Genetic Changes in Tumor - A Detailed Description

Introduction:

Genes are a part of DNA (deoxyribonucleic acid), which carry instructions to make several proteins. Changes in the genes such as alteration, mutation, or variation, can cause the cells to grow or multiply. Cancer can occur due to genetic changes such as errors in the DNA during the multiplication of cells, alteration of DNA by carcinogens such as tobacco, UV rays, and human papillomavirus, or by inherited genes. Cancer itself does not pass down from parents but can increase the risk of getting cancer by passing down genetic changes.

What Are Genes and DNA?

The cell is the smallest unit that makes up our body, inside the cell it contains a nucleus, which controls the cell. The nucleus contains 23 pairs of chromosomes, in each pair one is inherited from the mother and another from the father. These chromosomes are thread-like structures and contain a protein and a single molecule of DNA (deoxyribonucleic acid). DNA are molecules that carry genetic information, which is in the form of a twisted ladder and one strand of DNA is around six meters. A segment of DNA is called a gene, which carries instructions to make several proteins and there are around 25,000 genes in 23 pairs of chromosomes.

What Are the Types of Cancer Genes?

There are three types which include:

• Oncogenes: These are the mutated genes that cause the multiplication of cells. These are present as normal genes called proto-oncogenes, after mutation, they turn into oncogenes.

• Tumor suppressor genes: These genes slow down cell growth, when these are mutated, they cannot control cell growth.

• DNA repair genes: when DNA is copied sometimes errors can occur, if those are not corrected, they can become mutations. These errors are repaired by DNA repair genes. If they are mutated, their action gets suppressed.

What Are the Genetic Changes Noted in a Tumor?

To find out the genetic changes, a biomarker test is done to identify the alterations in the genes; it is also called tumor profiling or molecular profiling. Biomarker tests use a sample of a tumor cell or blood. There are various changes in genetics due to tumors, which are:

• DNA Mutation: It is also called a genetic variant, which is a change in DNA code, which occurs due to errors in the DNA during the multiplication of cells, exposure to mutagens such as UV (ultraviolet) light, certain chemicals, radioactive substances, or certain diseases or viral infections. Somatic mutations (alteration in DNA after fertilization or occurs during a person’s life) or acquired mutations cannot be passed down, whereas germline mutation or inherited cancer (altered DNA which gets inherited from the egg or sperm) can be passed down. When the mutation affects a single nucleotide (replaced or missing) is called a point mutation. The types of mutation are:

  • Missence Mutation: This mutation refers to a change in the single DNA base, which changes the amino acid sequence.

  • Frameshift Mutation: This mutation refers to the addition or deletion of DNA bases.

  • Nonsense Mutation: This mutation refers to a change in a single DNA base, that forms a stop codon and stops the translation.

  • LOH (loss of heterozygosity): It is a type of mutation, where the genetic contribution from one of the parents is lost.

Some mutated genes are:

• BRCA gene Mutations: These mutations cause a risk of developing breast, ovarian, prostate, and pancreatic cancers.

• TP53 Gene Mutations: These mutations are common and are seen in more than 50 % of cancers.

• DNA Mismatch Repair Genes: Found in Lynch syndrome.

• Adenomatous Polyposis Coli Gene: Found in familial adenomatous polyposis (FAP).

• HER2 (ERBB2) Gene Mutations: Found in esophageal, breast, and stomach cancers.

• BCR-ABL Fusion Gene: These cause blood cells to grow abnormally in the bone marrow and are found in chronic myelogenous leukemia (CML).

• KRAS Gene Mutations: Found in case of colorectal cancer.

• EGFR Gene Mutations: Found in non–small cell lung cancer.

• ALK Gene Mutations: Found in adenocarcinoma.

• BRAF Gene Mutations: These cause growth in melanoma cells.

• NTRK Gene Fusions: Found in cancers of the colon, thyroid, primary brain tumors, and lungs.

• Chromosomal Rearrangements: This occurs, when the large segments of DNA get copied, inserted, rearranged, translocated, inverted, or deleted. They can cause fusion genes, where two different genes join together. The case of chronic myelogenous leukemia is a blood cancer that occurs due to the rearrangement of chromosomes.

• Epigenetic Changes (Epimutations): These are the alteration in the chemical structure of DNA and not in the DNA sequence. These changes occur due to exposure to chemicals, drugs, environmental factors such as tobacco, smoke, diet, cadmium (a metal), Epstein-Barr virus, and age.

What Are the Genetic Changes in Specific Tumors?

Most malignant tumors occur due to disruption in a p53 signaling pathway which is a tumor suppressor gene, which can cause cancer cells to multiply.

• Neuroendocrine Lung Tumors: In carcinoids LOH (loss of heterozygosity) at one or more 3p (chromosome 3) regions frequently changes. LOH at the MEN1 gene (a gene that provides instruction in the formation of menin protein) is commonly found in neuroendocrine lung tumors. An increase in the severity of the tumor was correlated with increased LOH and p53 gene abnormalities. Poor survival was correlated with LOH at the 5q21 gene.

• Breast Tumor: Changes in the TP53 and PTEN gene (tumor suppressor genes) causes breast tumor growth. Alterations in these genes are also associated with germ cell tumors and acute megakaryoblastic leukemia.

• Gastroenteropancreatic Neuroendocrine Tumors: These tumors develop from neuroendocrine cells (similar to hormone-producing and nerve cells). Different tumors and their associated gene alterations are:

  • Multiple endocrine neoplasias 1 (MEN1): This contains at least two combinations of parathyroid adenomas, enteropancreatic endocrine tumors, or pituitary adenomas. These correlated with somatic mutations or loss of heterozygosity (LOH) at the 11q13 gene.

  • Multiple endocrine neoplasias 2 (MEN2): Mutation in RET protooncogene, which is present on 10q11.2 correlated with MEN2.

  • Tuberous sclerosis complex (TSC): The LOH mutation of TSC1 on 9q34 and TSC2 on 16p13.3 have correlated with these tumors.

  • Von Hippel–Lindau syndrome (VHL): Mutation in the VHL gene, which is a tumor suppressor, located on 3p25,35 are associated with this tumor.

Conclusion:

As said above cancer itself does not pass down from parents, but can increase the risk of getting cancer by passing down the genetic changes. Changes in DNA can be acquired during one’s life which cannot be passed down but changes in DNA that are inherited from parents can be passed down.