The study, conducted by a team at Tokyo University of Science and Nippon Medical School and led by Professor Tadayoshi Hayata, focused on a gene called CTD nuclear envelope phosphatase 1, or CTDNEP1. This gene encodes a phosphatase, an enzyme class that removes phosphate groups from target molecules, placing it at the crossroads of intracellular signaling and lipid metabolism. Phosphatases of this kind help regulate how cells respond to their environment, how membranes are built and maintained, and how growth signals are transmitted. Because these are precisely the processes that go awry in cancer, abnormalities in CTDNEP1 have attracted attention before. Earlier work has suggested links between the gene and medulloblastoma, a malignant brain tumor that primarily affects children, and the same research group had previously reported that low CTDNEP1 expression was associated with poor prognosis in pancreatic ductal adenocarcinoma.

That history made the new result all the more striking. When the team examined CTDNEP1 in renal cell carcinoma, they found that higher expression of the gene was associated with poorer survival outcomes in clear cell renal cell carcinoma, the most prevalent subtype of the disease. This is the opposite direction of the association the group had documented in pancreatic cancer, where low expression signaled worse outcomes. The same molecule, in other words, can carry a completely different clinical meaning depending on the cancer type and even the subtype within a cancer type. Professor Hayata noted that in the earlier pancreatic cancer work, low CTDNEP1 expression was associated with poor prognosis, while in clear cell renal cell carcinoma the team observed the opposite direction, underscoring that context determines the gene’s clinical significance.

To understand the scale of the analysis, it helps to appreciate the landscape of kidney cancer itself. Renal cell carcinoma accounts for roughly ninety percent of all kidney cancers and arises when cells lining the kidney’s small tubules begin to grow uncontrollably. Within this category, clear cell renal cell carcinoma represents approximately eighty percent of cases and is named for the clear-looking appearance of its cancer cells under the microscope. Papillary renal cell carcinoma, the second most common subtype at roughly ten to fifteen percent of cases, instead forms distinctive finger-like structures called papillae. The two subtypes differ not only in appearance but in their cellular origins, genetic makeup, and the tumor microenvironments in which they develop. Yet reliable molecular markers for assessing prognosis in these subtypes have remained limited, which is precisely the gap the Japanese team set out to address.

The researchers’ first clue came from a broader observation: CTDNEP1 expression was elevated in tumor tissue compared with normal tissue across several cancer types, including renal cell carcinoma. Encouraged by this pattern, they turned to the TCGA Pan-Cancer Atlas, a comprehensive and widely used public database of genomic and clinical data, to examine the gene’s expression in 512 patients with clear cell renal cell carcinoma and 283 patients with papillary renal cell carcinoma. The team divided patients into groups based on their CTDNEP1 expression levels and compared survival outcomes between the groups, carefully accounting for confounding variables including age, sex, and pathological stage. This kind of database-driven approach, sometimes called an in silico study, allows researchers to detect associations across large patient cohorts that no single hospital could assemble on its own.

The results in clear cell renal cell carcinoma were clear-cut. Patients whose tumors showed higher levels of CTDNEP1 had significantly poorer survival outcomes, and the association was particularly pronounced in Stage III disease. Across the overall clear cell cohort, the hazard ratio for overall survival in the high-expression group was 2.16 compared with the low-expression group, meaning that high expression roughly doubled the risk of death over the study period after adjustment for the measured covariates. When the researchers drilled down to Stage III clear cell renal cell carcinoma specifically, high CTDNEP1 expression was significantly associated with poorer overall survival, poorer disease-specific survival, and shorter progression-free interval, although no significant association emerged for disease-free interval. These stage-specific findings suggest the gene’s expression may be most informative in the intermediate stage of disease, where prognostic refinement could have the greatest practical impact on treatment decisions.

In papillary renal cell carcinoma, by contrast, the picture was far murkier. The association between CTDNEP1 expression and prognosis was limited and inconsistent, with no consistent relationship observed for overall survival, disease-specific survival, or progression-free interval. Even the findings for disease-free interval shifted depending on which statistical model the researchers applied. This subtype-dependent divergence is not merely a statistical curiosity. The authors suggest that the genetic and biological differences between the two subtypes may explain it: clear cell and papillary renal cell carcinoma may arise from different types of kidney cells, carry different genetic backgrounds, and develop within different tumor environments, any of which could influence the biological processes connected to CTDNEP1 expression.

Supporting that interpretation, the team identified different biological pathways linked to CTDNEP1 expression in each subtype. In clear cell renal cell carcinoma, higher expression of the gene was associated with immune- and inflammation-related pathways, hinting that CTDNEP1 may intersect with the tumor’s inflammatory milieu in ways that worsen outcomes. In papillary renal cell carcinoma, the gene’s expression was instead associated with immune responses and metabolic processes, including pathways involved in energy production. These distinct pathway signatures reinforce the idea that the same gene can be wired into different biological circuits in different tumor contexts, a phenomenon increasingly recognized across cancer genomics and one that complicates any attempt to read a biomarker’s meaning from one cancer type and apply it to another.

The researchers are careful about what their findings do and do not establish. The study demonstrates an association rather than a direct cause-and-effect relationship, and further experimental work is needed to determine whether CTDNEP1 directly contributes to renal cell carcinoma progression. The stage-specific analyses were exploratory and based on limited patient numbers, and the threshold used to separate high- and low-expression groups was derived from the same cohort being analyzed, which means the results require validation in independent patient cohorts before they can inform clinical practice. Even so, the study positions CTDNEP1 as a candidate prognostic biomarker, particularly for clear cell renal cell carcinoma, and Professor Hayata emphasized that the findings suggest the gene may serve as a candidate prognostic marker in renal cell carcinoma while calling for further experimental studies to clarify whether it directly contributes to disease progression. The research, published in Volume 46, Issue 10 of the journal Anticancer Research, also stands as an example of cross-institutional collaboration, with first author Mayuka Nii, a Ph.D. candidate at Tokyo University of Science, working alongside Kazutaka Ota, then a third-year medical student at Nippon Medical School who participated through the school’s Project Semester III research placement course. For a disease in which subtype-specific prognostic tools remain scarce, a gene whose meaning flips between cancer types is a vivid reminder that in modern oncology, context is everything.

Subject of Research: Subtype-dependent association of CTDNEP1 gene expression with survival outcomes in renal cell carcinoma

Article Title: Gene expression linked to survival differs by kidney cancer subtype

Article References: Gene expression linked to survival differs by kidney cancer subtype. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: renal cell carcinoma, CTDNEP1, clear cell renal cell carcinoma, papillary renal cell carcinoma, prognostic biomarker, gene expression, TCGA Pan-Cancer Atlas, survival analysis, kidney cancer, phosphatase, tumor microenvironment, Anticancer Research

The study, conducted at a single center between May 2008 and February 2020, followed 48 consecutive patients who were treated for a total of 53 biopsy-confirmed papillary renal cell carcinoma tumors. These were not healthy surgical candidates: the patients had been deemed unfit for partial nephrectomy, the current gold-standard operation for localized kidney cancer, because of advanced age, impaired kidney function, or poor overall condition, while some had simply declined surgery. Every case was reviewed by a multidisciplinary tumor board that included urologists, oncologists, radiologists, pathologists, and radiation oncologists before cryoablation was chosen. The cohort was predominantly male, with 39 men and 9 women, and the median age was 69.5 years, with patients ranging from 36 to 88 years old.

Papillary renal cell carcinoma is a distinct entity within the family of kidney cancers. While clear cell renal cell carcinoma is the most common histological type, papillary tumors account for roughly 10 to 15 percent of all renal cell carcinomas and are generally associated with better outcomes. The World Health Organization formally listed the entity in its 2016 classification of renal tumors, and pathologists further divide papillary tumors into two subtypes: type 1, which tends to be slower growing and more indolent, and type 2, which carries more aggressive features such as higher tumor grade, necrosis, and lymphovascular invasion. In the French series, type 1 tumors dominated the cohort, making up 46 of the 53 lesions, or 88.8 percent, while type 2 tumors accounted for the remaining 11.2 percent.

The technical execution of the procedure reveals why cryoablation has become such a powerful tool in interventional oncology. All treatments were performed by experienced interventional radiologists under general anesthesia or sedation, with the patient staying in hospital. Using computed tomography or magnetic resonance imaging for guidance, the radiologists inserted between two and four thin cryoprobes, typically 15 to 17 gauge, directly through the skin and into the tumor. The number, type, and positioning of the probes were tailored to each tumor’s size, location, and morphology, with the goal of enveloping the entire tumor in a lethal ice ball that extended 5 to 10 millimeters beyond its visible margins. For MRI-guided procedures, the team used MRI-compatible probes and near real-time multiplanar MRI fluoroscopy, allowing them to watch the ice ball grow in three dimensions as it formed.

Each ablation followed a standardized freeze-thaw protocol: two freezing cycles of 10 minutes each, separated by a 10-minute passive thawing period. This repetition is critical to the biology of cryodestruction. Rapid freezing causes ice crystals to form inside and around cells, rupturing their membranes, while the thawing and refreezing cycles amplify vascular damage, cutting off the tumor’s blood supply and ensuring that cells at the margin of the ice ball, where temperatures are less extreme, are still lethally injured. When tumors sat close to vulnerable structures such as the bowel or the abdominal wall, the team performed hydro-dissection or pneumo-dissection, injecting fluid or gas to physically push those organs out of harm’s way. In one striking example described in the study, sterile gloves filled with warm saline were placed over the skin at the probe entry sites to prevent frostbite, because MRI-compatible cryoprobes are not insulated along their shafts.

The results were striking on nearly every measure. Technical efficacy, defined as the absence of contrast enhancement and tumor enlargement on imaging within three months of the procedure, was achieved in all 53 tumors, a 100 percent success rate in destroying the treated lesion. The overall complication rate was just 11 percent, and every single complication was minor, classified as grade 2 or lower on the standard Clavien-Dindo scale. No patient required hemodialysis after treatment, a crucial finding given that many of these patients already had compromised kidney function, and a quarter of the cohort had only a single kidney. The median hospital stay was three days, and the median procedure took 127 minutes.

Oncologic outcomes were equally impressive. Only three of the 53 tumors, or 5.7 percent, recurred locally during follow-up, with a mean time to recurrence of 36 months. Two of the recurrences occurred in type 1 tumors and one in a type 2 tumor, a difference that was not statistically significant but is consistent with the known biology of the more aggressive type 2 subtype, which in this study also carried higher International Society of Urologic Pathologists grade scores. Two of the three recurrences were successfully treated with a second cryoablation. When these salvage treatments were factored in, the five-year estimates for local recurrence-free survival reached 95.9 percent for primary treatment and 97.8 percent for secondary effectiveness. Most remarkably, cancer-specific survival and metastasis-free survival were both 100 percent: no patient died of papillary renal cell carcinoma, and no patient ever developed distant metastases. Overall survival at five years was 90.3 percent, with the deaths that did occur attributable to unrelated cancers such as gastric, lung, and duodenal malignancies.

Perhaps the most provocative comparison in the study is with surgery itself. The authors point to a large surgical series of 626 patients with papillary renal cell carcinoma treated with partial nephrectomy, in which five-year cancer-specific survival was 83 percent, local recurrence-free survival was 91 percent, and overall survival was 82 percent, all figures lower than those reported in the cryoablation cohort. The authors are careful to caution against overinterpreting this comparison: there was no direct head-to-head analysis, the surgical series involved larger tumors averaging 4 to 5 centimeters compared with 2 to 3 centimeters in the ablation studies, and the sample sizes differ dramatically. Still, the findings add to a growing body of evidence that thermal ablation can match surgical outcomes for early-stage kidney tumors while avoiding the risks of major surgery, with prior studies showing fewer complications and shorter hospital stays for ablated patients.

The study does carry limitations that the authors acknowledge candidly. Its retrospective design and relatively small sample size, a consequence of the rarity of papillary renal cell carcinoma compared with the clear cell type, mean that larger multicenter studies will be needed to confirm the results. The effect of operator experience was not formally evaluated, although the authors note that their center performs more than 60 renal cryoablations per year, suggesting a consistently high standard of practice. The potential for inter- and intra-observer variability in imaging assessments was also not eliminated. And because the cohort was dominated by type 1 tumors, the findings for the more aggressive type 2 subtype rest on only seven lesions, a reminder that subtype-specific evidence remains thin.

Even with those caveats, the message for clinical practice is clear. For patients with biopsy-confirmed, localized papillary renal cell carcinoma who cannot undergo or decline surgery, percutaneous cryoablation delivered under image guidance offers a treatment that is safe, kidney-preserving, and, on the evidence of five years of follow-up, extraordinarily effective. The authors suggest that when treating type 2 tumors, radiologists should aim for larger ablation safety margins to account for their more aggressive biology. As interventional oncology continues to mature, they argue, cryoablation for renal cell carcinoma, particularly for indolent histologic subtypes like papillary tumors, deserves increased consideration in clinical practice and in future guideline development. For a disease increasingly caught early by incidental imaging, the freezer may prove to be as mighty as the scalpel.

Subject of Research: Percutaneous cryoablation as a treatment for papillary renal cell carcinoma

Article Title: Safety and oncologic efficacy of percutaneous cryoablation of papillary renal cell carcinoma: a 5-year single-center follow-up study

Article References: Mulot, B.-M., de Marini, P., Tan, A. S. M., Orkut, S., Garnon, J., Weiss, J., Autrusseau, P. A., Tricard, T., Lang, H., Cazzato, R. L., & GANGI, A. (2025). Safety and oncologic efficacy of percutaneous cryoablation of papillary renal cell carcinoma: a 5-year single-center follow-up study. CVIR Oncology, 1(1), Article 4. https://doi.org/10.1007/s44343-025-00003-5

Image Credits: AI Generated

DOI: 10.1007/s44343-025-00003-5

Keywords: cryoablation, papillary renal cell carcinoma, kidney cancer, interventional radiology, renal tumors, minimally invasive treatment, oncology, MRI guidance, CT guidance, cancer survival, thermal ablation, nephron-sparing