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Minute Amounts of DNA Used to Map Genetic Alterations

Minute Amounts of DNA Used to Map Genetic Alterations

NEW YORK--Comparative geno-mic hybridization (CGH), a new molecular cytogenetic technique for mapping chromosomal and subchromosomal imbalances, is breaking new ground in cancer genetics.

According to speakers at an international meeting on CGH held at Memorial Sloan-Kettering Cancer Center, CGH is being used to detect chromosomal aberrations in glioblastomas and bladder, prostate, and breast tumors, and to locate chromosomal regions that contain genes that may contribute to cancer.

In addition, the burgeoning amount of information yielded by CGH is now being correlated with the clinical behavior of tumors.

Even minute amounts of genomic DNA are sufficient to perform CGH tests so that genetic alterations can be detected in a few microdissected tumor cells or cells from precursor lesions.

In CGH analysis, samples of normal and tumor DNA are simultaneously hybridized to metaphase chromosomes from a normal individual. If more of the tumor DNA than the normal DNA hybridizes to a chromosomal region, it means that there have been amplications in the tumor DNA. If less hybridizes, there have been deletions in the tumor DNA.

Guido Sauter, MD, of the Institute of Pathology, University of Basel, predicted that molecular cytogenetic analysis will be a powerful tool in the diagnosis and prognosis of bladder cancer, since bladder cancer cells are so easily accessible in the patient's urine.

Dr. Sauter reported finding marked genetic differences between minimally invasive and noninvasive bladder carcinomas. The minimally invasive tumors (pT1) had more aberrations than the noninvasive carcinomas (pTa). Yet, there was no significant increase of aberrations in muscle-invasive tumors (pT2-4). The difference in aberrations between pTa and pT1 tumors, Dr. Sauter said, challenges the validity of grouping pTa and pT1 tumors together as superficial bladder cancer.

Patterns of Aberrations

Burt Feuerstein, MD, PhD, of the Brain Tumor Research Center, University of California, San Francisco, reported finding patterns of genetic aberrations associated with the progression of neuroblastomas.

The aberrations fell into one of two categories. In one, whole copies of chromosomes were lost. In the other, the pieces of chromosomes were scrambled. Patients whose tumors had whole chromosome additions or deletions did better than those whose tumor cells were marked by subchromosomal scrambling.

"Understanding the patterns of genetic aberrations will be useful in discovering mechanisms of malignant progression, establishing the diagnosis, and planning therapy," Dr. Feuerstein said.

Lymphomas

Raju S.K. Chaganti, PhD, chief of Memorial Sloan-Kettering's Cytogenetics Service and chairman of the CGH conference, reported that he is using CGH to identify genetic changes associated with non-Hodgkin's lymphoma progression.

Peter Lichter, PhD, of the German Cancer Research Center, Heidelberg, has used CGH to provide a genetic basis for a new subtype of lymphoma known as primary mediastinal (thymic) B-cell lymphoma,which has previously been defined by morphological and immunological criteria.

"Those of you who have ever tried to understand lymphoma classification know there are a lot of uncertainties," Dr. Lichter said. His analysis revealed that more that half of the tumor set classified as primary mediastinal had a gain along chromosome 19, while other forms of lymphomas did not.

Drug Resistance

In yet another application, CGH is being used by researchers at the National Center for Human Genome Research (NCHGR), the NCI, and Fox Chase Cancer Center to study the relationship between DNA gains or losses and sensitivity or resistance to chemotherapeutic compounds.

These investigators are analyzing a panel of human tumor cell lines developed by the NCI as a primary drug screen, Dr. Stanislas Du Manoir, of the NCHGR told Oncology News International. Detecting such relationships will help to identify a chemotherapeutic agent's mechanism of action and/or the chromosomal location of genes involved in the metabolism of the drug.

 
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