Hereditary papillary renal cancer and genetics
Hereditary papillary renal cancer, also known as hereditary papillary renal cell carcinoma (HPRCC), is a genetic condition that significantly increases the risk of developing renal cell carcinoma, particularly of papillary origin. This rare form of kidney cancer can lead to multiple tumors in both kidneys. The condition is primarily linked to mutations in the MET gene, which plays a critical role in cell growth and proliferation. There are two types of hereditary papillary renal cancer: type 1 and type 2, with type 1 being autosomal dominant. While not all individuals with the MET mutation develop cancer, the risk is notably higher among family members of affected individuals.
Symptoms often include hematuria (blood in urine), flank pain, and abdominal masses, although many cases are now discovered incidentally. Diagnosis typically involves imaging techniques like CT scans and ultrasounds. While treatment usually focuses on surgical removal of tumors to preserve kidney function, research into targeted therapies that inhibit the growth factor receptor associated with the MET gene is ongoing. Given the hereditary nature of this condition, genetic screening for at-risk individuals is crucial for early detection and management. Despite its potential seriousness, the clinical course can vary, and many cases are less aggressive than other types of kidney cancers.
Hereditary papillary renal cancer and genetics
ALSO KNOWN AS: Hereditary papillary renal cell carcinoma (HPRCC); hereditary papillary renal carcinoma (HPRC); familial papillary renal cell carcinoma
DEFINITION Hereditary papillary renal cancer is a rare, genetic condition that, when inherited, increases the likelihood that one will develop renal cell carcinoma (kidney cancer) of papillary origin. People with this condition are predisposed to develop multiple kidney tumors in both kidneys. Overall, papillary renal cancer is the second-most common type of renal cancer, behind non-clear cell subtypes.
Risk Factors
Because hereditary papillary renal cancer is genetic, the risk of developing it is greatest for relatives of family members who have the condition. The MET gene has been linked to this condition. Therefore, individuals who have a mutated form of this gene are at risk of developing it.
Etiology and Genetics
Two types of hereditary papillary renal cancer exist, type 1 and type 2, which is also called hereditary leiomyomatosis. Familial studies of individuals affected by type 1 hereditary papillary renal cancer have demonstrated that the disease is transmitted in an autosomal dominant pattern. These analyses also led to the identification of the MET gene as the proto-oncogene responsible for causing this type of cancer. Missense mutations of the MET gene, which are characterized by a single mutation in the DNA coding sequence, cause the gene to become constitutively active segregate with the disease. This gene, which is located on chromosome 7q31-34, codes for a receptor tyrosine that functions as a growth factor. As its name implies, this factor induces growth and proliferation of cells in many organs, such as the kidneys. Trisomy for chromosome 7, which develops when a chromosome containing the mutant allele of the MET proto-oncogene is duplicated, results in an increased production of the growth factor receptor. As a result, cell proliferation is amplified, leading to tumor growth and cancer development. Often this type of duplication event is found to be the cause of both hereditary and sporadic forms of papillary renal cancers. Because the mutated MET gene may be inherited, kidney cells are at a high risk of acquiring this mutation from birth.
Interestingly, the MET mutation and resultant development of hereditary papillary renal cancer is incompletely penetrant, which means that not every person who inherits this mutation develops renal cancer. Therefore, some investigators suggest that other loci and epigenetic factors may play a role in this cancer as well. For example, three families affected by hereditary papillary renal cancer have demonstrated an age-dependent penetrance. The clinical course of this disease is highly variable but for the most part, hereditary papillary renal cancers are less aggressive, but they can metastasize and sometimes result in mortality.
Preclinical animal studies have confirmed the role of MET in hereditary papillary renal cancers. Upon introduction into cells derived from normal mice, the mutated MET protein has the capacity to transform these normal cells into cancerous ones.
Symptoms
Historically, most cases of renal cancer presented as a triad of flank pain, hematuria, and an abdominal mass. However, the majority of renal cancers now are found incidentally when diagnosing other conditions. Of patients with symptoms, hematuria is found in 50 percent of cases, making it the most common symptom. Approximately 40 percent of patients experience pain and abdominal mass. Nonspecific symptoms such as fatigue, weight loss, fever, and malaise also may lead to diagnosis.
Screening and Diagnosis
Patients suspected of having renal cancer undergo a complete physical examination including blood chemistry studies. Radiographic interpretation of renal tumors is difficult; however, computed tomography (CT) scans of the abdomen and pelvis correctly identify malignances more than 90 percent of the time. Renal ultrasounds also may be employed to help differentiate between cysts and tumors.
Treatment and Therapy
Effectively managing patients with hereditary papillary renal cancer involves preserving renal function and preventing metastasis. Because these tumors tend to affect multiple spots in both kidneys, the risk of metastasis is high. Therefore, lesions typically are surgically removed with a goal of preserving as much kidney functioning as possible. The utility of molecular agents that inhibit the growth factor receptor involved in this condition as well as the signaling cascade activated by MET are being investigated as potential treatments for hereditary papillary renal cancer as well.
Prevention and Outcomes
It is important for individuals at risk (those who have relatives with hereditary papillary renal cancer) to be screened for the disease. In some families, all the offspring of affected individuals inherit the condition, while some or no offspring inherit it in others. Screening for the disease involves genetic testing for the MET mutation. Overall, renal cell cancers have worse prognoses as they become more advanced. Their survival rate when found very early is approximately 66 percent and for those found very late is 11 percent. According to the National Cancer Institute, papillary renal cancer made up 15 percent of all kidney cancers, making it the most common type of kidney cancer. It was estimated to affect less than 1 in 100,000 people.
Bibliography
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