Driver and Passenger Gene Mutations

Applying next generation sequencing (NGS) and RNA expression studies has provided clarity to understanding the origins of cancer. By aggregating and analyzing thousands of samples obtained from a wide variety of cancer types, researchers continue building The Cancer Genome Atlas, a public catalog of variants, epigenomic modifications, and abnormal gene expression profiles, which is visualized in the GDC. This endeavor along with Project Genomics Evidence Neoplasia Information Exchange (GENIE) housed in the cBioPortal (https:// www.cbioportal.org/) and the Pediatric Cancer Genome Project (PCGP) with illustrated data via the PECAN portal (https:// pecan. stjude.cloud/ ) are tremendous undertakings toward the annotation and classification of genomic variation detected in human cancers. These efforts continue to grow, and findings thus far are extremely informative. The number of mutations present in a tumor can vary from just a few to many tens of thousands. In general, pediatric cancers are more “silent” than adult tumors in terms of the number of mutations detected; however, there are notable exceptions to this trend (e.g., constitutional biallelic pathogenic variants in the mismatch repair (MMR) genes result in a very high mutational burden in both pediatric and adult tumors). When identified, this exceptionally high tumor mutational burden indicates a consideration for immunotherapy. Most variants identified through tumor sequencing appear to be random, are not recurrent in particular cancer types, and likely occurred as the cancer developed rather than directly causing the neoplasia to develop or progress. These are referred to as passenger mutations. However, a subset of a few hundred genes has repeatedly been found to be mutated at a frequency too high to be considered simply passenger in nature. These mutated genes occur in many samples of the same cancer type and often in multiple different types of cancers. They are presumed to be involved in the development or progression of the cancer itself and are therefore referred to as driver genes; that is, they harbor mutations (so- called driver mutations) that are likely to be causing a cancer to develop or progress. Although some driver genes are specific to particular tumor types, some, such as those in the TP53 gene encoding the p53 protein, are found in the vast majority of cancers. Although the most common driver genes are now known, it is likely that additional, less common driver genes will be identified as The Cancer Genome Atlas continues to grow. Another resource in identifying driver genes, (https://cancerhotspots.org/) provides evidence for variants as oncogenic based on gene size, expected mutation rate, and cancer types detected. This database is supported by mathematical modeling and statistical rigor to determine the likelihood that a specific variant is oncogenic.

Spectrum of Driver Mutations

Various genomic alterations can act as driver mutations. In some cases, a single nucleotide change or small insertion or deletion can be a driver mutation. Large numbers of cell divisions are required to produce an adult organism of an estimated 1014 cells from a single- cell zygote. Given a frequency of 10−10 replication errors per DNA base per cell division, and an estimated 1015 cell divisions during the lifetime of an adult, replication errors alone result in thousands of new single nucleotide or small insertion/ deletion variants in the genome in every cell of the organism. Some environmental agents, such as carcinogens in cigarette smoke or ultraviolet or X- irradiation, will increase the rate of mutation across the genome. If, by chance, mutations occur in critical driver genes in a particular cell, then the oncogenic process may be initiated and in some instances be evidenced by a tumor signature.

Gross chromosome and subchromosomal changes can also serve as driver mutations. Particular translocations or fusions are sometimes highly specific for certain types of cancer and involve specific genes (e.g., the BCR- ABL translocation in chronic myelogenous leukemia) (Case 10). In contrast, other cancers can have complex rearrangements in which chromosomes break into numerous pieces and rejoin, forming novel and complex combinations (a process known as chromothripsis [“chromosome shattering”]). Finally, large genomic alterations involving many kilobases of DNA can form the basis for loss of function or increased function of one or more driver genes. Large genomic alterations include deletions of a segment of a chromosome or multiplication of a chromosomal segment to produce regions with many copies of the same gene (gene amplification). The nature of these chromosomal events may be driven by somatic or germline events. In the case of fusions, these are nearly always postzygotic events. Complex combinations may be driven by constitutional alterations, for example, in the case of TP53 germline pathogenic variants associated with chromothripsis in some cancers. Large duplications or deletions may reflect constitutional or somatic origin.

The Cellular Functions of Driver Genes

The nature of some driver mutations comes as no surprise: the mutations directly affect specific genes that regulate processes that are readily understood to be important in oncogenesis. These processes include cell cycle regulation, cellular proliferation, differentiation and exit from the cell cycle, growth inhibition by cell- cell contacts, and programmed cell death (apoptosis). However, the effects of other driver mutations are not so readily understood and include genes that act more globally and indirectly affect the expression of many other genes. Included in this group are genes encoding products that maintain genome and DNA integrity or genes that affect gene expression, either at the level of transcription by epigenetic changes, at the posttranscriptional level through effects on messenger RNA (mRNA) translation or stability, or at the posttranslational level through their effects on protein turnover (see Table 1). Other driver genes affect translation, including, for example, genes that encode noncoding RNAs from which regulatory microRNAs (miRNAs) are derived. Many miRNAs have been found to be either overexpressed or down- regulated in various tumors, sometimes strikingly so. Because each miRNA may regulate as many as 200 different gene targets, over- or underexpression of miRNAs may have wide spread oncogenic effects because many driver genes will be dysregulated. Noncoding miRNAs that impact gene expression and contribute to oncogenesis are referred to as oncomirs. DICER1 is a gene encoding a protein involved in the production of miRNAs, and germline pathogenic variants in this gene predispose individuals to a number of benign and malignant tumors, including (among others) thyroid cancer, multinodular goiter, Sertoli- Leydig cell tumors, cystic nephroma, and pleuropulmonary blastoma.

Table1. Classes of Driver Genes Mutated in Cancer

Fig. 1 outlines how mutations in specific regulators of growth and in global guardians of DNA and genome integrity perturb normal homeostasis (see Fig. 1A), leading to a vicious cycle of loss of cell cycle control, uncontrolled proliferation, interrupted differentiation, and defects in apoptosis (see Fig. 1B).

Fig1. (A) Overview of normal genetic pathways controlling normal tissue homeostasis. The information encoded in the genome (black arrows) results in normal gene expression, as modulated by the epigenomic state. Many genes provide negative feedback (purple arrows) to ensure normal homeostasis. (B) Perturbations in neoplasia. Abnormalities in gene expression (dotted black arrows) lead to a vicious cycle of positive feedback (brown dotted lines) of progressively more disordered gene expression and genome integrity.

Oncogenes and Tumor Suppressor Genes

Both classes of driver genes— those with specific effects on cellular proliferation or survival and those with global effects on genome or DNA integrity (see Table 1)— can be further divided into two functional categories depending on how they drive oncogenesis when mutated.

The first category includes proto- oncogenes. When mutated in particular ways, these genes become drivers through alterations that lead to excessive levels of activity. Once mutated in this way, driver genes of this type are referred to as activated oncogenes. Only a single mutation on one allele is typically sufficient for activation. The mutations that activate proto- oncogenes range from highly specific point mutations causing dysregulation or hyperactivity of a protein, to chromosome translocations that drive overexpression of a gene, to gene amplification events that create an overabundance of the encoded mRNA and protein product (Fig. 2).

Fig2. Different mutational mechanisms leading to proto- oncogene activation. These include a single point mutation leading to an amino acid change that alters protein function, mutations or translocations that increase expression of an oncogene; a chromosome translocation that produces a novel product with oncogenic properties; and gene amplification leading to excessive amounts of the gene product.

The second, and more common, category of driver genes includes tumor suppressor genes (TSGs), mutations that cause a loss of expression of proteins necessary to control the development of cancers. To drive oncogenesis, loss of function of a TSG typically requires variants on both alleles. There are many ways that a cell can lose the function of TSG alleles; loss- of- function mechanisms range from missense, nonsense, or frame shift mutations to gene deletions or loss of a part or even an entire chromosome. Loss of function of TSGs can also result from epigenetic transcriptional silencing due to altered chromatin conformation or promoter methylation or from translational silencing by miRNAs or disturbances in other components of the translational machinery.

Cellular Heterogeneity Within Individual Tumors

The accumulation of driver mutations does not occur synchronously, in lockstep, in every cell of a tumor. To the contrary, cancer evolves along multiple lineages within a tumor, as chance mutational and epigenetic events in different cells activate proto- oncogenes and cripple the machinery for maintaining genome integrity, leading to more genetic changes in a vicious cycle of more mutations and worsening growth control. The lineages that experience an enhancement of growth, survival, invasion, and distant spread will come to predominate as the cancer evolves and progresses. In this way the original clone of neoplastic cells evolves and gives rise to multiple sublineages, each carrying a set of mutations and epigenomic alterations that are different from but overlap with what is carried in other sublineages. The profile of mutations and epigenomic changes can differ between the primary and its metastases, between different metastases, and even between the cells of the original tumor or within a single metastasis. A paradigm for the development of cancer (Fig. 3) provides a useful conceptual framework for considering the role of genomic and epigenomic changes in the evolution of cancer, a point we emphasize throughout this chapter. It is a general model that applies to all cancers.

Fig3. Stages in the evolution of cancer. Increasing degrees of abnormality are associated with sequential loss of tumor suppressor genes from several chromosomes and activation of proto- oncogenes, with or without a concomitant defect in DNA repair. Multiple lineages, carrying different mutations and epigenomic profiles, occur within the primary tumor itself, between the primary and metastases and between different metastases.

Although the focus of this chapter is on genomic and epigenomic changes within the tumor, the surrounding normal tissue also plays an important role by providing the blood supply that nourishes the tumor, by permitting cancer cells to escape from the tumor and metastasize, and by shielding the tumor from immune attack. Thus cancer is a complex process, both within the tumor and between the tumor and the normal tissues that surround it.

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اخبار العتبة العباسية المقدسة

شعبة الحرم الشريف تستعد لاستقبال زائري النصف من شهر شعبان

العتبة العباسية المقدسة تنشر لافتات الفرح بمناسبة ذكرى ولادة الإمام المهدي (عجّل الله فرجه)

العتبة العباسية المقدسة تفتتح التسجيل لتأدية الزيارة بالنيابة في ليلة النصف من شعبان

قسم المقام يعلن جاهزيّته لاستقبال زائري النصف من شعبان

المزيد

الآخبار الصحية

الصحة العالمية تكشف حقيقة انتشار فيروس نيباه خارج الهند

متى يصبح محيط الخصر "مؤشر خطر"؟

دراسة تكشف دور "العوامل الوراثية" في تحديد عمر الإنسان

رائحة كريهة في الجسم.. "علامة خفية" أخطر مما تتصور

المزيد

الآخبار التكنلوجية

مايكروسوفت تكشف عن الجيل الثاني من شرائحها للذكاء الاصطناعي

خرافة "ثمانية أكواب يوميا".. كم من الماء يحتاج جسمك فعليا؟

هل توجد حياة خارج كوكبنا؟.. اكتشاف جديد يثير اهتمام العلماء

اكتشاف الخلايا المسؤولة عن فقدان ذاكرة الطفولة

المزيد

مواضيع ذات صلة

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Genes and Environment in Development

Gene Therapy

The Genetics of mtDNA Disease

The APOE Gene Is an Alzheimer Disease Susceptibility Locus

The Genetics of Alzheimer Disease

Molecular Testing for Spinal Muscular Atrophy

Genetics of Spinal Muscular Atrophy

The Phenotypes of Spinal Muscular Atrophy

Chondrodysplasias are Caused by Mutations in Genes Encoding Type II Collagen & Fibroblast Growth Factor Receptors