Previous studies are consistent with the hypothesis that aberrant crypt foci (ACF) could be intermediate biomarkers in colorectal carcinogenesis. The present controlled experimental trial was performed to sequentially analyze ACF progression in rat colonic mucosa. F344 rats were administered 2-weekly doses of azoxymethane (15 mg/kg body weight, s.c.) and sacrificed 6, 12, 20, 30 and 36 weeks after the first carcinogen injection. Control groups of untreated rats were sacrificed at the same time points. The number of ACF per area, their multiplicity (number of crypts per focus), ACF frequency and multiplicity according to each colonic site, histology of ACF and macroscopic lesions were recorded. No ACF were found in control animals. In treated animals, the number of ACF per area and the multiplicity progressively and significantly increased throughout the study. ACF were prevalent in the mid colon. Lower frequencies were registered in the distal colon and rectum. ACF were rare in the proximal colon and cecum. By histology, ACF presented superficial and extensive hyperplasia. Tumors were found in the 30th and 36th week. Adenomas and well-differentiated adenocarcinomas were in the distal colon. All proximal neoplasms were signet ring cell carcinomas. In our study, ACF growing features and distribution are not correlated to adenoma and adenocarcinoma distribution. It is conceivable that signet ring cell carcinomas arising in the proximal colon, where ACF are rare, could present a different pathway of growth. The preneoplastic role of ACF and their function as intermediate biomarkers in colorectal carcinogenesis remain to be clarified.

This study tested the effect of a new gastrin receptor antagonist, CR2945, on colorectal cancer induced by 1,2-dimethylhydrazine (DMH) in mice. 75 CD1 male mice were divided into 3 groups: group 1 received 1 weekly injection of 20 mg/kg of DMH and 2 daily intraperitoneal injections of 0.5 ml of NaCl 0.9% solution for 5 weeks; groups 2 and 3 received the same weekly dose of DMH and 2 daily injections of CR2945 at the respective doses of 2.5 and 7.5 mg/kg for 5 weeks. The animals were sacrificed 25 and 38 weeks after the first injection. No tumours were found at the 25th week. A lower cancer frequency (4%) was observed in treated animals compared to controls (37.4%) at the 38th week (p = 0.002). These data show that CR2945 could prevent chemically induced colon cancer development in mice.

Abstract. Hereditary breast cancer accounts for 5-10% of all cases of breast cancer and 10-15% of ovarian cancer and is characterised by dominant inheritance, early onset, the severity of the disease and bilaterality. About 30% of cases with hereditary breast and ovarian cancer have mutations in the BRCA1 and BRCA2 genes. Women with a mutation in the BRCA1 gene have a 80-90% lifetime risk of developing breast cancer, and 40-65% chance of developing ovarian cancer. Most studies carried out throughout the world indicate that the prevalence of BRCA1 and BRCA2 mutation is lower than originally suggested by early studies on large families with several affected members. Studies performed in Italy have reported different prevalence of BRCA1 and BRCA2 mutations, probably due to different selection criteria and to the variability of the techniques used. In this study, we performed a screening of BRCA1 and BRCA2 in families from northern Italy with familial recurrence of breast cancer or ovarian cancer in which the individual risk of patients of being carriers of BRCA1 and BRCA2 mutation was evaluated using BRCAPRO (CAGene) software. We enrolled 27 patients of 101 unrelated families selected when they fulfilled the inclusion criteria of the American Society of Clinical Oncology (ASCO). Specific risk evaluation, genetic test administration if needed, and discussion of the results were offered during multidisciplinary genetic, surgical and psychological counselling. Seven probands (35%) found BRCA1/2 sequence variation carriers; no BRCA1 and BRCA2 mutations were detected in the remaining 13 probands. Two (15%) patients had BRCA1 mutations and 5 (25%) patients had BRCA2 mutations. In the latter case, BRCA2 delA 9158fs+29stop mutation in exon 22, never previously described and a new sequence variation (T703N) in exon 11 were identified.

Background/Aims: The potential role of gastrin and the cholecystokinin-B (CCK-B)/gastrin receptor in the genesis of colon cancer is debated. Aberrant crypt foci (ACF) are considered to be preneoplastic lesions of colon cancer. We aimed to assess whether the CCK-B/gastrin receptor antagonist, CR2945, may prevent the development of ACF and adenocarcinoma in the experimental model of dimethylhydrazine (DMH)-induced colorectal cancer. Materials and Methods: 226 CD1 mice were randomized into 3 groups (sham, control and treated) and received intraperitoneal injections of NaCl 0.9%, DMH, and DMH + CR2945, respectively, for 5 weeks. 168 mice were sacrificed at 15, 38, 45 and 52 weeks after the first injection day. The colon and rectum were investigated for frequency, multiplicity and distribution of ACF as well as for adenocarcinoma at histology. The expression of gastrin was assessed in tumor samples at histology by immunohistochemistry. Results: ACF frequency and multiplicity significantly increased with time in both controls and treated mice with no difference between groups except that at week 45. 38.8% of controls and 14.3% of treated mice developed cancer (p = 0.004). No cancer was positive for gastrin at immunohistochemistry. The mean number of cancers per mouse and the proportion of mice with cancer increased with time with statistically significant difference between controls and treated mice at week 38 only but not afterwards. A significant correlation between cancer and ACF frequency (r = 0.35) and multiplicity (r = 0.25) was observed. Conclusions: Our findings support the preneoplastic significance of ACF and indicate that CR2945 treatment does not interfere with the DMH-induced cancerigenic process.