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Mismatch repair gene mutations in renal cell carcinoma

Fredrick S Leach1, Moon Koh, Kirti Sharma

  • 1Urologic Oncology Branch/NCI, National Institutes of Health, 10 Center Drive, Bldg.10/Room 2B47, Bethesda, MD 20892-1501, USA. leachf@mail.nih.gov

Cancer Biology & Therapy
|December 24, 2002
PubMed

Insights

Mismatch repair (MMR) deficiency is uncommon in renal cell carcinoma (RCC). When present, it primarily results from inactivating mutations in the hMLH1 gene, impacting DNA repair in kidney tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mismatch repair (MMR) deficiency is implicated in various cancers, influencing hereditary and sporadic carcinogenesis.
  • Understanding MMR gene status in renal cell carcinoma (RCC) is crucial for comprehending kidney cancer development.
  • Key MMR genes include MLH1, MSH2, MSH6, and PMS2, which maintain genomic stability.

Purpose of the Study:

  • To investigate the spectrum and genetic basis of MMR deficiency in renal cell carcinoma (RCC).
  • To determine the frequency and specific genetic alterations leading to MMR deficiency in kidney tumors.
  • To identify the predominant MMR gene involved in RCC carcinogenesis.

Main Methods:

  • Analysis of 25 renal cell carcinoma (RCC) cell lines for MMR deficiency.
  • Assessment of microsatellite instability (MSI) as a marker for MMR deficiency.
  • Genetic analysis including reverse transcription of RNA coupled with polymerase chain reaction (RT-PCR) and DNA sequencing of MMR genes (MLH1, MSH2, MSH6, PMS2).

Main Results:

  • Three RCC cell lines exhibited undetectable MLH1 expression.
  • Two of these cell lines and their corresponding tumors showed microsatellite instability (MSI) and inactivating mutations in the hMLH1 gene.
  • Other MMR proteins (MSH2, MSH6, PMS2) were detectable in the analyzed RCC lines, indicating alterations were specific to MLH1.

Conclusions:

  • Complete inactivation of the mismatch repair (MMR) system is infrequent in renal cell carcinoma (RCC).
  • The primary mechanism for MMR deficiency in RCC involves inactivating mutations in the hMLH1 gene.
  • These findings highlight the specific role of hMLH1 in the pathogenesis of a subset of kidney cancers.

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