#WorldCancerDay: The fault in our genes!

Advances in genetics and molecular biology have improved our knowledge of the inner workings of cells, the basic building blocks of the body. Cancer, as we all know is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. In this era of modern medicine & treatment, certain genetic mutations have been identified to be responsible for cancer, and targeting such mutations play a major role in the overall management of the disease, to improve the quality of life and cure. The presence of gene mutation increases the predisposition of cancer.

According to the Globocan 2018 data, about 1.16 million new cancer cases in India were reported with close to 7.9 lakh deaths. In India, the cancer subtypes in descending order are — breast cancer (14 percent), lip/oral cavity cancers (10.4 percent), cervical cancer (8.4 percent), lung cancer (5.9 percent) and stomach cancer (5 percent) followed by others.

The question that arises is that “How genetic testing would help in understanding genetic mutation and its relation to cancer?

The simple answer to this question is, ‘whatever one asks for’. Genetic testing provides varied answers, starting from predisposition, and events before onset of cancer to treatment planning and monitoring as well as detection of early relapse/recurrence.

The Cellular and Molecular Hallmarks of cancer are

• Self-sufficiency in growth signals (proliferating without external stimuli)

• Insensitivity to growth-inhibitory signals

• Altered cellular metabolism (switch to aerobic glycolysis, Warburg effect)

• Evasion of apoptosis

• Limitless replicative potential

• Sustained angiogenesis to provide adequate nutrition& waste removal

• Ability to invade and metastasize

• Ability to escape immune recognition and regulation

Biomarkers help in evaluating the preventive measures or therapies and the detection of the earliest stages of oral mucosal malignant transformation. It reveals the genetic and molecular changes related to early, intermediate and late end-points in the process of oral carcinogenesis. It refines the ability to enhance the prognosis, diagnosis, and treatment of oral carcinomas – Monitor progression/ recurrence, treatment compliance and it is also useful in early stages of cancer drug development.

The biomarkers could be classified into five groups based on their biological functions:

• 1) Cell cycle progression and proliferation

• 2) Tumour suppression and apoptosis

• 3) Hypoxia

• 4) Angiogenesis

• 5) Cell adhesion and matrix degradation

Examples of which are EGFR, p53, p63, VEGF

Foremost among these are tumor suppressors and most commonly TP53 gene. The TP53 (tumor protein p53) gene encodes for the p53 protein, “guardian of the genome.” TP53 is one of the most frequent and  earliest mutated genes in HNSCC tumors and even premalignant lesions. Occurring in more than 50% of cases, mutation is significantly associated with decreased survival. The p53 protein acts as a tumor suppressor that accumulates in response to stress, including DNA damage . Accumulation of p53 induces cell cycle arrest to allow the cell to perform DNA repair.

Mutations in TP53 have been associated with

• decreased overall survival,

• increased locoregional recurrence rates

• decreased response to therapy.

In Head and Neck cancers and Lung cancers, overexpression of the EGFR gene is seen in about 80-90% of tumors. Increased EGFR expression correlates with increased local recurrence and worse overall survival.

Additionally, p16 protein overexpression is consistently seen in HPV-related oropharyngeal cancers. The mechanism is related to the inactivation of retinoblastoma protein by the E7 viral protein, resulting in unregulated overexpression of p16

Molecular epidemiologic studies have provided conclusive evidence that individual susceptibility to cancer is mediated by both genetic and environmental factors. The integration of genome-based knowledge into healthcare has the potential to improve primary and secondary prevention.

Among the greatest promises of genomic medicine is that the unravelling of the genetic origins of common diseases will eventually lead to individualized medicine, in which prevention and treatment strategies are personalized on the basis of the results of predictive genetic tests. Findings from meta-analyses of genetic association studies have the potential to provide a comprehensive view of the impact of genetic risk factors in disease aetiology, especially when exploring gene-environment.

Human gene therapy is defined as the treatment of disorder or disease through the transfer of engineered genetic material into human cells, often by viral transduction.

There are few main strategies to target any solid tumor with gene therapy. First, immunomodulatory therapy seeks to increase the visibility of the tumor cells to the immune system in vivo or to modify the effector cells ex vivo to increase targeting of the tumor via the introduction of specific gene expression.

Second, oncolytic viruses have been developed that can selectively target, multiply in, and destroy cancer cells.

Cancers comprise a complex genetic disease. Although much has been learned about the molecular genetics of various cancers, continued study of multiple genes is critical for further progress. Gene therapy, although promising, must also overcome this complexity.

I think it’s all about memory what our body’s each cell is carrying in the form of genes.

It’s curious to see that we are carrying our great forefathers feature in us and it’s all about gene which has immense power to carry memories of human development. Finding a cure for cancers while struggling with so many genetic changes is the holy grail we all are striving for and till then we can say there is a fault in our genes.

About Author: With vast experience in this field, Dr Rakesh Katna is one of the best oncologist surgeons in Mumbai and currently practicing as Surgical Oncologist in Jaslok Hospital Mumbai, India.