Understanding How Genetic Changes in Cancer Have Modified Diagnosis


R.G. Wiseman Pinto

M.D., D.N.B., M.N.A.M.S, M.I.A.C.

Professor and Head,

Department of Pathology,

Goa Medical College, Bambolim, Goa 403 402.


Dean, Faculty of Medicine,

Goa University, Bambolim, Goa.



Genetic changes seen in cancer may either be minute or large enough to be detected by karyotype techniques. Various genetic abnormalities in cancer may be due to either abnormalities in the structure or number of chromosomes. The abnormality in number is called as aneuploidy. The structural abnormalities are given below:

  1. Balanced translocations as seen in Burkitt’s Lymphoma t(8;14)(q24;q32). This converts the MYC proto-oncogene into the MYC oncogene and there is over expression of MYC protein which is an oncoprotein that leads to uncontrolled cell proliferation. Another example of balanced translocation is the Philadelphia chromosome seen in chronic myeloid leukemia. This translocation is t(9;22)(q34;q11.2) in which there is a fusion gene or chimera gene called as BCR-ABL oncogene. BCR (Breakpoint Cluster Region) and ABL (Abelson Murine Leukemia Virus) is a fusion gene that causes cell division and inhibits apoptosis.
  2. Deletions are seen with tumor suppressor genes and causes loss of tumor suppressor gene protein. For example, deletion of RB gene (Retinoblastoma gene) on Chromosome 13q14.
  3. Point mutation involves substitution of a single nucleotide base by a different base in a gene. Examples of point mutations are seen in RAS genes (Rat Sarcoma Virus genes) seen in pancreatic cancer and colorectal cancer and the BRAF mutation seen in malignant melanoma and papillary carcinoma of thyroid.
  4. Gene amplification produces several hundred copies of the proto-oncogene. For example, double minutes which are extra chromosomal. Multiple, small structures and HSR (Homogenous Stainable Regions). An example of this is seen in the N-MYC gene amplification in neuroblastoma and HER 2/Neu also called as ERBB2 in breast cancer.
  5. Chromothripsis is a phenomenon of dramatic rearrangement of clusters of chromosomes which includes chromosome shattering. It occurs in 1-2% of cancers.
  6. Noncoding RNAs have been discovered to play an important role. Many genes do not encode proteins. Instead their products play important regulatory functions such as small, noncoding, single stranded RNAs called as micro RNAs (miRNAs). Their mechanism of action is at the post-translational level involving regulation of gene expression by increased expression of oncogenes and reduced expression of tumor suppressor genes.

Approximately 5% to 10% of all cancers are hereditary. The hereditary cancer panels are detected by NGS (Next Generation Sequencing). Hereditary cancer panels are used in cancer syndromes, colorectal, pancreatic, renal, breast, and ovarian cancer. Somatic mutation cancer panels  are  by  NGS. This will differentiate somatic and germ line mutations, determine the prognosis of patients, screen for therapeutic markers, and determine the sensitivity or resistance to targeted therapy drugs.

Some of the targeted therapy drugs now made available are Gefitinib, Erlotinib, Adatinib, Crizotinib, Ceritinib, Dacomitnib, Vermurafenib, Dabrafenib, Trametinib, Selumetinib, Vandetinib, mTor inhibitors, Imatinib, Dasatinib, Sunitinib, Nilotinib, Ruxolitinib, Lapatinib, Neratinib, Sorafeinib, Quizartinib, Tivantinib, Amuvantinib, Herceptin, Pertuzumab, Cetuximab, Panitumumab, and Lenalidomide.