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Top 10 gene mutations in non small cell lung cancer (NSCLC) that drives the outcome



Mutations are common in cancer genome

Cancer genome is heterogenous. There are many mutations. Over time, the cancer genome mutates more and more. Some of these mutations can alter protein functions. For example, TP53 is a known oncogene and is mutated in many different cancer types. The figure below shows the different mutation hotspots in TP53 in NSCLC.




A majority of mutations occur in amino acid positions 175, 245, 248, 273, and 282 (NM_000546) (Olivier et al., 2010).


TP53 is a tumor suppressor

TP53 gene is located in the short arm of chromosome 17. To fulfill its proper biological function four TP53 polypeptides, synthesized from the gene, must form a tetramer which functions as a transcription factor. This transcription factor regulates expression of many genes including genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. To learn more about TP53 tumor suppressor protein, click here. While a large proportion of cancer genomics research is focused on somatic variants, TP53 can also be mutated in the germline leading to cancer-prone Li-Fraumeni syndrome. TP53 is the most frequent mutation observed in cancer.



Is TP53 mutation treatable in NSCLC?

No. Not yet. The mutations seen in TP53 protein are "loss of function" mutations. As TP53 protein acts as a tumor suppressor, loss of function causes tumors to form. In the future, it may be possible to correct the single nucleotide mutations through therapeutic genome editing technologies such as CRISPER/Cas9.


Are there other NSCLC mutations that are treatable?

Yes. If a mutation causes a gain of function that contributes towards the tumor formation, then it can be treated with a drug to inhibit the improper function of the mutated protein, such as the KRAS and the EGFR mutations.


How can you determine the mutations in the NSCLC genome?

It can be done via NextGen DNA sequencing. Molecular profiling of the lung cancer genome is necessary in order to ensure the best treatment approach.


Is there something that can be done to avoid TP53 mutation?

Cancer is a biological accident. Mutations happen when the protein (called a DNA polymerase) puts in the wrong DNA base during DNA replication process by accident. Some of these mutations may change a protein function, which may lead to cancer. Cancer is the loss of cell cycle regulation resulting in unlimited cell division. These cancer cells keep dividing and replace the normal cells in the our organs. As a result, the organs fail to function properly and the patient dies. But cancer is a not a death sentence anymore. Cancer treatment has improved cancer survival a lot in the past 25 years. It is only going to get better. Eventually cancer is going to become a chronic disease, which may not be curable but patients may be able to live a long good quality life.



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Author: Anirban Mukherjee, PhD

June 2, 2021

Founder | Cancer Therapies 4 U LLC

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