5th March 2024

Oncogenesis

Pathogenesis of cancer

Cancer Biology

Cancer is an all-encompassing condition affecting multiple systems and is typically clonal in origin. Cell division is a tightly controlled process with multiple checkpoints within the cycle to ensure cell division does not progress unchecked. Multiple enzymatic pathways also help with DNA mutation recognition and repair. Errors within any of these pathways can result in the development of tumours. Studies have looked into the features that cancer displays, and the typical hallmarks of cancer are highlighted in the image below.

In essence, somatic cells would need to acquire the ability to bypass the normal cell regulation processes. This will require the cell to acquire multiple specific genetic mutations. Increased cell turnover and genetic instability are common findings in all tumour cells as this encourages the generation of genetic mutations necessary for the tumour cells to bypass standard cell regulations. Environmental factors like diet, smoking, alcohol and sun exposure can increase tumorigenesis risks.

A better understanding of the cancer hallmarks has allowed us to identify the responsible signalling proteins, receptors and enzymes that permit the cancer cell to allow it to escape the usual cell cycle regulations. New treatment options have been developed to target these receptors and proteins, allowing treatment tailored towards the patient’s malignancy.

Novel immunotherapies have been developed to target molecules that drive some of the hallmarks of cancer, including checkpoint inhibition ( allows WCC to target cancer cells that would usually evade the immune system with examples including pembrolizumab), monoclonal Ab targeting specific cell receptors ( e.g., trastuzumab, rituximab), tyrosine kinase inhibitors ( split into EGFR inhibitors, PDGF inhibitors and VEGF inhibitors as examples). While it is important to acknowledge that these treatments are available, the specifics of these treatments are outside the scope of the MRCP part 1 examination.

Image Source: Wikimedia Commons (2021). The Hallmarks of cancer & The Hallmarks of aging, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:The_Hallmarks_of_cancer_%26_The_Hallmarks_of_aging.jpg (Accessed: 5 January 2024).

Oncogenes

Oncogenes are highly conserved DNA segments responsible for regulating normal cell growth. They often express growth factors, growth factor receptors, nuclear transcription factors and signal transduction molecules. Oncogene activation can occur via:

• Amplification of oncogene – HER2 amplification in breast cancer
• Point mutation or intragenic deletion – EGFR mutation in lung cancer, KIT mutation in gastrointestinal stromal tumours, RET mutation in MEN2
• Chromosomal rearrangement – BCR-ABL fusion gene in CML ( t9:22 fusion gene); mantle cell lymphoma (t11:14 translocation); Burkitt lymphoma (t8:14 translocation); Acute promyelocytic leukaemia (t15:17 translocation)

Most oncogenes exert a dominant influence as only one mutated copy of the gene is sufficient to result in the malignant transformation of the cell. Most oncogene mutations are gain-of-function mutations that result in abnormal or increased gene expression and increasing protein levels.

Tumour suppressor gene

Tumour suppressor genes typically produce the necessary enzymes and signalling proteins that control cell proliferation. This includes DNA repair mechanisms, inhibiting cell replication and inducing cell death via apoptosis. Most conditions involving tumour suppressor genes are inherited in an autosomal dominant fashion, while on a cellular level, the cells display a homozygous recessive pattern before displaying a malignant phenotype. This stems from the “2-hit theory”, whereby the initial genetic mutation provides the first hit against the tumour suppressor genes, making it more likely for a second mutation to occur in the other functioning copy of the gene, resulting in tumorigenesis.

Examples of such genes include the BRCA1/BRCA2 gene, RB1 gene in retinoblastomas, APC in familial adenomatous polyposis, TP53 in Li-Fraumeni syndrome, ATM gene in ataxic telangiectasia and NF1/NF2 genes in neurofibromatosis types 1 and 2 respectively.

DNA mismatch repair

Mismatch repair systems exist within all cells to help correct errors made during DNA replication by DNA polymerase. Mutation in the genes responsible for this system results in microsatellite instability. Microsatellites are short repeat tandem sequences within the gene that can obtain fewer or extra repeats during DNA replication. Instability occurs when the mismatch repair mechanism fails, resulting in additional nucleotides being added to the strand and can result in frameshift mutations that inactivate the gene. This is most commonly associated with colorectal, stomach and endometrial cancers.

HNPCC or Lynch syndrome is the most common example of inheritable cancer caused by microsatellite instability resulting from mutations in the MSH2 or MLH1 genes.

References

• Gallagher, C., Lister, T., & Smith, M. (2012). Malignant disease In P. Kumar & M. Clark (Eds.), Kumar and Clark’s Clinical Medicine. Spain: Elsevier Saunders.
• Strachan, T., & Read, A. (2019). Cancer Genetics and Genomics. In Human Molecular Genetics. United States: CRC Press.
• Read, A., & Donnai, D. (2021). Chapter 7 – Is cancer genetic? In New Clinical Genetics (4th ed.). United Kingdom: Scion Publishing Ltd.
• Kingston, H. (2002). Genetics of Cancer. In ABC of Clinical Genetics (3rd ed.). Malaysia: BMJ Books.
• Jorde, L., Carey, J., & Bamshad, M. (2016). Cancer Genetics. In Medical Genetics. Canada: Elsevier.
• Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70. doi:10.1016/s0092-8674(00)81683-9
• Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674. doi:10.1016/j.cell.2011.02.013