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Molecular mechanisms underlying the regulation of tumour suppressor genes in lung cancer
Jia Yee Lee1, Richie R Bhandare2, Sai H S Boddu2
1School of Health Sciences, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia.
Abstract:
Tumour suppressor genes play a cardinal role in the development of a large array of human cancers, including lung cancer, which is one of the most frequently diagnosed cancers worldwide. Therefore, extensive studies have been committed to deciphering the underlying mechanisms of alterations of tumour suppressor genes in governing tumourigenesis, as well as resistance to cancer therapies. In spite of the encouraging clinical outcomes demonstrated by lung cancer patients on initial treatment, the subsequent unresponsiveness to first-line treatments manifested by virtually all the patients is inherently a contentious issue. In light of the aforementioned concerns, this review compiles the current knowledge on the molecular mechanisms of some of the tumour suppressor genes implicated in lung cancer that are either frequently mutated and/or are located on the chromosomal arms having high LOH rates (1p, 3p, 9p, 10q, 13q, and 17p). Our study identifies specific genomic loci prone to LOH, revealing a recurrent pattern in lung cancer cases. These loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), 17p13 (TP53), exhibit a higher susceptibility to LOH due to environmental factors such as exposure to DNA-damaging agents (carcinogens in cigarette smoke) and genetic factors such as chromosomal instability, genetic mutations, DNA replication errors, and genetic predisposition. Furthermore, this review summarizes the current treatment landscape and advancements for lung cancers, including the challenges and endeavours to overcome it. This review envisages inspired researchers to embark on a journey of discovery to add to the list of what was known in hopes of prompting the development of effective therapeutic strategies for lung cancer.
Insights
Tumour suppressor gene alterations drive lung cancer development and treatment resistance. This review details key genes and genomic regions prone to loss of heterozygosity (LOH), informing new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumour suppressor genes are critical in preventing cancer, and their alterations are implicated in numerous human cancers, notably lung cancer.
- Lung cancer's high incidence worldwide and the common issue of acquired resistance to initial treatments necessitate a deeper understanding of its molecular underpinnings.
- Loss of heterozygosity (LOH) on specific chromosomal arms is frequently observed in lung cancer, suggesting critical tumour suppressor genes reside in these regions.
Purpose of the Study:
- To review the molecular mechanisms of tumour suppressor gene alterations in lung cancer.
- To identify frequently mutated genes and chromosomal arms with high LOH rates (1p, 3p, 9p, 10q, 13q, 17p) in lung cancer.
- To summarize current lung cancer treatment strategies, challenges, and future directions.
Main Methods:
- Compilation and review of current scientific literature on tumour suppressor genes and LOH in lung cancer.
- Identification of specific genomic loci (e.g., 3p14.2, 9p21.3, 10q23, 17p13) frequently affected by LOH.
- Analysis of contributing factors to LOH, including environmental and genetic elements.
Main Results:
- Specific genomic loci, including 3p14.2 (FHIT), 9p21.3 (p16INK4a), 10q23 (PTEN), and 17p13 (TP53), show high susceptibility to LOH in lung cancer.
- LOH at these loci is influenced by environmental factors like carcinogen exposure and genetic factors such as chromosomal instability and mutations.
- A recurrent pattern of LOH at these specific sites is identified across lung cancer cases.
Conclusions:
- Understanding the role of tumour suppressor genes and LOH patterns is crucial for deciphering lung cancer development and progression.
- Environmental and genetic factors contribute significantly to LOH, highlighting the complex etiology of lung cancer.
- This review provides a foundation for further research into targeted therapies aimed at overcoming treatment resistance in lung cancer.
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