Somatic mutation of CDKN1B in small intestine neuroendocrine tumors.

The diagnosed incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, and the underlying genomic mechanisms have not yet been defined. Using exome- and 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-NETs.

Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance.

TCF4 and CDX2, major transcription factors for intestinal function, converge on the same cis-regulatory regions.

Surprisingly few pathways signal between cells, raising questions about mechanisms for tissue-specific responses. In particular, Wnt ligands signal in many mammalian tissues, including the intestinal epithelium, where constitutive signaling causes cancer. Genome-wide analysis of DNA cis-regulatory regions bound by the intestine-restricted transcription factor CDX2 in colonic cells uncovered highly significant overrepresentation of sequences that bind TCF4, a transcriptional effector of intestinal Wnt signaling.

Profiling critical cancer gene mutations in clinical tumor samples.

Background: Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting.

Methodology: We developed and implemented an optimized mutation profiling platform ("OncoMap") to interrogate approximately 400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies.

Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer.

Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma. However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).

Experimental Design: Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by immunohistochemistry.

High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss.

Carcinoid tumors of the small intestine are characterized by an indolent clinical course, secretion of neuropeptides, and resistance to standard cytotoxic chemotherapy. To evaluate the molecular events underlying carcinoid tumorigenesis, we used high-resolution arrays of single nucleotide polymorphisms to study chromosomal gains and losses in 24 primary and metastatic small bowel carcinoid tumors derived from 18 patients. Regions of gain or loss comprising whole chromosomes or large chromosomal regions constituted the most common class of anomalies.

Bone marrow engraftment analysis after granulocyte transfusion.

We present the case of a 6-year-old male who received an allogeneic bone marrow transplant as part of treatment for acute lymphoblastic leukemia. The patient relapsed 5 months after transplantation and received additional chemotherapy. He acquired an angioinvasive fungal infection that required transfusion of granulocytes.

Increased prevalence of the BRCA2 polymorphic stop codon K3326X among individuals with familial pancreatic cancer.

Germline BRCA2 mutations predispose to the development of pancreatic cancer. A polymorphic stop codon in the coding region of BRCA2 (K3326X) has been described, and although an initial epidemiological study suggested it was not disease causing, subsequent studies have been inconclusive. To investigate the biological significance of the K3326X polymorphism, we determined its prevalence in patients with sporadic and familial pancreatic cancer.

Evaluation of temperature gradient capillary electrophoresis for detection of the Factor V Leiden mutation: coincident identification of a novel polymorphism in Factor V.

Aim: The Factor V Leiden mutation (G1691A) is a clinically important polymorphism that results in an increased risk of thrombosis. The goal of this study was to compare a temperature gradient capillary electrophoresis (TGCE) platform for the detection of Factor V gene mutations to a conventional restriction fragment length polymorphism (RFLP) assay.

Methods: Three hundred and four samples were analyzed by both TGCE and a common clinical Mnl I/RFLP assay.