Cancer is a disease caused by an abnormal
proliferation of clonal cells caused by aberrations in the DNA. These can be seen
in the form of mutations, deletions, substitutions, rearrangements, or
amplifications which produces abnormal protein and function. These genetic
alterations can be inherited or acquired due to environment factors like
exposure to carcinogens, infections, life style etc.
The human genome project has estimated 80,000
to 1,00,000 genes in human, which are the functional unit of inheritance. Genomic
information about cancer has revolutionized our understanding of cancer
development and progression. The application of next generation sequencing has
provided unprecedented opportunity to understand the biological basis of different
cancer types. This has led to better
diagnosis and treatment strategies that are tailored to patient’s tumor, also
known as precision medicine.
The main objective of genomics and precision
medicine is to give the right diagnosis at the right time to choose the right
treatment. Genomic sequencing solves the diagnostic dilemma in difficult cases
on histopathology and helps to understand the genetic background of cancer
patients. Patients with same type of cancer might respond differently to
different drugs. Pharmacogenomics can also help to define the behavior of the
tumor to a particular drug and helps to identify genomic biomarkers of drug
response and resistance. By using genomic data and machine learning algorthims,
one can accurately predict who will respond better and who will face the side
effects of a particular treatment. Recently, robotics has been introduced which
provides greater accuracy and expedites the process by automation of gene
mapping and DNA sequencing.
Circulating tumor cells (CTCs) are molecular
signatures of cancer cells that are shed from the primary tumor site, enter the
circulatory system and are responsible for distant metastasis. This streamlines
the monitoring of the patients to chemotherapy and radiotherapy. Cell free (cf)
DNA helps in identification of the disease when the tissue biopsies are
negative for tumor while PET CT shows hot spots of tumor nodules. Monitoring of
minimal residual disease (MRD) by reverse transcriptase polymerase chain
reaction (RT-PCR) in hematological malignancies helps to understand the
response to targeted therapies. Some germline panels help to understand various
syndromes like hereditary breast and ovarian cancers (HBOC) etc. BRCA1 and 2 genes are involved in spectrum of
diseases involving multiple organ system like female genital tract, breast,
pancreas, prostate etc. FDA has approved Poly (ADP-ribose) Polymerase (PARP)
inhibitors eg Olaparib has been proven to be of a great therapeutic value. The targeted drugs act like small molecules,
antibody based or direct inhibitors which block the gene expression, inhibit
signaling pathway or aberrant protein expression.
Beyond the identification of targetable
alterations, genomic methods can gauge tumor mutational burden (TMB), MSI and
PDL-1 which might predict a therapeutic response to immune checkpoint
inhibitors. Tumor agonistic or histology agonistic therapy for specific
molecular fusions or alterations have revolutionized the therapeutic approach
to tumors at different sites.
“The Ultimate Validation of Genomics and Precision Oncology is when it gives a twinkle in patient’s eyes”
