Driver Mutations in Cancer
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Driver Mutations in Cancer
Cancer cells are abnormal copies of cells caused by somatic mutations in the DNA.[1]. These mutations are acquired over the years, some of which randomly occur in normal cells, some that are inherited, and some that arise due to mutagens, such as tobacco smoke and ultraviolet light, that damage DNA in normal cells[1]. Although the number varies based on tumor type, there are typically a large number of mutations in a human cancer cell[2]. For instance, in common solid tumors like breast cancer, there are approximately 33–66 genes that contain somatic mutations per cell, though they do not all necessarily contribute to cancer development[1][2]
Driver Mutations vs. Passenger Mutations
Cancer genomes typically consist of several “driver” and “passenger” mutations. Driver mutations are mutations that “confer growth advantage” to cells, thus allowing survival and proliferation.[1]. The rest of the mutations that do not confer this growth advantage are called passenger mutations[1]. Passenger mutations that can be found in cancer genomes must have been acquired in the ancestor of the cancer cell, but were not involved with its development[1]. Driver genes, however, play an essential role in cancer development by affecting one or more of 12 signaling pathways regulating three essential cellular processes: cell fate, cell survival, and genome maintenance[2]
Cell Fate
Cell fate involves the cell’s decision to differentiate as opposed to divide. Many driver mutations in cancer disrupt this distinction between cell differentiation and division, resulting in an increase in cell division, thus increasing cell proliferation rate.[2]. This is considered a growth advantage because cells that differentiate ultimately die or will be dormant[2]. APC, HH, and NOTCH are examples of pathways involved in cell fate[2]. In addition, in typical cells, “epigenetic alterations affecting DNA and chromatin proteins” are involved in this distinction. Thus, mutations in genes that are responsible for DNA modification can also alter cell fate, ultimately resulting in cancerous cell growth[2]
Cell Survival
Cancer cells divide abnormally compared to normal cells, and as a result, the vasculature of tumor cells is unique.[2]. Why is tumor vasculature relevant? Cancer cells can acquire mutations that confer selective growth advantage by allowing them to survive and divide in stressful microenvironments with inadequate nutrients[2]. This way, the cancer cells outgrow surrounding normal cells that cannot survive under these conditions[2]. An example of this is seen in mutations in genes KRAS and BRAF[2]. These mutations allow cancer cells to survive and proliferate in low glucose microenvironments[2]. Moreover, genes such as CDKN2A, MYC, and BCL2 are involved in cell cycle progression and apoptosis, which are also commonly mutated in cancer genomes[2]
Genome Maintenance
Because it is common for mutations to occur in normal cells, cells have evolved ways to check for damaged DNA and repair or destroy damaged cells through apoptosis.[2]. Mutations in TP53 and ATM genes, which are involved in these cell cycle processes, provide a growth advantage. This is because tumor cells with damaged DNA can survive by surpassing these checkpoints and avoiding apoptosis[2]. In addition, genes that regulate mutation rates, such as MLH1 or MSH2, may develop mutations themselves, which increases the risk of acquiring mutations that affect one of these cellular processes[2]
Driver Mutations
As of 2013, there have been 138 cancer driver genes discovered.[2]. As mentioned above, studies have suggested that different tumor types require a different number of driver mutations in order for cancer to develop. For solid tumors, cancer cells seem to need approximately 5–8 driver mutations, whereas pediatric tumors require a lower number for cancer development[3][2]. Recent studies, however, have suggested that a cancer might require up to 20 driver mutations, compared to previous findings[1]
Oncogenes and Tumor Suppressor Genes
Two common driver mutations occur in oncogenes and tumor suppressor genes.[3]. Oncogenes work by activation or by creating new functions[3]. Genes like PIK3CA and IDH1 are identified as oncogenes because >20% of their mutations are localized at the same position and are missense mutations[2]. PIK3CA, for instance, aids in tumor metastasis[2]. Tumor suppressors work as inactivators[2]. Genes like RB1 and VHL are identified as tumor suppressor genes because >20% of their mutations result in inactivation[2]. The Rb gene, for instance, acts as a negative regulator for tumorigenesis[4]. When Rb is mutated, it is inactivated, causing tumor development[4]
Examples of Driver Mutations in Cancer
Although they are difficult to identify, researchers have discovered a handful of possible driver mutations in breast cancer. Mutations in genes like ARID5B, CDH1, CTCF, HDAC9, and NCOR2 act as possible driver mutations.[5]. These genes are responsible for encoding proteins involved with chromatin structure, which is important for mitosis and meiosis, preventing chromosome damage, and regulating gene expression[5][6]. In addition, genes such as ATR and FANCA are crucial players in DNA repair pathways in breast cancer[5]
There are different driver mutations in pancreatic cancer, including activating KRAS mutations and loss of function mutations like P16/CDKN2A, TP53, and SMAD4/DPC4.[7]. KRAS mutations aid in transforming normal cells into cancer cells[7]. Once transformed, P16/CDKN2A, TP53, and SMAD4/DPC4 aid in tumor progression and proliferation[7]
There are also many common driver mutations that have been “re-discovered” in various tumor types. Mutations in genes like MLL2 and MLL3 are found in medulloblastomas, non-Hodgkin lymphomas, prostate cancers, and breast cancers.[2]
Heterogeneity of Cancer
Cancer is known to be highly heterogeneous, which makes treatment difficult. First, cancer cells can be variable within one tumor, also known as intratumoral heterogeneity[2]. Cells can also differ based on their metastatic potential within one patient, which is known as intermetastatic heterogeneity[2]. This makes treatment difficult once a patient has formed several metastases. Fortunately, this variability is typically found in passenger genes rather than driver genes[2]. More specifically, there is heterogeneity among cells in a single metastasis. As each metastasis grows, it will develop more and more mutations[2]. This is how tumor cells become resistant to cancer therapies. These therapies target the original “founder cell” of the metastasis, but cannot keep pace with the multiple mutations that follow[2]. Lastly, tumor cells between patients are vastly different. There are many reasons for this. Two patients with the same cancer could have acquired different driver mutations in different genes, which could have affected different pathways or cellular processes[1][2]. Cancer is an extremely complex, rapidly evolving disease that can arise in multiple forms due to multiple causes.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Stratton, Michael R.; Campbell, Peter J.; Futreal, P. Andrew (9 April 2009). "The cancer genome". Nature. 458 (7239): 719–724. Bibcode:2009Natur.458..719S. doi:10.1038/nature07943. PMC 2821689. PMID 19360079.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 Vogelstein, Bert; Papadopoulos, Nickolas; Velculescu, Victor E.; Zhou, Shibin; Diaz, Luis A.; Kinzler, Kenneth W. (29 March 2013). "Cancer Genome Landscapes". Science. 339 (6127): 1546–1558. Bibcode:2013Sci...339.1546V. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594.
- ↑ 3.0 3.1 3.2 Pon, Julia R.; Marra, Marco A. (2015). "Driver and Passenger Mutations in Cancer". Annual Review of Pathology: Mechanisms of Disease. 10: 25–50. doi:10.1146/annurev-pathol-012414-040312. PMID 25340638.
- ↑ 4.0 4.1 Cooper, Geoffrey M. (2000). "Tumor Suppressor Genes". The Cell: A Molecular Approach. 2nd edition. Retrieved 15 December 2018.
- ↑ 5.0 5.1 5.2 Rajendran, Barani Kumar; Deng, Chu-Xia (19 April 2017). "Characterization of potential driver mutations involved in human breast cancer by computational approaches". Oncotarget. 8 (30): 50252–50272. doi:10.18632/oncotarget.17225. PMC 5564847. PMID 28477017.
- ↑ "Chromatin Structure & Function: a guide by Abcam". www.abcam.com. Retrieved 15 December 2018.
- ↑ 7.0 7.1 7.2 Korc, Murray (15 September 2010). "Driver mutations". Cancer Biology & Therapy. 10 (6): 588–591. doi:10.4161/cbt.10.6.13128. PMC 3040949. PMID 20716952.
Driver Mutations in Cancer
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