Molecular and biologic basis of upper gastrointestinal malignancy. Gastric carcinoma

Gastric cancer is one of the world's most common cancers and is a leading cause of cancer death worldwide. Neoplasia of the stomach is mainly composed of adenocarcinomas, which for more than 95% of cases. Although mesenchymal tumors (i.e., stromal tumors, leiomyomas and leiomyosarcomas, and schwannomas), primary lymphomas, and carcinoid tumors can also arise in the stomach, malignant tumors of these types occur much less often

Molecular biology of gastric cancer

Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons. The majority of gastric tumors are sporadic in nature. However, there are rare, inherited gastric cancer predisposition traits, such as germline p53 (Li-Fraumeni syndrome) as well as E-cadherin (CDH1) alterations in familial diffuse gastric cancers. Gastric cancer has been observed to be part of the spectrum of neoplasms associated with germline mismatch repair gene (MMR) alterations that give rise to the hereditary nonpolyposis colorectal cancer (HNPCC) entity. Comparative genomic hybridization analyses have identified several amplifications and losses of DNA copy numbers in gastric cancers. Loss of heterozygosity (LOH) studies have shown several chromosomal loci with significant allelic loss, thus indicating the possibility of harboring a tumor suppressor gene important in gastric tumorigenesis. Microsatellite instability (MIS) and associated alteration of the TGF-bIIR, IGFRII, BAX, E2F-4, hMSH3, and hMSH6 genes are found in a subset of gastric carcinomas. Cell adhesion molecule abnormalities such as those involving CDH1 may play an important role in diffuse-type gastric cancer development. Although, multiple somatic alterations have been described in gastric carcinomas at the molecular level, the significance of these changes in gastric tumorigenesis remains to be established in most instances. The critical molecular alterations in gastric cancers that may lead to advances in our armamentarium to combat this lethal disease remain to be fully characterized

Comparison of fluorescein isothiocyanate‐ and Texas red‐conjugated nucleotides for direct labeling in comparative genomic hybridization

In this study, we investigated whether fluorescein isothiocyanate (FITC)‐labeling of test DNA and Texas‐red (TR) labeling of reference DNA in comparative genomic hybridization (CGH) experiments cause the results to differ from those obtained using the opposite combination (reverse labeling). Analysis was performed on a total of 20 DNA specimens consisting of 13 frozen bone marrow aspirates from patients with acute myeloid leukemia, and fresh peripheral blood samples from seven healthy donors. For CGH, one aliquot from each test DNA sample was labeled using nick‐translation with FITC‐dUTP and another with TR‐dUTP. Afterwards, the FITC‐dUTP and TR‐dUTP‐labeled test DNAs were hybridized to TR‐dUTP‐ and FITC‐dUTP‐labeled normal reference DNAs, respectively. The results using the two combinations were compared with each other and with the results of G‐banding karyotype analysis. Karyotype data was used to detect artifacts known to occur in some chromosome regions in CGH analysis. The control DNAs labeled with FITC or TR showed no DNA copy number changes. Regardless of the fluorochrome employed for labeling, no DNA copy number changes were detected using CGH in patients with normal karyotypes, nor in patients whose karyotype aberrations were present in less than 40% of cells. In the remaining patients, CGH revealed DNA copy number changes that coincided with the results of the G‐banding analysis. Hybridization artifacts known to occur in CGH experiments affecting chromosome regions 1p33‐pter, 16p, 17p, 19, and 22 were observed in 15–23% of the tumor samples labeled with FITC, but not in samples labeled with TR. In addition, other previously unreported overrepresentations affecting 7q21, 9q34, 16q, 17q, and chromosome 20 were observed at very low frequencies in up to 10% of the samples when FITC was used to label test DNA. However, when TR was used, overrepresentations were observed at 4q13–q21, 11q21–q23, 13q21‐qter, and Xq21–q22, whereas 19p was underrepresented. The results demonstrate that TR‐labeling confirms abnormalities detected using FITC‐labeling and reduces hybridization artifacts in the known problematic regions of the human genome. Cytometry 31:174–179, 1998. © 1998 Wiley‐Liss, Inc

Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: A review

This paper reviews data on the prognosis of gastrointestinal stromal tumors (GISTs). These tumors are specific KIT-expressing and KIT-signaling–driven mesenchymal tumors, many of which have KIT-activating mutations. GISTs occur in the entire gastrointestinal (GI) tract and may also arise from the omentum, mesenteries, and retroperitoneum. They range from small benign tumors to sarcomas at all sites of occurrence. A KIT tyrosine kinase inhibitor, STI-571 (imatinib [Gleevec]; Novartis, Basel, Switzerland), has recently shown promise in the treatment of metastatic GISTs. Understanding the natural history of GIST before introduction of STI-571 will help assess the impact and position of this new treatment. The frequency of benign versus malignant GISTs varies between sites. Benign GISTs outnumber malignant GISTs in the stomach, whereas malignant GISTs are more common in the intestines. Tumors that have metastasized at presentation have a very poor prognosis. Traditionally, the 3 key prognostic factors have been mitotic rate, tumor size, and site. Tumors that are small (≤2 cm) and show mitotic activity not exceeding 5 mitoses per 50 high-power fields (HPFs) have an excellent prognosis, probably independent of site, although this has not been shown specifically for all sites. In the stomach, most epithelioid GISTs are benign, provided that mitotic counts do not exceed 5/50 HPFs. However, a small proportion of tumors apparently lacking mitotic activity do metastasize. Tumors with a mitotic rate >5/50 HPFs usually have a malignant behavior. The Ki67 index may help identify tumors with malignant potential, but large site-specific series are not yet available. Genetic markers, including DNA-copy number changes, telomerase activity, and KIT mutation status, may be useful in more accurately identifying tumors with malignant potential. HUM PATHOL 33:478-483. Copyright 2002, Elsevier Science (USA). All rights reserved

Clinical management of gastrointestinal stromal tumors: Before and after STI-571

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Until recently, surgery has been the only effective therapy for GIST. However, even after complete resection of tumor, many patients still eventually die of disease recurrence. Conventional chemotherapy and radiation therapy have been of limited value. Within the last few years, it was discovered that most GISTs have a gain-of-function mutation in the c-kit proto-oncogene. This results in ligand-independent activation of the KIT receptor tyrosine kinase and an unopposed stimulus for cell growth. STI-571 is a small molecule that selectively inhibits the enzymatic activity of the ABL, platelet-derived growth factor receptor, and KIT tyrosine kinases and the BCR-ABL fusion protein and is a landmark development in cancer therapy. Its clinical development marks a new era of rational and targeted molecular inhibition of cancer that emanates from direct collaborations between scientists and clinicians. It provides proof of the principle that a specific molecular inhibitor can drastically and selectively alter the survival of a neoplastic cell with a particular genetic aberration. The advent of STI-571 has markedly altered the clinical approach to GIST. It has proven to be effective in metastatic GIST and is also under investigation as a neoadjuvant and adjuvant therapy. HUM PATHOL 33:466-477. Copyright 2002, Elsevier Science (USA). All rights reserved

Prognostic Value of Metaphase-Fluorescence In Situ Hybridization in Follow-up of Patients With Acute Myeloid Leukemia in Remission

Abstract The presence of residual leukemic cells was studied using metaphase-fluorescence in situ hybridization (FISH) in 22 patients with acute myeloid leukemia treated with chemotherapy only or chemotherapy followed by allogeneic bone marrow transplantation. The patients were followed up during their complete remission (CR) for 4 to 108 months (median, 21 months). A total of 88 BM samples was studied. In most of the samples more than 1,000 metaphase cells were analyzed. Residual leukemic cells were detected in 9 of 22 patients (41%). All patients who had an increasing and/or persisting level of abnormal cells in two or more subsequent samples or whose initial samples contained more than 1% of abnormal cells relapsed with one exception, in whom the later subsequent samples showed disappearance of abnormal cells. The time span before the first positive sample seems to be insignificant with regard to the outcome of relapse. Absence or single occurrence of abnormal cells followed by their disappearance was in agreement with CR in all the cases (16 patients). Our results indicate that metaphase-FISH is a reliable tool in the quantitation of residual leukemic cells and provides valuable prognostic information for patients with AML