What are the causes and risk factors of renal cell carcinoma?

Risk Factors and Causes of Renal Cell Carcinoma

Obesity is the strongest modifiable risk factor for renal cell carcinoma (RCC), contributing to approximately half of all diagnosed cases, while other significant risk factors include hypertension, smoking, male gender, and specific genetic mutations. 1

Major Risk Factors

Demographic Factors

• Gender and Age: RCC is more common in men than women with a 2:1 ratio, with peak incidence in the sixth and seventh decades of life (median age 64) 1
• Ethnicity: Highest rates in Native Americans, Indigenous Alaskans, and African Americans; lowest rates in Asian Americans and Pacific Islanders 1

Modifiable Risk Factors

• Obesity: The strongest modifiable risk factor, contributing to approximately half of all diagnosed cases 1
• Hypertension: Independent risk factor increasing RCC risk by 70% 1
• Smoking: Shows a dose-dependent relationship with RCC risk 1, 2
• Alcohol consumption: Interestingly appears to have a protective effect against RCC 1

Medical Conditions

• Chronic kidney disease: Associated with increased RCC risk 1
• Acquired cystic kidney disease: Common in patients with end-stage renal disease 1
• History of kidney transplantation: Increases RCC risk 1
• Advanced kidney disease requiring dialysis: Increases RCC risk 1, 2

Genetic and Hereditary Factors

Hereditary Syndromes

• Von Hippel-Lindau (VHL) disease: Most well-established genetic syndrome, accounting for a portion of the 3-5% of all RCCs that are hereditary 1
• Other hereditary syndromes: Associated with specific genetic mutations 1

Genetic Mutations

• VHL gene: Most common genetic alteration in sporadic clear cell RCC 3, 4
• Other significant genes: BAP1, PBRM1, SETD2, PIK3CA, PTEN, TP53 3, 1, 4
• At least 11 genes implicated in familial RCC: Including BAP1, FLCN, FH, MET, PTEN, SDHB, SDHC, SDHD, TSC1, TSC2, and VHL 1

Occupational and Environmental Factors

• Trichloroethylene exposure: Associated with increased RCC risk 1
• Occupational exposure to nephrotoxic chemicals: Suspected risk factor, though evidence is not conclusive 2

Histological Subtypes and Molecular Pathways

Common Subtypes

• Clear cell RCC: Most common subtype (70-75%) 1
  • Frequently associated with VHL gene alterations 3, 4
  • mTOR pathway mutations also common 3
• Papillary RCC: Associated with MET gene mutations 4
• Chromophobe RCC: Characterized by chromosome loss and fewer somatic mutations, with TP53 being the most frequently mutated gene (32%) 3

Risk Reduction Strategies

• Weight management: Critical given obesity's strong association with RCC 1
• Blood pressure control: Important for reducing hypertension-related risk 1
• Smoking cessation: Essential for reducing dose-dependent risk 1, 2
• Regular physical activity: May help reduce RCC risk 1
• Moderate alcohol consumption: May have a protective effect 1
• Avoiding occupational exposures: Particularly to nephrotoxic chemicals 1

Screening Considerations

• High-risk individuals: Regular abdominal imaging (ultrasound or CT) recommended for those with genetic predisposition or significant risk factors 1
• Confirmed hereditary syndromes: Should undergo regular screening with MRI 1

Clinical Pitfalls and Caveats

• Only up to 10% of RCC patients present with characteristic clinical symptoms; over 60% are detected incidentally during routine ultrasound examinations 5
• Despite increasing incidence of RCC globally, mortality rates have leveled off, likely due to earlier detection and improved treatments 6
• Sarcomatoid differentiation can occur in any RCC subtype and typically indicates poor prognosis 4
• Some risk factors like specific dietary habits have inconclusive evidence in the literature 2