A gene variant is a permanent change in the DNA sequence that makes up a gene. This type of genetic change used to be known as a gene mutation, but because changes in DNA do not always cause disease, it is thought that gene variant is a more accurate term. Variants can affect one or more DNA building blocks (nucleotides) in a gene.
Germline mutations. These are less common. A germline mutation occurs in a sperm cell or egg cell. It passes directly from a parent to a child at the time of conception. As the embryo grows into a baby, the mutation from the initial sperm or egg cell is copied into every cell within the body. Because the mutation affects reproductive cells, it can pass from generation to generation.
The most commonly mutated gene in people with cancer is p53 or TP53. More than 50% of cancers involve a missing or damaged p53 gene. Most p53 gene mutations are acquired. Germline p53 mutations are rare, but patients who carry them are at a higher risk of developing many different types of cancer.
If a person has an error in a DNA repair gene, mistakes remain uncorrected. Then, the mistakes become mutations. These mutations may eventually lead to cancer, particularly mutations in tumor suppressor genes or oncogenes.
Mutations in DNA repair genes may be inherited or acquired. Lynch syndrome is an example of the inherited kind. BRCA1, BRCA2, and p53 mutations and their associated syndromes are also inherited.
Researchers have learned a lot about how cancer genes work. But many cancers are not linked with a specific gene. Cancer likely involves multiple gene mutations. Moreover, some evidence suggests that genes interact with their environment. This further complicates our understanding of the role genes play in cancer.
Cystic fibrosis is caused by mutations, or errors, in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which result in either no CFTR protein being made or a malformed CFTR protein that can't perform its key function in the cell.
If a parent carries a gene mutation in their egg or sperm, it can pass to their child. These hereditary (or inherited) mutations are in almost every cell of the person's body throughout their life. Hereditary mutations include cystic fibrosis, hemophilia, and sickle cell disease.
Most gene mutations have no effect on health. And the body can repair many mutations. Some mutations are even helpful. For example, people can have a mutation that protects them from heart disease or gives them harder bones.
Bloom's syndrome (BS) is a rare autosomal recessive disease predisposing patients to all types of cancers affecting the general population. BS cells display a high level of genetic instability, including a 10-fold increase in the rate of sister chromatid exchanges, currently the only objective criterion for BS diagnosis. We have developed a method for screening the BLM gene for mutations based on direct genomic DNA sequencing. A questionnaire based on clinical information, cytogenetic features, and family history was addressed to physicians prescribing BS genetic screening, with the aim of confirming or guiding diagnosis. We report here four BLM gene mutations, three of which have not been described before. Three of the mutations are frameshift mutations, and the fourth is a nonsense mutation. All these mutations introduce a stop codon, and may therefore be considered to have deleterious biological effect. This approach should make it possible to identify new mutations and to correlate them with clinical information.
The colorectal cancer (CRC) modern therapy is using adjuvant and neoadjuvant companion therapeutic agents, part of them having an anti-angiogenic action. Their benefic effect can be annulated by some gene mutations, which are interfering in signal transduction pathways. One of the more frequent activating mutations is occurring in the KRAS gene. We assessed the KRAS mutations by two molecular methods, in a group of patients with a follow-up until 144 months, aiming to establish eventual correlations between the presence of mutations and the evolution of patients. We tried to appreciate the prognostic value of these mutations. A retrospective study was conducted on 74 patients treated by radical surgery; the surgical specimens were analyzed macroscopically and the histopathological type and degree were established. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and pyrosequencing were performed on paraffin-embedded tumor specimens. Statistical analysis showed significant differences in survival between patients with wild type gene and patients with mutation in codon 13; the same results were also obtained regarding TNM I, II stages or Dukes type A and B cases. However, for the patients in stage IV pTNM, the evolution was slightly better in association with a KRAS mutation than in wild type cases.
Genes provide the instructions for making proteins within the cell. If a gene has a change or mutation, the protein may not function properly. Genetic mutations that cause diabetes affect proteins that play a role in the ability of the body to produce insulin or in the ability of insulin to lower blood glucose. People typically have two copies of most genes, with one gene inherited from each parent.
NDM is a monogenic form of diabetes that occurs in the first 6 to 12 months of life. NDM is a rare condition accounting for up to 1 in 400,000 infants in the United States.4 Infants with NDM do not produce enough insulin, leading to an increase in blood glucose. NDM is often mistaken for type 1 diabetes, but type 1 diabetes is very rarely seen before 6 months of age. Diabetes that occurs in the first 6 months of life almost always has a genetic cause. Researchers have identified a number of specific genes and mutations that can cause NDM. In about half of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM). In the rest of those with NDM, the condition is transient, or temporary, and disappears during infancy but can reappear later in life. This type of NDM is called transient neonatal diabetes mellitus (TNDM).
Clinical features of NDM depend on the gene mutations a person has. Signs of NDM include frequent urination, rapid breathing, and dehydration.5 NDM can be diagnosed by finding elevated levels of glucose in blood or urine. The lack of insulin may cause the body to produce chemicals called ketones, resulting in a potentially life-threatening condition called diabetic ketoacidosis. Most fetuses with NDM do not grow well in the womb, and newborns with NDM are much smaller than those of the same gestational age, a condition called intrauterine growth restriction. After birth, some infants fail to gain weight and grow as rapidly as other infants of the same age and sex. Appropriate therapy may improve and normalize growth and development.
A number of different gene mutations have been shown to cause MODY, all of which limit the ability of the pancreas to produce insulin. This leads to high blood glucose levels and, in time, may damage body tissues, particularly the eyes, kidneys, nerves, and blood vessels.
Clinical features of MODY depend on the gene mutations a person has. People with certain types of mutations may have slightly high blood sugar levels that remain stable throughout life, have mild or no symptoms of diabetes, and do not develop any long-term complications. Their high blood glucose levels may only be discovered during routine blood tests. However, other mutations require specific treatment with either insulin or a type of oral diabetes medication called sulfonylureas.
Most forms of NDM and MODY are caused by autosomal dominant mutations, meaning that the condition can be passed on to children when only one parent carries or has the disease gene. With dominant mutations, a parent who carries the gene has a 50 percent chance of having an affected child with monogenic diabetes.
More information about the genes that cause NDM and MODY, the types of mutations responsible for the disease (autosomal dominant, autosomal recessive, X-linked, etc.), and clinical features is provided in the American Diabetes Association Standards of Medical Care in Diabetes.
Another cancer progression model was suggested for pancreatic cancer. This model follows the progression from normal ductal epithelium to duct lesions and eventually to invasive ductal adenocarcinoma. This succession is once again associated with multiple genetic aberrations, including mutation in k-ras, over expression of HER-2/neu, and inactivation of CDKN2A (p16), DPC4, BRCA2, and TP53. In this model, the TP53 gene was suggested to be lost late in the development of pancreatic neoplasia.22
Another important example of carcinogen-induced mutations in the TP53 gene was observed in lung cancer, where TP53 was reported to be mutated in approximately 50% of non-small-cell lung cancer cases and more than 70% of small-cell lung cancers.44 Tobacco smoke is the best-known and studied mutagen involved in lung carcinogenesis, and TP53 mutational patterns differ between smokers and nonsmokers, with an excess of G to T transversions in smoking-associated cancer.45,46 This transversion, which is uncommon in most cancers with the exception of HCC, is found to be associated with specific carcinogenic agents. The most prominent carcinogens in tobacco smoke, polycyclic aromatic hydrocarbons (PAHs) and especially benzo(a)pyrene, were found to be able to form DNA adducts in the coding region of the TP53 gene. In addition, there is a correlation between the mutational hotspots of TP53 in lung cancer (at codons 154, 157, 158, 245, 248, and 273) and the hotspots of adducts formation by PAHs in tobacco smoke. An additional examination of the lung cancer p53 hotspot mutants revealed that they are all defective for transactivation ability with less than 20% of WT activity on all p53-responsive elements.47 It seems, therefore, that both a specific transversion associated with PAH adducts and loss of transactivation are the major driving forces in shaping the p53 mutation pattern in this type of cancer. 2b1af7f3a8