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Biology of Wilms Tumor

Biology studies have become the cornerstones of clinical research. Clinical trials are conducted by the Children's Oncology Group (COG), formerly the National Wilms Study Group (NWTSG) in North America, and the International Society of Pediatric oncology (SIOP) in Europe. Understanding the biology of Wilms tumor allows doctors to target the treatment to each individual child, depending on the make up of each individual tumor. Specific genes are being analyzed to help with the understanding of this disease.

WT1 Gene

Wilms tumor gene (WT1) was the first gene identified in the development of Wilms tumor. WT1 is located on the short arm of chromosome 11 (11p13) and is responsible for the WAGR and Denys-Drash syndrome. Patients with the WAGR syndrome usually loose both copies of the WT1 gene and produce no WT1 protein. In contrast, patients with the Denys-Drash Syndrome usually have only one abnormal WT1 gene and produce an abnormal protein. The abnormal protein is thought to disrupt the function of the normal protein. The WT1 gene is required for the normal development of the kidneys and the genitourinary system. The WT1 gene also functions as a regulator of other genes.

WT2 Gene

A second Wilms tumor gene (WT2) is located on chromosome 11p15. This gene is thought to be responsible for Beckwith-Wiedeman Syndrome (BWS) and hemihypertrophy. BWS is an overgrowth disorder associated with a 10-20% risk of developing Wilms tumor.

At least 10 imprinted genes (genes that are passed down and expressed from either the father or mother) are present on chromosome 11p15. Genes located in this region, such as insulin-like growth factor-II (IGFII) are involved in the development of the normal kidney. It is believed that the increased activation of genes such as IGFII, are responsible for the development of Wilms tumor. Other genes include H19 and LIT1

Familial Wilms Tumor (FWT1 and FWT2)

Roughly 2% of children diagnosed with Wilms tumor have a relative who was also diagnosed with Wilms tumor. Families with two or more Wilms tumor patients are considered Wilms tumor families. The occurrence of these rare Wilms tumor families suggests that the Wilms tumor patients in these families have inherited an altered gene that is important in the development of Wilms tumor.

The mode of inheritance is thought to be autosomal dominant (only one affected parent with the trait is needed to pass it down to their child). However, the true risk estimate for children of Wilms tumor patients is currently unknown and is studied as part of the clinical trials by COG and SIOP. The risk might vary depending on the disease. For example, the risk might be higher in a patient with familial Wilms tumor, in a patient with Wilms tumor of both kidneys, or in a patient with Wilms tumor associated with a syndrome.

Several genes have been found to be associated with familial Wilms tumor. The first familial Wilms tumor gene, FWT1, is located on chromosome 17q. The second gene, FWT2, is located on chromosome 19q. In addition, other chromosomes such as chromosomes 4q, 9p, 20p, and 3q have been linked to familial Wilms tumor. The familial Wilms tumor genes are much less studied than the WT1 gene and nothing is known about their function yet.