Introduction

A somatic mutation is any alteration at the cellular level in somatic tissues that occurs after fertilization. These mutations do not involve the germline and consequently do not pass on to offspring. Somatic mutations are a normal part of aging and occur throughout an organism’s life cycle either spontaneously as a result of errors in DNA repair mechanisms or a direct response to stress. Mutations occurring early in development can cause germline mosaicism, affecting organismal development. The effects of mosaicism on overall health depend on the specific gene affected by the mutation.

Environmental stressors and errors that occur during cellular replication increase the risk of somatic mutations.[1] Radiation, exposure to certain chemical compounds, and intracellular processes that generate free radicals are stressors that can cause cellular damage and DNA mutations. After a mutation occurs, the newly altered DNA undergoes normal cellular replication and then becomes incorporated into all subsequent progeny cell lines within the individual.

Somatic mutations have received the most study in human carcinogenesis. Various mutations in oncogenes, tumor suppressor genes, and DNA repair mechanisms can confer a growth advantage and promote tumor survival.[2] Mutations that alter the machinery of DNA replication or repair arrest the cell cycle, leading to cell death. As a result of defects in tumor suppressor genes, oncogenes, and genes required for genome stability, the individual inherits an increased risk for cancer in corresponding genes as somatic mutations continue to accumulate within already unstable genes.[3]

Cellular

Cellular stressors generate free radicals, causing damage to DNA. The resulting DNA damage creates mutations that are normally repaired by DNA mismatch repair systems. If stressors induce mutations in DNA mismatch repair or replication systems, this can lead to irreversible genomic breaks, damage, and loss of the original genome template.[2] The mutations can accumulate faster than repair mechanisms can repair them, rendering DNA repair ineffective and resulting in loss of function in the respective gene. Mutations can manifest as point mutations, single-nucleotide variants, or copy number variants. Copy number variants create variable numbers of genes resulting from somatic mutations, which, on a large scale, present as chromosomal mosaicism. These mutations cause genome mosaicism as the variant allele fraction (VAF), or the number of mosaic variations occurring in a cell line, increases with the accumulation of mutations. The more prevalent the mutations are and the earlier in development they occur, the greater the VAF and risk for detrimental effects within the organism.[4]

The rate of somatic mutations often exceeds that of the mismatch repair system, allowing mutated cells to continue proliferating.[5] As a cell accumulates more mutations, it becomes unable to pass key replication checkpoints, cannot be repaired, and dies. Mutations that allow cells to bypass these replication checkpoints and mutations that provide survival and replicative advantage among cell lines are crucial in the development of carcinogenesis. The mutations that do not increase carcinogenesis alter cell function without causing a noticeable downstream effect. Normal cellular aging leads to an increase in mutation frequency and an increased risk of carcinogenesis as the genes responsible for replication begin to lose efficiency.[5] The increasing mutation burden outstrips cellular repair capacity, leading to death or tumor formation in the affected tissues.

Somatic mutations early in cell development can lead to variation in the typical phenotypic presentation of a cell line. Mutations arising in early neurocognitive development can cause mosaicism of progenitor cell lines, contributing to brain development. Large-scale mosaicism in neurocognitive tissues can cause intellectual disability and epilepsy.[6] In individuals with Down syndrome, mosaicism can occur within the trisomy on chromosome 21. As a result, mutations in the extra chromosome are only present in some but not all cells in the genome, causing milder phenotypic presentation of trisomy 21.[6] In immature cells with high replication rates, somatic mutations are more likely to be phenotypically represented. In the postmitotic cell, phenotypical changes are less likely to occur. When considering cancer specifically, cancers with the highest somatic mutation rates arise from tissues with high cellular turnover. This turnover rate could result from mutations accumulated by the cancer cell line or from constant exposure to stress.[1] One study illustrated lung carcinomas having the greatest rate for somatic mutations, followed by gastric cancer, as these surface epithelia experience recurrent mutagen exposure.[1] In another study, the more rapid cellular turnover of epithelial cells results in a tenfold higher mutation rate than in cells like peripheral lymphocytes, which replicate less.[5]

Mechanism

There is a general lack of knowledge about the exact mechanisms of somatic mutations outside the context of carcinogenesis.[2] However, somatic mutations are also responsible for general cellular aging and for diseases that occur later in life. Most mutations within somatic tissues are random and rarely beneficial to organisms. In general, somatic mutations are low-frequency and are only detectable by genome amplification.[2] Mutations involving fewer than 10% of cells in a tissue sample are not normally detectable using genome amplification strategies. Limitations of current amplification strategies restrict current studies to sizeable mutations, most often in cancer.[2] To detect smaller mutations, recent studies show the effective sequencing of entire genomes from single cells.[7] Mutations that do not involve DNA replication processes continue to propagate with each cell division and accumulate within cells.[2] 

Subsequent cell divisions increase the number of mutated cells, which accumulate and impair cell function, potentially leading to cell death. Exposure to mutagens such as radiation, chemicals, and processes that generate free radicals within the cellular environment increases the incidence of cancer through mutations.[2] Cigarette smoke produces carcinogens from burning the various chemical compounds within tobacco. Over 5000 chemicals have been identified in tobacco smoke. Within these chemical components, the International Agency for Research on Cancer classifies over 70 as having sufficient evidence for carcinogenesis, and over 20 classified as true lung carcinogens.[8] The chemical compounds produced by tobacco cause metabolites to covalently attach to DNA, forming DNA adducts.[9] DNA adducts accumulate with continued tobacco use, affecting DNA repair and replication. Adducts resulting in mutations that inhibit cell death cause tumor formation. Studies show a 10-fold higher incidence of mutations in tumors from individuals with lung cancer in smokers when compared to lung cancer tumors in those who have never smoked.[10]

Clinical Significance

The accumulation of somatic mutations appears to be a component of cellular aging, various disease processes, and cancer. Oxidative damage resulting from normal cellular processes contributes to aging and cancer in mammalian species with higher metabolic rates than humans, whose metabolism is lower.[11] However, somatic mutations are a normal part of cellular aging and the human life cycle. As the number of mutated cells increases within a tissue, organ aging occurs, with function declining, ultimately causing deterioration of systems and eventual death.[2] One study illustrated this concept by comparing younger and older individuals with cancer. In younger individuals, there were more somatic mutations in their tumors than in older individuals’ tumors, suggesting that mutations occur throughout development and contribute to aging.[12]

Somatic mutations that confer a growth advantage within the tissue or prevent cell death are the most likely to contribute to carcinogenesis. Mutations in tumor suppressor genes or proto-oncogenes result in uncontrolled cell division, ultimately leading to a massive accumulation of these mutated cells into a tumor. The rates at which somatic mutations occur in cancerous tissues are studied via sequencing and used to identify patterns in a tumor’s growth state.[13] The sequencing of tumor cells provides a more in-depth understanding of tumor biology while creating avenues for developing new therapeutic approaches and optimizing current therapies. The clinical significance of somatic mutations is vast. Some of the more well-known pathologies include McCune-Albright Syndrome, Paroxysmal Nocturnal Hemoglobinuria, Sturge-Weber, and variants of Lissencephaly.

McCune-Albright Syndrome (MAS) results from somatic mutations in the GNAS1 gene, causing gain-of-function mutations in G protein receptors that affect the skin, bone, and endocrine tissues. The continuous activation of G protein receptors in these tissues leads to excessive cell proliferation, predisposing individuals with this mutation to precocious puberty, polyostotic fibrous dysplasia of the bone, which can lead to weak bones and recurrent fractures, and café au lait pigmentation that does not cross the midline.[14]

Paroxysmal nocturnal hemoglobinuria (PNH) is a consequence of a somatic mutation in the PIGA gene, resulting in the absence of glycosylphosphatidylinositol (GPI) anchored proteins CD55 and CD59 on the red blood cell membrane. These anchor proteins protect red blood cells from the complement. The absence of these proteins from the red blood cell membrane allows intravascular hemolysis to occur whenever the body initiates the complement cascade in response to cellular stress. The somatic mutation commonly causes a frameshift, shortening the mRNA and resulting in failure to form the GPI surface protein.[15] The somatic mutation commonly causes a frameshift, shortening the mRNA and resulting in failure to form the GPI surface protein.

Sturge-Weber syndrome is caused by a somatic mutation in the GNAQ gene and is a neurocutaneous disorder with disruptions in vascular development.[16] Patients present with excess angiogenesis, causing a unilateral “port wine” stain along with the trigeminal distribution (nevus flammeus), arteriovenous malformations in the brain that trigger seizures, and/or causing intellectual disability and possible glaucoma of the eye as a result of excess capillary proliferation. The hallmark finding on MRI is a leptomeningeal angioma, usually on the ipsilateral side, as a port-wine stain. A computed tomography scan can show calcification; however, this is not a hallmark of the disease and usually appears later in the disease course. Somatic mutations in the lissencephaly-1 gene cause a loss of function in neurons, affecting the proper migration of neurons to their respective positions within the cortex, producing subcortical band heterotopia in the brain.[6] Failure of neuronal migration results in a band of cortical cells located between the cortex and the lateral ventricles.

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Disclosure: Brielle Miles declares no relevant financial relationships with ineligible companies.

Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.