differences in bone microstructural features at extrction sites, between CD24-knockout mice and wild-type mice. RESULTS: CD24-Knockout mice displayed impaired bone healing at extraction sites that was manifested as decreased trabecular bone density, and decreased number and thickness of trabeculae. CONCLUSIONS: This pilot study suggests that CD24 plays an important role in extraction socket bone healing and may be used as a novel biomarker of bone quality and potential therapeutic target to improve bone healing and density following alveolar bone injury.

Role of CD24 polymorphisms in the susceptibility to inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) results from an inappropriate inflammatory response in which genetic, immune, and environmental factors all play important roles. Recently, single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of several autoimmune diseases. AIM: To evaluate whether CD24 SNPs, are associated with risk of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: The CD24 polymorphisms C170T (rs8734), TG1527del (rs3838646), A1626G (rs1058881), and A1056G (rs1058818) were assessed in a case-control study of an Israeli cohort comprising 117 IBD patients and 105 age and gender-matched healthy controls. Restriction fragment length polymorphism (RFLP) analysis was performed using BstX1, Bsr1, Mfe1, and BstU1 restriction enzymes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models. RESULTS: Carriers of the C170T SNP were at increased risk of IBD (OR=3.022, 95% CI: 1.748-5.223, p=0.001), UC (OR=3.002, 95% CI: 1.661-5.427, p=0.001) and CD (OR=3.077, 95% CI: 1.334-7.095, p=0.008). Carrying the A1626G and A1056G SNPs was found to be a risk factor for IBD (OR=2.460, 95% CI: 1.420-4.259, p=0.001 and OR=1.856, 95% CI: 1.011-3.405, p=0.01), UC (OR=2.218, 95% CI: 1.207-4.075, p=0.01 and OR=1.944, 95% CI: 0.995-3.798, p=0.01) but not for CD (p=0.086 and p=0.299). The A1626G and TG1527del were found to be associated with younger age of IBD onset (p=0.022 and p=0.027, respectively). CONCLUSIONS: The CD24 C170T polymorphism is associated with IBD risk. The A1626G and A1056G SNPs might be associated only with UC risk. These findings suggest CD24 as a new genetic susceptibility factor, with clinical implications in the prediction of IBD prognosis and therapy.

The role of low-dose aspirin in the prevention of colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is a prevalent disease that is associated with considerable morbidity and mortality. The progression of normal mucosa through adenomatous polyps to overt cancer can span for 10 - 15 years, making early detection, as well as the use of chemopreventive agents such as aspirin, an attractive option. The effects of aspirin in reducing CRC incidence and mortality have consistently been demonstrated in a number of studies. However, a greater understanding of how aspirin exerts its anti-cancer effects is warranted. AREAS COVERED: The aim of this non-systematic review, which was developed using published randomized and epidemiological studies, as well as key references known to the authors, was to consider the role of aspirin in CRC prevention. Areas covered include the effects of aspirin on cardiovascular disease, CRC and colorectal adenoma (CRA) prevention, mode of action of aspirin and the benefit-to-risk of aspirin in disease prevention. EXPERT OPINION: Incorporating CRC and CRA benefits into coronary heart disease (CHD) risk scores would be particularly useful for determining the benefit-to-risk ratio for aspirin use in borderline cases. For instance, patients with an annual CHD risk around 0.7 - 1.4%, but with a high risk of colorectal neoplasm may benefit from aspirin. The strong association between CRC and age may also be useful for re-examining the benefit-to-risk ratio for aspirin use in older patients. However, it has to be noted that a cancer prevention indication for aspirin is not approved regulatory-wise anywhere.