history cancer cytogenetics

History of Cancer Cytogenetics

The Discovery of Philadephia Chromosome


It is known that human cytogenetics was started in 1955, with the discovery of normal human cells contain 46 chromosomes by Tjio and Levan that normal human cells contain 46 chromosomes. Few years later, Peter Nowell and David Hunger ford have discovered a minute abnormal chromosome, the Philadelphia (Ph) chromosome, as a hallmark of chronic myeloid leukemia (CML) in 1960. This is the first proof that cancer can be resulted from a specific genetic abnormality.


The Association of Cytogenetics and Cancer


Along with the advancing of chromosomal preparation techniques improved, Janet Rowley has successfully demonstrated that the Ph chromosome was due to the translocation between the long arms of chromosome 9 and 22 in 1973. Further studies have shown that this translocation leads to the formation of a new fusion oncogenic protein called BCR-ABL1, which overexpresses an aberrant tyrosine kinase in leukemia cells. This circumstance occurs in every patient with CML, and therefore providing strong evidence of its pathogenetic role.


Targeted Therapy for Leukemia Patients according to Cytogenetics Analysis


All these findings and the description of the Ph chromosome ushered the field of cancer cytogenetics into a new era. In addition, the discovery of the remarkable drug, imatinib for the treatment of Ph-positive CML has led to the emergence of molecularly targeted therapies, a field now known as personalized or targeted medicine. The accumulation of strong evidence and informative genetic data that are intimately associated with the diagnosis and prognosis of many cancers have thereby moved cancer cytogenetics studies from the bench to clinical practice. In 2008, the World Health Organization (WHO) has further classified four unique acute myeloid leukemia (AML) subtypes according to cytogenetics based on the association between specific cytogenetic abnormalities, certain cytological morphology, and clinical features.


The Emergence of Cytogenetics Analysis as a Clinical Standard Protocol


Therefore, karyotyping of neoplastic cells is currently a mandatory clinical protocol for all newly diagnosed leukemias, owing to its advantages in diagnosis, classification, and prognostication. Furthermore, karyotyping of cancer cells remains the golden standard for understanding the relationship between clonal evolution and disease progression, as it provides a global analysis of the abnormalities in the entire genome of a single cell. Apart from the conventional karyotyping analysis, fluorescence in situ hybridization (FISH) assay has been introduced to cancer cytogenetics for better clinical application. FISH relies on the ability of single stranded DNA to hybridize to complementary DNA sequence. This technique can be used to map gene loci on specific chromosomes, detect both structural and numerical chromosomal abnormalities, and reveal cryptic abnormalities. It has overcome many of the drawbacks of chromosome analysis, such as poor quality metaphases of cancer cells, low mitotic index, low specimen cell yield, and other unpredictable technical difficulties.


Recently, FISH remains an indispensable and powerful tool in modern genetic laboratories. It is widely used for the detection of structural rearrangements such as translocations, inversions, insertions, and microdeletions, and for the delineation of unidentified (or marker) chromosomes and chromosomal breakpoint regions of genetic abnormalities. Of note, FISH has greatly enhanced the efficiency and accuracy of karyotype analysis by supplementing the technical pitfalls of karyotyping and molecular genetic technology.



The development of FISH has helped to overcome many of the drawbacks in the assessment of genetic alterations in cancer cells by karyotyping. Subsequent methodological advances in molecular cytogenetics based on the principle of FISH have greatly enhanced the efficiency and accuracy of karyotype analysis by complementing conventional cytogenetics with molecular technologies. All of these molecular cytogenetic techniques add colors to the monotonous world of chromosomal banding. Both karyotyping and FISH have emerged as indispensable tools for both basic and clinical research, which parallel their clinical diagnostic application in leukemia and cancers.