A Practical Guide to Biomarkers in Renal Cell Carcinoma

Kidney cancer has changed a lot in the past decade. We used to lean almost entirely on scans and surgical pathology. Today we also look under the hood of the tumor to find biologic clues that can refine diagnosis, estimate risk, and sometimes point to a better therapy. Those clues are biomarkers. Think of them like a check engine light and a mechanic's diagnostic readout combined. This guide translates the science into plain language so you can understand what tests exist, what they mean, and where they help in real decisions.

Kidney cancer basics in one page

Most adult kidney cancers start in the kidney's tiny tubules and are called renal cell carcinoma.¹ Clear cell RCC is the most common type. Others include papillary, chromophobe, translocation RCC, collecting duct carcinoma, and rarer hereditary forms. RCC is more common in men, usually diagnosed in the 60s to 70s, and linked with smoking, high blood pressure, excess body weight, and some occupational exposures like trichloroethylene.² There is no validated screening blood test for RCC. Diagnosis generally begins with imaging and is confirmed with tissue from a biopsy or surgery.

What counts as a biomarker and why they matter in RCC

A biomarker is a measurable feature that tells you something about the tumor or the host. In RCC, biomarkers appear in different formats and time points.

Where we look for biomarkers

Tissue from the tumor is still the main source. A pathologist can stain for specific proteins, examine chromosome changes, and read DNA and RNA with next generation sequencing. Blood and urine can sometimes provide signals, like tumor DNA fragments or proteins, though this is still developing for RCC. Imaging features and routine labs can also be used as prognostic tools, even if they do not directly measure the cancer's biology.

The core biology of clear cell RCC and why it matters

Clear cell RCC typically starts with a gene called VHL going offline in the tumor.³ VHL is a cellular oxygen sensor. When it fails, the cell behaves like it is living at high altitude all the time. That flips on hypoxia inducible factors, which push the cell to make growth and blood vessel signals such as VEGF.^{4 5} The result is a tumor rich in abnormal blood vessels and hungry for nutrients. This biology explains two modern treatment strategies. VEGF pathway blockers act like turning down a firehose that feeds the tumor. HIF-2 alpha inhibitors aim higher up the pathway to cut off the switch itself.⁶ VHL alterations are found in most clear cell tumors, yet testing for VHL in a sporadic tumor does not currently decide therapy in routine care. That is because drugs targeting this pathway can work even if a specific mutation is not identified. In contrast, very high CAIX protein expression in clear cell RCC reflects this hypoxia driven program and helps confirm the diagnosis on tissue,⁷ but it is not used to choose a drug.

Beyond VHL: common tumor gene changes and what they mean

Clear cell RCC often accumulates additional gene changes that shape behavior.

PBRM1

PBRM1 is a chromatin remodeling gene, and its loss is frequent in clear cell RCC. Several studies have linked PBRM1 loss with a less aggressive course.⁸ Some research suggests it may correlate with better response to immune checkpoint therapy, but results have been inconsistent and do not support routine use to pick treatment. Consider it a potential prognostic note in a larger symphony rather than a soloist that sets therapy.

BAP1

BAP1 loss is associated with more aggressive disease and shorter survival in clear cell RCC across multiple cohorts.^{8 9} It may travel with higher grade and necrosis. There is no approved therapy based on BAP1 status today. Still, if a pathology report mentions BAP1 loss, clinicians often integrate that information when discussing risk and surveillance intensity.

SETD2 and chromatin complex genes

SETD2 mutations occur in a subset of clear cell tumors. These changes affect how DNA is packaged and repaired. They can co-occur with PBRM1 and contribute to genomic instability.¹⁰ Clinical utility is currently limited to prognosis and potential trial matching.

mTOR pathway genes

Alterations in TSC1, TSC2, or MTOR can drive the mTOR growth pathway.¹¹ In RCC, these changes are occasionally linked to better responses to mTOR inhibitors in small series, but there is no guideline that mandates using these results to select therapy in the first line. They may nudge a regimen choice later in the disease course, especially when options are otherwise equivalent.

TERT promoter

TERT promoter mutations increase telomerase activity and are seen across many cancers, including some RCC. At present, they mainly inform biology rather than treatment.

Histology matters: biomarkers by RCC subtype

Not all RCC is clear cell. Subtype drives which biomarkers matter most.

Papillary RCC

Papillary RCC comes in two broad flavors that used to be called type 1 and type 2. MET pathway activation is common in type 1 and can occur via mutations or amplification.¹² This matters because a subset of papillary tumors with true MET activation may respond better to MET targeted therapy in trials. In practice, multikinase VEGF TKIs and immunotherapy are widely used. MET testing by sequencing or copy number can be helpful when considering trials or targeted options if available. Papillary RCC is also the histology in hereditary papillary RCC syndrome caused by germline MET mutations.

Chromophobe RCC and oncocytic tumors

Chromophobe RCC often features whole chromosome copy losses rather than single gene mutations. FLCN mutations point to Birt Hogg Dube syndrome, which typically presents with fibrofolliculomas on the skin, lung cysts, and multiple oncocytic renal tumors.¹³ Sequencing helps separate chromophobe RCC from oncocytoma when morphology is ambiguous, sometimes aided by mitochondrial markers and cytokeratin staining panels. There is no routine predictive biomarker for drug choice in sporadic chromophobe RCC today.

Translocation RCC

Translocation RCC is defined by TFE3 or TFEB gene rearrangements.¹⁴ These tumors are more common in younger patients and can mimic clear cell on imaging. Pathologists confirm the diagnosis using immunohistochemistry for TFE3 or TFEB followed by FISH or RNA based tests to detect the fusion. Identifying the translocation is critical because these tumors often behave differently and may respond variably to VEGF TKIs and immunotherapy.

FH deficient RCC and SDH deficient RCC

Loss of FH is the hallmark of hereditary leiomyomatosis and RCC. These FH deficient tumors are aggressive and have a distinctive appearance and immunostain pattern that includes 2 succinated protein accumulation.¹⁵ Germline testing for FH is standard when this pattern is seen or when a patient has compatible personal or family history. SDH deficient RCC shows loss of SDHB staining and links to SDH germline variants that also raise risks for paragangliomas.¹⁶ Recognizing these patterns directs genetic counseling and screening for other associated tumors.

Collecting duct carcinoma and renal medullary carcinoma

These rare, high grade tumors require precise pathology. Renal medullary carcinoma is strongly associated with sickle cell trait. SMARCB1 loss is typical in medullary carcinoma and is detected by INI1 immunostaining. Early identification guides rapid referral to expert centers and trial consideration.

Germline testing: when the DNA story begins before the tumor

A sizable minority of RCC arises in a hereditary context. Current expert guidelines recommend considering germline testing when RCC presents young, is bilateral or multifocal, has non clear cell histology with suggestive features, or there is a family history of RCC or related tumors.¹³ Syndromes to know include VHL disease, Birt Hogg Dube, hereditary papillary RCC, HLRCC, SDH related syndromes, and tuberous sclerosis. Germline results inform personal care and cascade testing for relatives. They also steer imaging intervals for the remaining kidney after surgery and watch for other syndrome linked tumors. Germline testing should be clearly distinguished from somatic tumor sequencing. The reports look different and the implications reach beyond the cancer treatment plan.

Immune biomarkers in RCC

Immune checkpoint inhibitors are now a backbone of RCC care. Naturally, everyone asks whether PD-L1 staining can predict benefit. Unlike in some other cancers, PD-L1 immunohistochemistry has not been a reliable go or no go test in RCC across large trials.¹⁷ Differences in antibodies, scoring systems, and intratumoral heterogeneity contribute to inconsistent results. Tumor mutational burden is usually low in RCC and does not predict response in the way it can in smoking related cancers. What does help in real life is a pathologist's note of sarcomatoid differentiation.¹⁸ Sarcomatoid features reflect a highly inflamed tumor microenvironment, and these tumors often respond well to immunotherapy combinations. Research grade gene expression signatures that capture T cell inflammation or angiogenesis have explained why certain regimens work better in some patients than others, but these signatures are not yet standard of care.

Circulating and routine blood biomarkers: what is useful today

Unlike some cancers, RCC sheds relatively little tumor DNA into the bloodstream.¹⁹ That means a negative liquid biopsy does not rule out targetable alterations. When positive, plasma sequencing can sometimes identify a translocation or a MET alteration and can help track evolving resistance, but sensitivity is modest. Routine blood tests remain practical and prognostic. The International Metastatic RCC Database Consortium risk model uses performance status together with hemoglobin, calcium, absolute neutrophils, absolute platelets, and time from diagnosis to systemic therapy.²⁰ Mechanistically, low hemoglobin reflects chronic inflammation and anemia of chronic disease, high calcium can reflect tumor derived signaling that mobilizes calcium from bone, and elevated neutrophils and platelets reflect systemic inflammation. LDH correlates with tumor turnover and can rise with bulky or rapidly growing disease. C reactive protein often parallels inflammation. These labs do not diagnose RCC or pick a specific drug, but they help frame risk and follow trends.

Urine biomarkers: promising ideas, not yet clinic ready

Several studies have reported that urinary proteins like aquaporin 1 and perilipin 2 can be elevated in RCC, and urinary cell free DNA and methylation assays are being explored. None are validated for screening or routine surveillance. If a lab markets a urine test for RCC, ask for peer reviewed, prospective data in diverse populations. At present, imaging is the standard for surveillance after treatment.

How biomarkers show up across the RCC journey

Diagnosis and classification

Imaging finds a renal mass, but tissue makes the diagnosis. Core needle biopsy or surgical pathology establish the subtype and grade. Pathologists use routine staining plus targeted tests. CAIX supports clear cell RCC when morphology fits. TFE3 or TFEB immunostaining with confirmatory FISH or sequencing detects translocation RCC. FH and SDHB immunohistochemistry uncover metabolic deficiency tumors that prompt germline testing. When morphology is equivocal, RNA fusion panels and DNA sequencing can be decisive. Getting the subtype right matters because it shapes prognosis, genetic counseling, and trial eligibility.

Prognosis and risk

Risk is a blend of tumor stage and grade, performance status, and a few lab markers.²⁰ Tissue based molecular results can add context. BAP1 loss points toward higher risk. PBRM1 loss often appears in less aggressive disease. Sarcomatoid features indicate higher risk yet greater likelihood of responding to immune therapy. These signals do not replace standard staging they refine it.

Treatment selection

For most advanced clear cell RCC, combinations of immunotherapy and VEGF targeted therapy are first line options. PD-L1 status does not restrict access in RCC. If pathology shows sarcomatoid change, immunotherapy containing regimens are often favored based on trial data showing strong responses in this subgroup.²¹ HIF-2 alpha inhibitors have become options after prior therapies and for VHL disease associated RCC,⁶ reflecting the central role of hypoxia signaling. In papillary RCC, identifying MET activation can open a door to targeted approaches or trials. mTOR pathway alterations may tilt decision making toward mTOR inhibitors later on, particularly when competing choices have similar evidence. Translocation RCC and collecting duct carcinoma benefit from expert center input and trial matching.

Monitoring and surveillance

After surgery, surveillance relies on CT or MRI at intervals guided by stage and risk. There is no validated blood or urine marker that detects recurrence early with high accuracy. During systemic therapy, clinicians trend symptoms, performance status, targeted labs like LDH or calcium, and imaging. Liquid biopsy can sometimes detect resistance mutations or fusions, but a negative plasma test is common in RCC and does not overrule imaging.

What might be ordered and why

Here is a compact map of common tests and the clinical questions they address.

• Tumor immunohistochemistry: CAIX for clear cell confirmation, TFE3 or TFEB in suspected translocation RCC, FH and SDHB for metabolic deficiency tumors, INI1 for renal medullary carcinoma
• Tumor DNA or RNA sequencing: Subtype confirmation, detection of fusions, MET alterations in papillary RCC, assessment of VHL, PBRM1, BAP1, SETD2, MTOR or TSC1 2, and other changes for prognosis or trial matching
• Germline testing: Evaluation for VHL, FLCN, FH, MET, SDH, TSC, and others when personal or family history fits guideline criteria
• PD-L1 immunohistochemistry: Sometimes reported, but not used as a gatekeeper for immunotherapy in RCC
• Routine bloodwork: Hemoglobin, calcium, neutrophils, platelets, and LDH to inform risk and track trends
• Plasma tumor DNA: Exploratory in RCC with limited sensitivity, sometimes useful for fusions or MET alterations and for resistance mechanisms

Limits and caveats that matter

Special situations

Younger patients or multifocal disease

When RCC presents before midlife, appears in both kidneys, or shows multiple tumors in one kidney, the chance of a hereditary syndrome rises. Germline testing with counseling can protect health far beyond the kidney cancer by prompting surveillance for other syndrome specific tumors in the individual and the family.

Chronic kidney disease

Pre existing kidney disease affects imaging choices and treatment tolerance. Biomarkers do not diagnose RCC in this setting, but tumor biology can intersect with kidney function. VEGF blockade can raise blood pressure and affect protein handling in the kidney, so the biology that makes a drug effective also explains its side effects. Coordinated care with nephrology helps balance tumor control with kidney preservation.

Pregnancy

RCC is rare in pregnancy. Imaging leans on ultrasound and MRI without contrast. Tissue based biomarkers follow the same principles, though timing and safety considerations lead care. There is no pregnancy specific predictive biomarker for RCC.

What is emerging on the horizon

Three areas are moving fast. First, gene expression signatures that capture the balance between angiogenesis and immune activation are helping explain why certain combinations outperform others in trials. If these signatures become standardized and reproducible across labs, they could personalize initial therapy. Second, HIF pathway targeting is expanding beyond VHL disease associated tumors with new combinations and resistance strategies under study. Third, better liquid biopsy methods for low DNA shedding tumors, including methylation and fragmentomics,¹⁹ may make blood based monitoring feasible. These advances are promising, yet they need prospective validation before they become part of routine care. As always, large, well controlled studies are the benchmark for adoption.

Putting it all together

Biomarkers in RCC work best when they are used in the right place in the care pathway. Pathology and a small set of stains classify the tumor accurately. Sequencing refines that picture, confirms fusions, flags rare subtypes, and opens doors to trials. Germline testing protects families when red flags are present. Routine labs ground prognosis, and imaging remains the anchor for surveillance. Some biomarkers influence probability rather than making binary decisions. The goal is to use them to raise the signal and lower the noise in shared decision making.

Key takeaways you can trust

• There is no validated blood or urine screening test for RCC; diagnosis relies on imaging and tissue
• Clear cell RCC biology is driven by the VHL HIF VEGF axis, which explains why VEGF blockers and HIF 2 alpha inhibitors work
• PD-L1 testing does not decide immunotherapy in RCC, while sarcomatoid features often track with better immunotherapy responses
• Germline testing matters when RCC presents early, is bilateral or multifocal, or when syndromic clues are present
• Plasma tumor DNA has limited sensitivity in RCC; a negative result is common and does not overrule imaging
• Molecular findings like BAP1 or PBRM1 inform prognosis but rarely dictate therapy on their own today

Science moves quickly, and kidney cancer is a prime example. The most reliable approach pairs solid pathology with carefully chosen molecular tests and integrates results with clinical context. That keeps care precise without chasing noise. When a report lists a biomarker, the next question is always what decision it supports. If the answer is clear, it belongs in the plan. If not, it belongs in the conversation, with an eye on emerging evidence.