New Study Suggests Papillary Renal Cell Carcinoma Are Two Distinct Diseases

A new genomic analysis is confirming that papillary renal cell carcinoma (PRCC) can be divided into two main subtypes.

A new genomic analysis is confirming that papillary renal cell carcinoma (PRCC) can be divided into two main subtypes. Traditionally, PRCCs are divided into two main subtypes (Type 1 and Type 2) based on pathology. Now, researchers at the Cancer Genome Atlas (TCGA) Research Network have confirmed that these subtypes are distinct diseases distinguished by certain genomic characteristics. These new findings pave the way for combating PRCC in a much more targeted fashion.

The TCGA researchers were led by Paul Spellman, PhD, who is with the Oregon Health and Science University in Portland, Ore., and Marston Linehan, MD, who is with the National Cancer Institute (NCI).  TCGA is a collaboration jointly supported and managed by the NCI and the National Human Genome Research Institute, both part of the National Institutes of Health (NIH). Their findings, which were first published online November 5, 2015, in TheNew England Journal of Medicine, may lead to new molecular targeted therapy for each subtype. In addition, these new findings suggest an entirely new approach to designing clinical trials for patients with PRCC.

Dr. Spellman and colleagues conducted a comprehensive genomic analysis of 161 tumors from patients with PRCC and found that Type 1 PRCC is characterized by alterations in cell signaling involving the MET gene. Alterations in the MET gene are known to drive cancer cell growth and to drive the growth of tumor blood vessels. Alterations in the MET gene are also associated with cancer metastasis.

The current investigation uncovered that MET gene mutations or other alterations that affect its activity were identified in 81% of Type 1 PRCCs. The researchers reported that it may now be possible to treat patients with Type 1 PRCCs with specific inhibitors of the MET cell signaling pathway, including the MET/VEGFR inhibitor foretinib. Currently, foretinib is being tested in phase II clinical trials in the treatment of patients with PRCC and other tumor types.

The findings were markedly different for Type 2 PRCC. The investigators found Type 2 PRCC is much more genomically heterogeneous. Interestingly, the study demonstrated that the CpG island methylation phenotype (CIMP) was found almost exclusively in Type 2 PRCC. In addition, CIMP was associated with the least favorable outcome in patients with Type 2 subgroup.

The researchers reported that CIMP is marked by increased DNA methylation. This chemical modification of DNA inhibits gene expression. Interestingly, the researchers found that 25% of all Type 2 PRCCs demonstrated decreased expression of CDKN2A, which is a tumor suppressor gene that helps regulate the cell cycle. Loss of CDKN2A expression was also associated with a less favorable outcome.