Inherited Cancers
Cancer is a genetic disease but is only rarely inherited. Most cancers are sporadic and arise in a particular tissue such as the colon, breast, lung or skin, following exposure of the normal tissue to carcinogens that cause somatic mutations in one or more oncogenes or tumor suppressor genes. Familial cancer syndromes, which in total account for less than one percent of all cancer, occur in individuals who have inherited a germline mutation in a tumor suppressor gene. Most familial cancers have autosomal dominant inheritance and are characterized by the development of cancer at a young age.
Inheriting a mutant tumor suppressor gene effectively knocks out one allele of the gene (i.e., the "first hit") in every cell in the body. This leaves the individual vulnerable to a "second hit" on the remaining normal gene allele. Some tissues or body organs such as the eye, the breast and colon, and soft tissues, are more susceptible to a "second hit" mutation which leads to complete loss of the tumor suppressor gene and the development of cancer in that particular tissue. This "two hit" hypothesis for the development of inherited cancers was described by Alfred Knudson in 1971.
Li-Fraumeni syndrome, first described by Li and Fraumeni in 1969, is one of the best-known familial cancer syndromes. This autosomal dominant disorder is caused by the inheritance of germline mutations in the p53 tumor suppressor gene (chromosome 17p13.1). Affected family members are prone to develop leukemia, melanoma, soft tissue sarcomas, bone tumors, and cancer of the colon, breast, prostate, brain, and lung, often before the unusually early age of thirty. Many different cancers can develop within the same family and some affected individuals may develop multiple different primary tumors.
Retinoblastoma, a rare eye tumor in children, is another autosomal dominant cancer syndrome. Children with familial retinoblastoma inherit a mutant allele of the RB1 tumor suppressor gene (chromosome 13q14.1) and are prone to develop multiple tumors in both eyes within months of birth. Sporadic retinoblastoma does occur but it usually develops later, and is confined to one eye.
Inherited breast cancer accounts for approximately 5% of all cases of breast cancer. wo different tumor suppressor genes, BRCA1 (chromosome 17q21), and BRCA2 (chromosome 13q12.3) cause an autosomal dominant pattern of inheritance. Individuals in families with BRCA1 mutations are prone to develop either breast or ovarian cancer at an early age, whilst families with BRCA2 mutations only develop breast cancer but have a higher frequency of males developing cancer of the breast.
A rare form of inherited stomach cancer has been described in the native New Zealand Maori population. Individuals who inherit mutations in the E-cadherin gene (chromosome 16q22.1) develop at an early age a rapidly fatal form stomach cancer. Presymptomatic gene testing of at risk individuals allows for early surgical treatment.
Some conditions do not directly cause cancer but are premalignant and predispose at risk individuals to the development of cancer. The most common premalignant syndrome is Neurofibromatosis is an autosomal dominant neurologic diseases caused by mutations in one of the neurofibromin genes (NF1 or NF2). In NF1 (Von Recklinghausen disease chromosome 17q11.2) multiple benign neurofibromas develop in the peripheral nerves. The neurofibromas may become malignant nerve sheath tumors, and malignant tumors can develop in the brain.
Another premalignant condition is the Beckwith-Wiedemann syndrome. This congenital overgrowth disorder is associated with neonatal hypoglycaemia (low blood sugar), macroglossia (large tongue), and a large birth weight and is caused by abnormal expression of the insulin-like growth factor 2 gene (IGF2 chromosome 11p). Some of these children later develop malignant tumors of the kidney (Wilms tumor), liver (hepatoblastoma), or adrenal gland (adrenocortical carcinoma).
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