Overview of Cancer

An overview of cancer, including the genetic alterations and non-genetic 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 tumor3,4

Figures from Cancer Research UK. What is cancer? Available at: https://www.cancerresearchuk.org/about-cancer/what-is-cancer. Accessed September 11, 2020.

Types of Cancer

There are many different types of cancer that can be categorized based on the specific type of cell from which the cancer originates4,5

The major types of cancer are:

Carcinoma4–9

  • The most common type of cancer; formed by epithelial cells
  • Carcinomas originate in organs and glands, including:

Skin

BAP1, BRCA2, CDK4, CDKN2A, MITF, PTCH1, PTCH2

Lung

APEX1, ATM, AXIN2, CHRNA3, CHRNA5, CLPTM1L, CXCR2, CYP1A1, CYP2E1, ERCC1, ERCC2, FGFR4, HYKK, MIR146A, MIR196A2, OGG1, PON1, REV3L, SOD2, TERT, TP53

Breast

ATM, BRCA1, BRCA2, CDH1, CHEK2, PALB2, PTEN, STK11, TP53

Pancreas

ATM, BRCA1, BRCA2, CDKN2A, MLH1, TP53

Sarcoma5,10–13

  • Sarcomas form in bone and soft tissues (e.g. muscle, fat, blood vessels, lymph vessels, and other connective tissues)

Bone sarcoma

ATRX, CDKN2A, IDH1, IDH2, TBXT, TP53

Soft tissue sarcoma

ATRX, CDKN2A, CDKN2B, RB1, TP53

Leukemia4,5,14–17

  • Leukemia originates from the blood-forming tissue of the bone marrow
  • It does not usually form solid tumors
  • There are several different types of leukemia that are divided into:

Myeloid Leukemia

ASXL1, BAALC, BCR-ABL1, CBL, CEBPA, DNMT, ERG, FLT3, IDH, KIT, MN1, NPM1, PTPN11, RAS, TET2, WT1

Lymphoblastic leukemia

ATM, KLHL6, KRAS, MYD88, NOTCH1, SF3B1, TP53, XPO1

Lymphoma5,18–20

  • Lymphoma originates from lymphocytes (T cells or B cells) and includes:

Non-Hodgkin lymphoma

AIF1, BAT4, IL-10, RING1/RXRB, SYK, TNF

Hodgkin lymphoma

ABL1, B2M, BCL10, BTK, CARD11, CD19, CREBBP, CSF1R, CSF2RB, EP300, FAS, MYB, NFKB2, NFKBIA, STAT6

Multiple myeloma5,21

  • Multiple myeloma originates from plasma cells of the immune system

Multiple myeloma

BRAF, CCND1, FCRL4, FGFR3, IRF4, LIG4, MAF, PWWP3A, chromosome 14

Melanoma5,22

  • 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

Melanoma

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 tumor5,23–25

  • These tumors form in the central nervous system and are classified based on the type of cell the tumor originates from

Brain

ATRX, BRAF, CDKN2A, CHEK2, IDH1, NF1, NF2, TSC1, TSC2, TP53, VHL

Spinal cord

BRAF, CDKN2A, H3F3A, HOXB5, IDH1, ITIH2, MMP9, NF1, NF2, PLA2G5, PTEN, VHL

Other tumor types5

Germ cell tumors

  • Tumors that originate from cells that develop into sperm or egg

Neuroendocrine tumors

  • Tumors 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, tumor-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, tumor-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 tumor-suppressor genes

Example: CNV in the ANO1 oncogene is associated with esophageal squamous cell cancer

  • Genome-wide hypomethylation and site-specific CpG island promoter hypermethylation may increase expression of oncogenes and silence tumor-suppressor genes, respectively
  • Histone modifications, including addition of acetyl and methyl groups, impact tumor 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 tumor-suppressor gene CDH1 decreases gene transcription and promotes tumorigenesis (as in prostate, breast, colon, and pancreatic cancers)

Genetic and Non-Genetic 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 include32:

  • Variants in tumor-suppressor genes such as TP53, BRCA1 and BRCA2, and PTEN

Genetic alterations can be induced by non-genetic factors including5,37–39:

cancer04.svg

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
cancer05.svg

References

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