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
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.
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.
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.