From the Journals

Primary, metastatic ccRCC share mutational features



A comparison of the genomic landscapes of both primary and metastatic clear cell renal cell carcinoma (ccRCC) found no significant differences in gene expression or mutational burden between the disease states, suggesting that there is no single genetic driver of metastases, investigators reported.

An analysis of targeted next-generation sequencing of both primary tumors and metastases in two independent patient cohorts showed that only the gene encoding for the tumor suppressor TP53 was significantly more frequently mutated in metastases, compared with primary tumors, but this finding did not pass a false positive test (false discovery rate), noted Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston, and his colleagues, in the British Journal of Cancer.

“No other gene had significant difference in the cohort frequency of mutations between the metastases and primary tumors. Mutation burden was not significantly different between the metastases and primary tumors or between metastatic sites,” they wrote.

Frequently mutated genes in ccRCC include VHL, the gene encoding for von Hippel–Lindau syndrome, as well as tumor suppressor genes such as PBRM1, SEDT2, BAP1 and KDM5C, but few mutations are clinically actionable, the investigators noted. “However, the value of genomic alterations will be determined by understanding the interactions between acquired genetic alterations, treatments received, heterogeneity, and the dynamics of mutations during evolution of disease.”

To see whether they could improve understanding of the genomic differences between primary and metastatic ccRCC and potentially develop personalized therapies, the investigators studied targeted next-generation sequencing data from two separate cohorts.

The first cohort included data on 349 ccRCC primary tumors and 229 unmatched cases of metastatic ccRCC from the Foundation Medicine database. The second, a validation cohort, included data on 177 ccRCC primary tumors and 80 metastases from patients treated at Dana-Farber. In each cohort, sequencing was performed on 275 genes and intronic regions in 30 genes for a total of 282 unique genes.

In cohort 1, which included tumor samples from 417 men and 169 women with a median age of 58 years, the frequency of mutations was similar in primary tumors and metastases. As noted before, mutations in TP53 were significantly more frequent in metastases than in primary tumors, detected in 14.85% versus 8.90% of samples, respectively (P = .031). This difference did not, however, pass the false discovery rate test (q = 0.21). Two other tumor suppressor genes, PBRM1 and KDM5C, were numerically but not significantly more frequent in metastases.

There were no differences in median tumor mutational burden between primary and metastatic samples and no difference in either mutations or mutational burden across different metastatic sites.

In cohort 2 there were no significantly different mutational frequencies between primary and metastatic samples for any gene and no differences in median tumor mutational burden.

An analysis comparing the frequency of gene mutations in primary tumors of patients in this cohort who went on to develop metastatic disease versus those of patients with only localized disease showed that, after a median follow-up of 21.9 months, there were no significant differences in either mutational frequency or tumor mutational burden.

“It is currently unknown if cohortwide genomic alterations in RCC metastases have a different genomic profile, including potential actionable mutations, compared to samples derived from the primary site. To our knowledge, our analysis is the largest genomic ccRCC study that compares cohortwide mutational differences between metastases and primary tumors,” the investigators wrote.

They acknowledged that because they did not match primary tumors with metastatic tumors in the same patients they were unable to evaluate how individual tumors evolve over time or how systemic therapies may alter the tumor genomic landscape.

Dr. Choueri is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at the Dana-Farber Cancer Institute. Six of the study’s coauthors are employed by Foundation Medicine. The remaining authors declared no competing interests.

SOURCE: Choueiri TK et al. Br J Cancer. 2018 May;118(9):1238-42.

Next Article: