Genetic Alterations

Genetic alternations include chromosomal abnormalities and gene mutations. Chromosomal abnormalities generally arise during cell division. They can be numeric, involving the number of chromosomes, or structural, involving the atypical configuration of one or more chromosomes. Many different chromosome abnormalities have been identified, some of which are associated with genetic disorders and diseases like cancer.

Gene mutations are permanent changes in DNA gene sequence. They can arise during normal DNA replication or in response to environmental factors. There are many classes of gene mutations. Certain mutations cause disease.

Chromosomal abnormalities

Each human has 46 chromosomes (23 pairs) (see section “What are Chromosomes?”). If a human does not have 46 chromosomes, a chromosomal abnormality has occurred. An umbrella term for a gain or loss of chromosome is aneuploidy.

Chromosome abnormalities often occur during cell division (meiosis and mitosis). There are two main groups of chromosome abnormalities — numeric and structural. Numeric abnormalities, as the name suggests, involve the number of chromosomes. Monosomy occurs when one of the two chromosomes is missing from a pair. An example of a monosomy disorder is Turner syndrome, in which part or all of a female’s second X chromosome is missing. Trisomy occurs in individuals with an extra chromosome. For example, those with Down syndrome have three copies of chromosome 21 instead of two copies.

In addition to chromosome losses or gains, chromosomes can simply be altered, which is known as structural abnormality. Many structural abnormalities exist. A translocation occurs when a piece of one chromosome breaks off and attaches to another chromosome. Deletions occur when a portion of the chromosome breaks and genetic material is lost or deleted. A duplication happens when part of a chromosome is copied and additional genetic material is present. When a chromosome has broken, rotated and reattached, an inversion has occurred. A pericentric inversion occurs in the centromere, and a paracentric inversion occurs in the p or q arms. Isochromosomes are another type structural abnormality in which the chromosome has two identical arms (eg, two p arms). A dicentric chromosome is a chromosome with two centromeres, and a ring chromosome is one in which the chromosome breaks in two places and the ends fuse together to form a ring shape.

Mutations

A gene mutation is a permanent change in the DNA sequence of a gene. Mutations can occur in a single base pair or in a large segment of a chromosome and even span multiple genes. Mutations can result from endogenous (occurring during DNA replication) or exogenous (environmental) factors. There are two main categories of mutations: germline and somatic.

Germline (hereditary) mutations
Germline mutations are inherited from a parent (ie, mutation was present in the parent’s egg or sperm cells). A person with a germline mutation will have the mutation in every cell in the body. Germline mutations are the cause of some diseases, such as cystic fibrosis and cancer (eg, breast and ovarian cancer, melanoma).

Cystic fibrosis is a hereditary genetic disorder that results in a thick, sticky buildup of mucus in the lungs, pancreas and other organs. Cystic fibrosis is the most common genetic disease and arises from a mutation in a single gene named the cystic fibrosis transmembrane regulator gene (CFTR). The location of this gene is on the long arm (q) of chromosome 7 (position 31.2).

Some forms of breast cancer can be hereditary. Two genes are associated with hereditary breast cancer, BRCA1 and BRCA2. The BRCA1 gene is located on chromosome 17, and the BRCA2 gene is located on chromosome 13. Carriers of mutated BRCA1 and BRCA1 genes are at an increased risk for both breast and ovarian cancers.

In approximately 10% of patients with melanoma, hereditary mutations may play a role. On chromosome 9, the gene CDK2N instructs protein development. Proteins made by CDK2N include p16 and p14. These proteins prevent cells from growing uncontrollably and are referred to as tumor suppressors. Some studies have also indicated that genes on chromosomes 1 and 2 may play a role in hereditary melanoma.

Somatic (acquired) mutations
Somatic mutations can occur at any point in a person’s life. These mutations are often caused by environmental or lifestyle factors and can also result from mistakes during cell division. This type of mutation is not passed down from parents to children and thus, is not present in every cell in the body.

Although several types of hereditary cancers can be linked to germline mutations in genes that alter the gene’s original function (eg, tumor suppression), most cancers arise from somatic mutations. Somatic mutations arise after conception and can affect any of the body’s cells, except for germ cells. Approximately 10% of cancers demonstrate both germline and somatic mutations. Alterations in genes, whether they occur in a germline or somatic fashion, change the function of the gene, which may contribute to the development or spread of cancer.

Types of mutations
There are many classes or types of mutations.

*Insertions, deletions and duplications can also be frameshift mutations.

Single nucleotide polymorphisms
A single nucleotide polymorphism (SNP, pronounced snip) is one difference in a single base pair, or nucleotide, in a section of DNA. SNPs result in genetic variation in humans. SNPs can occur with a gene or near a gene, but they are most commonly found in the DNA between genes. To be designated as a SNP, the change in the base pair must be found in at least 1% of the population.

SNPs are common and normal variations in the DNA and are responsible for many of the normal differences between people such as eye color, hair color and blood type. Many SNPs have no negative effects on a person’s health, but some variations may influence the risk of developing certain health problems such as diabetes, heart disease or cancer.

On average, SNPs occur once in every 300 nucleotide base pairs, which means that the human genome has roughly 10 million SNPs.

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