Overview of Cancer
An overview of cancer, including the genetic alterations and nongenetic factors that contribute to the development of the disease
What Is Cancer?
Cancer is the second leading cause of death in the world and has emerged as a key therapeutic target in gene therapy1,2
Cancer develops when there is an abnormal growth of cells in a particular part of the body3
These cancer-causing cells continue to grow, divide and multiply instead of dying, resulting in the formation of a tumour3,4
Types of Cancer
There are many different types of cancer that can be categorised based on the specific type of cell from which the cancer originates4,5
The major types of cancer are:
- The most common type of cancer; formed by epithelial cells
- Carcinomas originate in organs and glands, including:
BAP1, BRCA2, CDK4, CDKN2A, MITF, PTCH1, PTCH2
APEX1, ATM, AXIN2, CHRNA3, CHRNA5, CLPTM1L, CXCR2, CYP1A1, CYP2E1, ERCC1, ERCC2, FGFR4, HYKK, MIR146A, MIR196A2, OGG1, PON1, REV3L, SOD2, TERT, TP53
ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53
ATM, BRCA1, BRCA2, CDKN2A, MLH1, TP53
- Sarcomas form in bone and soft tissues (e.g. muscle, fat, blood vessels, lymph vessels and other connective tissues)
ATRX, CDKN2A, IDH1, IDH2, TBXT, TP53
ATRX, CDKN2A, CDKN2B, RB1, TP53
- Leukemia originates from the blood-forming tissue of the bone marrow
- It does not usually form solid tumours
- There are several different types of leukemia that are divided into:
ASXL1, BAALC, BCR-ABL1, CBL, CEBPA, DNMT, ERG, FLT3, IDH, KIT, MN1, NPM1, PTPN11, RAS, TET2, WT1
ATM, KLHL6, KRAS, MYD88, NOTCH1, SF3B1, TP53, XPO1
- Lymphoma originates from lymphocytes (T cells or B cells) and includes:
AIF1, BAT4, IL-10, RING1/RXRB, SYK, TNF
ABL1, B2M, BCL10, BTK, CARD11, CD19, CREBBP, CSF1R, CSF2RB, EP300, FAS, MYB, NFKB2, NFKBIA, STAT6
- Multiple myeloma originates from plasma cells of the immune system
BRAF, CCND1, FCRL4, FGFR3, IRF4, LIG4, MAF, PWWP3A, chromosome 14
- Melanoma originates from cells that become melanocytes
- In the majority of cases, melanoma occurs on the skin (cutaneous melanoma)
- In ~5% of cases, it develops in melanocytes of other tissues, including the eyes and lining of the mouth
ASIP, ATM, BAP1, BRAF, CASP8, CDK4, CDK10, CDKN2A, EGF, HERC2, IRF4, KITLG, MC1R, MITF, MTAP, MX2, MYH7B, NRAS, OCA2, PIGU, PLA2G6, POT1, SLC2A4, SLC45A2, TERT, TP53, TPCN2, TYR, TYRP1, XRCC3
Brain and spinal cord tumour5,23–25
- These tumours form in the central nervous system and are classified based on the type of cell the tumour originates from
ATRX, BRAF, CDKN2A, CHEK2, IDH1, NF1, NF2, TSC1, TSC2, TP53, VHL
BRAF, CDKN2A, H3F3A, HOXB5, IDH1, ITIH2, MMP9, NF1, NF2, PLA2G5, PTEN, VHL
Other tumour types5
Germ cell tumours
- Tumours that originate from cells that develop into sperm or egg
- Tumours that originate from hormone-producing cells
Causes of Cancer
- Cancer is a genetic disease that is caused by alterations in genes responsible for cell growth and function5
- These genes are of three main types — proto-oncogenes, tumour-suppressor genes and DNA repair genes5,26–28
- Encode proteins that stimulate cell division, inhibit cell differentiation and halt cell death
- When mutated, proto-oncogenes become oncogenes and result in increased cell division and differentiation
- Mutations in proto-oncogenes occur as a result of chromosomal rearrangements or gene duplication
- Encode proteins responsible for repairing damaged DNA
- Deficient DNA repair with prolonged existence of damaged DNA can lead to gene mutations, chromosomal rearrangements, genomic instability and eventually cancer
- Encode proteins that slow cell division, repair DNA and promote apoptosis
- When mutated, tumour-suppressor genes become inactivated, resulting in decreased inhibition of cell division and reduced apoptosis
Genetic Alterations in Cancer
The genetic alterations in cancer are heterogeneous and vary depending on the type of disease29
Schematic Representation of the Genetic Alterations in Cancer29–36
- This describes structural changes in chromosomes caused by an addition, deletion or altered segment of chromosomal DNA
- Chromosomal rearrangements can result in fusion genes, made by joining parts of two different genes. The fusion protein expressed may lead to cancer
Example: In thyroid cancer, chromosomal rearrangement involving the RET gene produces the fusion oncogene RET/PTC
- This includes duplication or deletion of genomic sequences that can lead to changes in gene expression, particularly for oncogenes and tumour-suppressor genes
Example: CNV in the ANO1 oncogene is associated with oesophageal squamous cell cancer
- Genome-wide hypomethylation and site-specific CpG island promoter hypermethylation may increase expression of oncogenes and silence tumour-suppressor genes, respectively
- Histone modifications, including addition of acetyl and methyl groups, impact tumour progression
Example: Hypomethylation of the oncogene RRAS causes transcriptional activation in gastric cancer
- SNPs affect gene expression; they are located in gene promoters, exons, introns and 5’- or 3’-untranslated regions
Example: A cytosine to adenine (C>A) SNP in the promoter region of the tumour-suppressor gene CDH1 decreases gene transcription and promotes tumourigenesis (as in prostate, breast, colon and pancreatic cancers)
Genetic and Nongenetic Risk Factors
Cancer-causing genetic alterations can:
- Be inherited
- Occur as a result of errors during cell division
- Arise from environmental exposures5
Inherited genetic alterations predispose individuals to developing cancer. Examples include:32
- Variants in tumour-suppressor genes, such as TP53, BRCA1 and BRCA2 and PTEN
Genetic alterations can be induced by nongenetic factors, including:5,37–39
Gene Therapy in Cancer
- Despite the heterogeneous nature of cancer, it involves genetic alterations that can be targeted by gene therapy40
- This has led to the development of innovative gene therapy approaches for the treatment of cancer40
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- National Cancer Institute. Genetics of skin cancer (PDQ®)–health professional version. Available at: https://www.cancer.gov/types/skin/hp/skin-genetics-pdq. Accessed 11 September 2020.
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- Lagunas-Rangel FA, et al. Int J Hematol Oncol Stem Cell Res 2017;11:328–339.
- National Institutes of Health. Chronic myeloid leukemia. Available at: https://ghr.nlm.nih.gov/condition/chronic-myeloid-leukemia#genes. Accessed 11 September 2020.
- My Cancer Genome. Acute lymphoblastic leukemia. Available at: https://www.mycancergenome.org/content/disease/acute-lymphoblastic-leukemia/. Accessed 11 September 2020.
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- Mata E, et al. Oncotarget 2017;8:111386–1113
- National Institutes of Health. Multiple myeloma. Available at: https://ghr.nlm.nih.gov/condition/multiple-myeloma#genes. Accessed 11 September 2020.
- National Institutes of Health. Melanoma. Available at: https://ghr.nlm.nih.gov/condition/melanoma#genes. Accessed 11 September 2020.
- American Society of Clinical Oncology. Von Hippel-Lindau syndrome. Available at: https://www.cancer.net/cancer-types/von-hippel-lindau-syndrome. Accessed 16 September 2020.
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- American Cancer Society. Oncogenes and tumor suppressor genes. Available at: https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html. Accessed 6 July 2020.
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- Gandhi M, et al. Mol Cell Endocrinol 2010;321:36–43.
- National Cancer Institute. Genetics of cancer. Available at: https://www.cancer.gov/about-cancer/causes-prevention/genetics. Accessed 19 June 2020.
- National Cancer Institute. Fusion gene. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/fusion-gene. Accessed 18 June 2020.
- Miller MA, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. In: Zachary JF (Ed). Pathologic Basis of Veterinary Disease. 6th edn. Maryland Heights, MO: Elsevier Inc, 2017:2–43.
- Shao X, et al. BMC Med Genet 2019;20:175.
- Yu Y, et al. Carcinogenesis 2019;40:1198–1208.
- American Society of Clinical Oncology. Understanding cancer risk. Available at: https://www.cancer.net/navigating-cancer-care/prevention-and-healthy-living/understanding-cancer-risk. Accessed 19 June 2020.
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