The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not been defined for these tumors. Using exome/genome sequence analysis of SI-NETs, we identified recurrent somatic mutations and deletions in CDKN1B, the cyclin-dependent kinase inhibitor gene, which encodes p27. We observed frameshift mutations of CDKN1B in 14 of 180 SI-NETs, and we detected hemizygous deletions encompassing CDKN1B in 7 out of 50 SI-NETs, nominating p27 as a tumor suppressor and implicating cell cycle dysregulation in the etiology of SI-NET.

Purpose Recent studies suggest that temozolomide has activity in neuroendocrine tumors. Low levels of the DNA repair enzyme, O6-methylguanine DNA methyltransferase (MGMT), are associated with sensitivity to temozolomide in other tumor types. We evaluated the prevalence of MGMT deficiency in neuroendocrine tumors and correlated MGMT deficiency with treatment response to temozolomide-based regimens. Experimental Design The prevalence of MGMT deficiency, measured by immunohistochemistry, was assessed in 97 archival neuroendocrine tumor specimens. Rates of treatment response and survival were next evaluated in a cohort of 101 consecutive neuroendocrine tumor patients who had received treatment with a temozolomide-based regimen at one of three institutions. MGMT expression was directly correlated with treatment response in 21 patients who had available tumor tissue and response data. Results In archival specimens, MGMT deficiency was observed in 19 of 37 (51%) pancreatic neuroendocrine tumors and 0 of 60 (0%) carcinoid tumors (P < 0.0001). In the clinical cohort, 18 of 53 (34%) patients with pancreatic neuroendocrine tumors but only 1 of 44 (2%) patients with carcinoid tumors (P < 0.001) experienced a partial or complete response to temozolomide-based therapy. Among 21 patients with evaluable tumor tissue who had also received treatment with temozolomide, 4 of 5 patients with MGMT-deficient tumors (all pancreatic neuroendocrine tumors) and 0 of 16 patients with tumors showing intact MGMT expression responded to treatment (P = 0.001). Conclusions MGMT deficiency, measured by immunohistochemistry, is more common in pancreatic neuroendocrine tumors than in carcinoid tumors as is treatment response to temozolomide-based therapy. Absence of MGMT may explain the sensitivity of some pancreatic neuroendocrine tumors to treatment.

BACKGROUND: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1 -7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2 -7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P ¼ 0.002) and shorter PFS (P ¼ 0.09). BRAF (P ¼ 0.0005) and PIK3CA (P ¼ 0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. CONCLUSIONS: These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.