Genomic Sequencing Reveals Unique Genetic Alterations in Chromophobe Renal Cell Carcinoma


Key Points

  • Chromophobe renal cell carcinoma represents a distinct cancer entity.
  • A majority of the samples were missing one copy or a major part of chromosomes 1, 2, 6, 10, 13, and 17. 
  • Whole-genome sequencing revealed significant amount of structural rearrangements or breakpoints involving the promoter region of the TERT gene.

An international scientific collaboration led by Baylor College of Medicine as part of The Cancer Genome Atlas initiative has revealed clues about genetic alterations that may contribute to a rare form of kidney cancer. The study, which describes the landscape of somatic genomic alterations of chromophobe renal cell carcinoma, was reported by Davis et al in Cancer Cell.

Chromophobe renal cell carcinoma is a rare type of kidney cancer, with approximately 2,000 new cases diagnosed each year in the United States. A majority of patients survive the disease.

Clinical Impact

“Although most patients are reassured when the pathology of their kidney tumor comes back as chromophobe, we all have cared for patients who developed and died from metastatic chromophobe kidney cancers,” said W. Kimryn Rathmell, MD, PhD, Associate Professor of Hematology and Oncology in the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill and a co–senior author on the study. “This report is incredibly exciting for physicians who care for these patients because all of the treatment plans we have had to this point have been based on the biology of the more common kidney cancer type, as if chromophobe must be a close relative of that disease.”

Study Details

The project shows with no uncertainty that chromophobe renal cell carcinoma represents a distinct cancer entity, and reveals the biology inherent to the disease that may allow new therapies to be developed specifically for the chromophobe type of kidney cancer, Dr. Rathmell said.

The team sequenced 66 tumor samples at Baylor’s Human Genome Sequencing Center. Other types of data were collected on these samples and integrated with the sequencing, including gene expression and epigenetic data. In addition to sequencing known genes, DNA from mitochondria and from the entire genome was also sequenced.

A majority (86%) of the samples were missing one copy or a major part of chromosomes 1, 2, 6, 10, 13, and 17.  Losses of chromosomes 3, 5, 8, 9, 11, 18, and 21 also were noted with significant frequencies (12%–58%). When scientists looked for genes that were altered or missing, only two genes, TP53 and PTEN, were identified with a sizable frequency.

Whole-Genome Sequencing

The most surprising and significant finding came after the team analyzed the entire genome instead of just looking specifically at the exome. Whole-genome sequencing is “something not typically done in these genomic studies,” noted Chad Creighton, PhD, Associate Professor of Medicine at Dan L. Duncan Cancer Center at Baylor and the lead and corresponding author on the report.

With whole-exome analysis, scientists are just looking within the boundaries of known genes, to see which are broken and may have caused the disease, he explained.

“However, when you look outside of the genes, there is much more going on,” said Dr. Creighton. “For example, gene regulatory features of the genome can be altered.”

Using whole-genome sequencing, the team observed a significant amount of structural rearrangements or breakpoints involving the promoter region of the TERT gene. TERT encodes for the most important unit of the telomerase complex, which plays a critical role in cell division.

Since it was the promoter region, not the actual gene, that was affected, this malfunction was not picked up in the whole-exome analysis, Dr. Creighton said.

The study also raised intriguing questions about the roles of mitochondrial DNA alterations and of the cell of origin involved in cancer initiation, the authors noted.

This could signify new approaches for how scientists should conduct molecular studies of cancer, Dr. Creighton said. “We need to survey the regulatory regions for other cancer types as well.”

Drs. Rathmell and Creighton are the corresponding authors for the Cancer Cell article.

Funding for the study was provided by the National Institutes of Health, National Institute of Environmental Health Sciences, Keck Center for Interdisciplinary Bioscience Training of the Gulf Coast Consortia, the J. Randall & Kathleen L. MacDonald Kidney Cancer Research Fund, the Tuttle Family Kidney Cancer Research Fund, the Korean Health Technology R&D Project Ministry of Health & Welfare, and the Korea Institute of Science and Technology Information.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.