How Genomics is transforming diagnosis and cancer treatment in modern era ?

 

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”