Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.
This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author,, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.
“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in.
“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.
The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.
The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).
Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.
Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.
“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.
The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.
SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.