Wilms´ Tumor - WT1, CTNNB1, AMER1, IGF2 or H19 genes

Wilms´ tumor or nephroblastoma is a kidney cancer, preferably infantile, derived from embryonic pluripotent cells. It is estimated that one of every 10,000 children suffers, being the most common abdominal cancer in childhood. In general, it is developed by children 5 years of age, although in cases with genetic predisposition they can develop at even younger ages and in extremely rare cases it can occur in adults, presumably given the persistence of embryonic tissues. Wilms´ tumors are thought to be vascularized and encapsulated tumors and to be located in the upper pole of the kidney. Histologically, it is described as a "three-phase" malignant tumor given the usual presence of undifferentiated epithelial, stromal and mesenchymal components ("blastic"). The survival rate is approximately 80%.

Signs and symptoms related to this process may include abdominal pain, fever, anemia, hematuria, hypertension, loss of appetite, weight loss, nausea, vomiting and fatigue. With proper treatment, children with Wilms´ tumor have a 90 percent survival rate. Tumors usually recur in the first 2 years after treatment and develop in the kidneys or other tissues, such as the lungs. People who have had Wilms´ tumor may have related health problems or late effects of their treatment in adulthood, such as decreased kidney function, heart disease and development of additional cancers.

This process is due to changes in any of several genes. Genes in which mutations have been described most frequently include the WT1 gene (Wilms tumor 1), located on the short arm of chromosome 11 (11p13); the CTNNB1 gene (beta 1 catenin), located on the short arm of chromosome 3 (3p22.1); and the AMER1 gene (APC membrane recruitment protein 1), located on the long arm of chromosome X (Xq11.2). These genes encode proteins that regulate the activity of genes and promote cell growth and proliferation. Mutations in these genes, lead to the proliferation of cells without control, which allows the development of tumors.

In addition to changes in the genes WT1, CTNNB1, AMER1, mutations have been identified in other genes that lead to the development of the condition. These additional genes are the IGF2 (insulin like growth factor 2) gene, located on the short arm of chromosome 11 (11p15.5); and the H19 gene (imprinted maternally expressed transcript), located on the short arm of chromosome 11 (11p15.5). In some cases of Wilms' tumor, abnormalities in the process of genomic imprinting on chromosome 11 result in a loss of activity of the H19 gene and in increased activity of the IGF2 gene in renal cells. The loss of activity of the H19 gene, which normally slows cell growth, and the increased activity of the IGF2 gene, which promotes cell growth, leads to uncontrolled cell growth and the development of tumors in people with Wilms tumor.

Occasionally, Wilms´ tumor can develop associated with certain syndromes that generate alterations in development. Thus, patients with WAGR syndrome (1% of Wilms' tumor cases) are carriers of constitutive deletions in the region where the WT1 gene (11p13) is located and patients with Denys-Drash syndrome (0, 5% of cases of Wilms tumor) are carriers of nonsense germline mutations that affect the functionality of the DNA binding domain or that cause complete inactivation of the protein.

Many children with Wilms´ tumor do not have mutations identified in any of the genes described above. In these cases, the cause of the development of the disease is unknown.

In many cases, the genetic basis for Wilms' tumor and the mechanism of inheritance are unclear. Approximately 90 percent of these cancers are due to somatic mutations, which means that mutations are acquired during a person's life and are present only in tumor cells. The remaining 10 percent of cases is due to germline mutations that are present in cells throughout the body. These cases follow an autosomal dominant inheritance, which means that a copy of the altered gene in each cell can lead to the development of a syndrome related to Wilms tumor or increase the chances of developing this process. Most of these cases are due to new mutations in the gene that occur during the formation of reproductive cells or early embryonic development. On the other hand, when the process is due to mutations in the AMER1 gene, the condition follows an X-linked dominant pattern. The X-linked dominant inheritance implies that in women, a mutation in one of the two copies of the gene in each cell it is enough to increase the possibility of a person developing cancer; however in males, a mutation in the single copy of the gene in each cell increases the risk of cancer.

Tests in IVAMI: in IVAMI we perform the detection of mutations associated with Wilms tumor, by means of the complete PCR amplification of the exons of the genes WT1, CTNNB1, AMER1, IGF2 or H19, respectively, and their subsequent sequencing.

Recommended samples: blood drawn with EDTA for separation of blood leukocytes, or card impregnated with dried blood sample (IVAMI can mail the card to deposit the blood sample) to detect germline mutations. For detection of somatic mutations, biopsia fron affected tissues.