Hereditary Kidney Cancer–Confusing but Critical!

Hereditary RCC: Genetic or Familial RCC


Most people are not surprised that there is no ONE thing called cancer. Tumors in all the organs or invasive cells in the blood or bones are referred to as cancer, but start when cells go wrong, whatever the cause.  As soon as you are told you cancer, whatever it, the quest begins to find out exactly which cancer it is.  With kidney cancer, or its more melodious name, renal cell carcinoma, there seem to be endless variations on what may be called kidney or renal cancer.  To treat it requires a very careful analysis of what is really is, starting with the pathology of the tumor when it is biopsied.  With kidney cancer that biopsy is usually done after surgery for the tumor. That biopsy will describe the shapes and type of cell in the tumor, which can be mix of types.  And then the real work begins.

A recent article in “European Urology” reviewed the mix of HEREDITARY renal cancers, those that arise due to one’s background. More common are the “sporadic” kidney cancer that could arise out of the blue or in response to some environmental toxin. There are ten Heredity Renal Cancers, or HRCs.  My goal is to alert the reader to the possibility that his cancer might be one of these. This would affect treatment, and may suggest the need to test family members.

If you have kidney cancer or RCC, you may be familiar with “clear cell” or “papillary” to refine the description of the cells in the tumors.  This may not be the whole story, as those HRCs—the hereditary kinds—may manifest a mix of ways, including as clear cell or papillary histology.

The most common HRC is Von Hippel-Lindau (VHL) disease, with both benign or malignant tumors.  RCC can be found in a 24-34% of VHL patients, appearing at mean age 39 years (far younger than non-heredity RCC), and often with multiple tumors and in both kidneys.  Cysts which appear not to be malignant must be watched–they have the potential to become malignant over time. Generally they are managed based on the size of the largest of these lesions.  Clear cell RCC is the one VHL-related subtype.

Hereditary papillary renal carcinoma (HPRC) is rarer, and typically occurs later in life.  Papillary tumors are the only phenotype with HPRC, and patients often develop numerous tiny tumors, 1000 or more.  These tumors are considered type 1 papillary renal cell carcinoma (pRCC) with a low nuclear grade, monitored with CT scans, and some do metastasize, though this is rare.  The MET gene is implicated in the growth of these tumors.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is newly identified as a HRC. Rarely do patients develop RCC, but are susceptible to developing multiple leiomylomas, which are generally benign.  When there is early onset of HLRCC, then RCC is found in about 20% of those patients.  These tumors can be aggressive, and about 2/3 display a papillary pattern.  Such tumors tend to be hyper-vascular.

Birt-Hogg-Dube (BHD) syndrome is quite rare, about 1 in 200,000 people, and thereby likely under diagnosed.  This raises the risk of developing kidney tumors, which occurs in 25-35% of BHD patients, and at mean age of 50. These tumors have varying histologic subtypes, generally chromophobe RCC or hybrid variants.  And there can be variants in the same tumor or within the kidney.  There is a risk of metastases, though rare. The characteristic skin lesions of BHD syndrome are not malignant.

Even more rare is Tuberous Sclerosis Complex (TSC), which can manifest itself in renal lesions, cysts and occasionally, RCC, the latter at a young, average age 28.  Neurologic complications can accompany this syndrome.

SDHB-associated paraganglioma/phaeochromoytoma is another heredity condition which may give rise to a mix of renal tumor, including clear cell RCC, chromophobe RCC and oncocytomas, i.e., a mix of histologically different types.

An HRCmay be suspected in patients with a family or individual history of renal tumors, in the instance of both kidney having tumors, or one kidney having multiple tumors or in early-onset renal tumor, i.e., under 50 years of age.

Clinical diagnosis can be further refined by genetic testing, and thorough review by an experienced uropathologist is fundamental to the diagnosis.  First consideration would be a VHL analysis and genetic analysis of SDHB and FLCN genes, as warranted.  Patients with type 1 papillaryRCC should be considered for MET analysis.  The presence of clinical symptoms related to any of the syndromes will guide the gene screening.  Testing on family members may well be warranted.

With these cancers, it is possible to have multiple lesions and affect both kidneys. Thus, treatment should preserve renal function and control the risk for metastases. Use of ablation to retain maximum renal function may be preferable to partial nephrectomies, for example.

Though these heredity renal cancers arise in a different manner than the more common sporadic RCC, the study of the molecular pathways provide some insight into new therapies for those patients as well.  Thanks always to those researchers who help in this struggle for information, as that is essential to provide treatments.

Peggy—Based on the European Urology 2010.

Leave a comment

Filed under Uncategorized

Molecular Marker for RCC/ Papillary RCC. Molecular

One of the many challenges in fighting kidney cancer is knowing where it all got started.  This research indicates that a gene gone astray, the MET gene, is part of the problem from some patients.  It is this type of study that will change the treatment for us, as there will be greater clarity as to the “target” to be reached by “agents of change”.  (Nothing political intended, but seems to work here!)  Especially of interest to patients who have the variant of papillary RCC, about 10% of us.

 MET Variant as a Prognostic Marker in Clear Cell Renal Cell Carcinoma

 Dr. Ari Hakimi of Memorial Sloan-Kettering Cancer Ctr.,New York USA

ASCO GU Congress 2014

eCancer reporter Peter Goodwin’s questions are in italics. Where I was not certain of the lecture, I added a (?) to show that. Link below to the actual lecture.

Ari, you have been looking at prognosis or prognostic features, or actually, molecular features of renal cell carcinoma. Can you tell me what you were doing in the study you’ve just been talking about?

There was a great paper that was published by the people at Harvard and Lancet (?) Oncology last year. It found for the first time a prognostic marker that was associated with poor survival in kidney cancer, a molecular marker. This was a variant, a normal variant in the gene, the MET gene. In that study they had several hypotheses they generated from that study, but they didn’t really have enough genetic data to try to figure out what was going on here with this variant in the genes. So what we did was, we took that same concept, that same variant, in the Cancer Genome Atlas Study, which has both patient information and then a host of genomic information. We tried to validate their finding and explore the biology of that marker.

It sounds like a needle in the haystack but you’ve but you become quite familiar with this variant called RS11762213. What you know about it so far?

 We know about that it is a variant in the MET oncogene, a very important gene in a lots of different cancers, particularly in papillary renal cell cancer. It’s a gene not thought to be very important in clear cell renal cell carcinoma, but we found that it is, and we explored the variant in an exonic region of the gene–meaning the coding region of the gene.  Because the variant is in a coding region of the gene, we thought it might be more than just a prognostic marker. It might also have some biological implications.

Biological implications?  What sort of biological implications?

 We think the marker may be; we figured out through computational methods, exploring the TCGene data(?) that it might be in the region of enhancement,  meaning the variant leads to higher activation of the MET oncogene.  In turn, this might explain why these patients have a poorer outcome.  It might also have potential therapeutic implications.

So what have you found so far then, about the level of additional risk if you happen to have this variant gene?

Great question.  We took about 270 patients from the cohort who had available information.  We genotyped them, meaning we determined what percentage of these patients had the risk variant, which is about 10 %, consistent with prior studies.  We showed that when these patients had that risk, in addition to the current prognostic features, they had about a 3-4 fold increased risk of cancer-specific death, or tumor recurrence after surgery.

That’s really quite powerful!  Am I right that there wasn’t any clear kind of molecular feature to give you some help in the past?

Until this study, which was published last year, there were really only tumor features and patient features that were associated with poor survival in kidney cancer. This is the first study that really showed, that they published last year, to show in two different cohorts that had a molecular feature that added to the prognostic models.  We showed, augmented their findings, that if you took the best current prognostic models and stratified patients, added to that model, meaning it improved the predictive accuracy of even the best post-surgical models that are out there.

You are looking actually disease mechanisms–mechanisms of cancer production. You established prognosis, but what about predicting response to therapy?

That’s a great question. Our goal now– that we’ve established that this is a valid biomarker, truly multiple cohorts now showing this marker can stratify patients for aggressive behavior, we can now explore—hopefully–whether this has therapeutic implications because it is in a gene that is a known cancer gene.  Because there are multiple drugs that target this gene, and because we think that this variant that is activating this gene, it stands to reason that an inhibitor for these patients with this variant might work. These patients might have another option.

So theoretically a new drug which is an inhibitor for this variant might work.  What about existing cancer drugs? Do you have any ideas about if any these do influence that variant?

We don’t know yet. We are trying to find it in cell lines, meaning cell lines that are derived from tumors that are used in the lab, to see MET inhibitors that currently exist and are in phase I or II trials in kidney cancer could potentially be used against patients against this variant. That could be a very powerful tool, and a kind of the precision medicine that were looking for.

This is an amazing achievement, actually going through the Cancer Genome Atlas to find information like this, information about expression. In the realm of the everyday cancer doctor with patients to treat today, tomorrow, what you think the doctor should take home from this development?

The exciting thing about this is to genotype the patient, that is to determine that this patient carries this risk variant, is something you can detect from the patient’s blood or even a swab from the cheek. It’s a very inexpensive. It costs about $10-$70 to get this information for a patient. You can have what is called a liquid biopsy, meaning you need any tissue. You can get it from their own normal cells, because this is germline variant. You can find out this information very affordably and very quickly to determine risk for these patients. Obviously, if we are able to show that it has implications for therapy, that as a whole opens a whole new avenue.

How much hope to have that this it will be possible to manipulate this gene expression by using this kind of drug to target this?

I think that the data there is quite strong for other types of cancers. We know that other genes that are overexpressed or mutated in activated fashion respond quite well to inhibitors. This exists in multiple cancer types, lung cancer, breast cancer, for example. It stands to reason that this would work as well in kidney cancer, and the hope would be that this variant would be actually an activating factor and that we could use that also.

We’re also hearing, and especially at this GU meeting here in San Francisco, about the heterogeneity of the tumors. In fact, you may have tracked down one particular cause of cancer, but there’s another five going to rear their ugly heads at the same time. What you make of that?

 Well, that’s definitely a major factor, particularly in kidney cancer, where heterogeneity was really first described in the clinical setting two years ago in the New England Journal. What the nice thing is about this variant is, is that it is germline. It exists in every cell. Thus heterogeneity does not exist in this situation. The variant is present in all cells, including the tumor cells. So if our data does hold up, and it is a therapeutic target, it will not be affected by tumor heterogeneity.

Give me a message to take home for the community cancer doctor very briefly..

The messages that we have truly validated this important finding that was published last year and we truly believe that this is a new prognostic marker and adds to the existing prognostic markers.  Time will tell if it will actually help guide treatment of metastatic disease and really change the paradigm for kidney cancer.

Thank you very much.



Leave a comment

Filed under genomic testing

Help Save Research Data; Your Signature Needed

This is a call to sign and save research data that may disappear and not be used for any purposes, which could impact not only current patients, but others who may be affected by this research.  We as cancer patients are aware of the value of other research suddenly being valuable to us. Having been diagnosed with a potentially fatal aneurysm (all OK now), I jumped at the chance to help.  Please do sign onto this petition. The link is below.

After 10 years of gathering data and tissue samples, this ongoing study has been canceled. All the work will simply be lost. The study is the major hope for people with potentially deadly connective tissue syndromes including fibromuscular dysplasia, Ehlers-Danlos syndrome, aneurysms, Marfans, and Stickler syndrome. We have communities at Smart Patients for FMD and EDS, but they don’t have enough people to carry this petition. Only a few hundred more signatures are needed. Help keep hope alive. Please sign the petition. Please share this petition with your own community and your friends elsewhere, just as been done at my favorite site,

It could save lives.

Leave a comment

Filed under Uncategorized

Morgan’s Morning Rant in the Hospital–”Treat Me Like a Person”

This young woman–aged 15–has just ‘explained’ in clear and articulate terms why it is so hard to get both well and respect in a hospital. Must it be this way?  Though it is referred to as a “rant”, that is not really the case–it is an indictment of the lack of respect for patients found too often in the health system.

Morgan has some serious health challenges, and has had to learn to advocate for herself to work to get better.  But the concerns she raises are typical for most patients, and the lack of coordination of care, and the lack of communication of care is huge barrier to getting well.  As do most of us, she understands that the failure to let her sleep is a barrier to that care.  And the further failure to let her wake up and be a part of her own care, communication symptoms, asking questions, is far too common.

I congratulate Morgan and her family for sharing this very important reminder.




Leave a comment

January 23, 2014 · 12:04 am

LA Area Patient Education Meeting–Free and “Fun” for All

Do you need a reminder that you are not alone and that progress is being made about RCC?  Do come to this free and important event.  Though I really cannot say it will be fun, it will likely be wonderful, and especially if you are here. Questions for the presenters and time to meet one another; who could resist?


Kidney Cancer Association Patient & Survivor Conference – Los Angeles

02/22/2014 08:00 AM – 02:00 PM ET
Cedars-Sinai Medical Center
Room Number: Harvey Morse Conference Center
8700 Beverly Blvd
West Hollywood, CA 90048
Admission: Free
Please save the date of Saturday, February 22, 2014 for our Regional Patient Conference to be held in Los Angeles. More details soon to follow!
Click here to register online

Parking information and directions

Leave a comment

Filed under Uncategorized

Early Stage RCC: We Caught it Early. I Was Lucky; –Maybe Not So!

One of the warnings about kidney cancer is that it is sneaky. Researchers call it aggressive and insidious in nature, as there is a 20-40% recurrence rate for clinically localized disease, i.e, small, hasn’t spread, not to worry, etc. There are many patients who feel reassured by the doctor, generally a surgeon, that “we got it all”, and that there was no need for additional follow up.  No CT scans, no blood tests, no nothing. 

Most patients are pretty grateful until RCC lives up to its sneaky reputation and makes a surprise return.  Since the return is indeed sneaky, is it also sporadic?  Is there a way to know which of those patients might need far closer monitoring, or should all of these patients have multiple CT scans or just wait until there is a return.  Most early tumors are found incidentally, while checking on something else. That “lucky” patient with a RCC diagnosis may be part of the group which will never have another problem again, or part of the  20-40% who gets “lucky” again.  That return of disease can also be silent, with the patient at an advanced stage and in far worse shape than the first time around.  What to do?  CT scans have their disadvantages, and living under a cloud is pretty hard, and getting RCC again beyond discouraging.

Those nameless researchers, for whom I say prayers of thanks often, have a new tool to determine which early RCC tumors are naturally more aggressive.  With this info, patients can be monitored more closely, while the others can live with greater confidence.  We’ve been hearing about BRCA genes in breast cancer, thanks to the attention-getting Angelina Jolie. Now we are learning about a related protein in RCC.  The expression of this protein helps refine the risks of the early stage RCC patient.

Now it gets a bit technical,but it is important to understand the science here to understand its impact.  he expression or lack of expression of some genes can impact prognosis, or clinical expectations, in cancer patients.  In clear cell RCC, not the rare variants,such as papillary or others, the  lowered or negative (or lack of) expression of BAP1 may signal a cancer that is naturally more aggressive than others.  BAP1, also called BRCA1 associated protein-1, is an enzyme which plays a role in cell development, can be mutated or changed in breast and lung cancers, which has been recognized for some time.  Recently the Mayo Clinic released a report which indicates that the lack of BAP1 in early stage RCC was associated with greater risk of death for those patients.  This is important stuff.

How do they know this?  The researchers can detect that expression in tumors.  They compared its presence with the outcomes of patients described above.  They used 1,479 tumors from patients with nephrectomies for localized ccRCC.  This is a very large sample, something important in any trial or research of this nature.  They were able to test 98% of the samples provided, and found 10.5% were negative for BAP1, 84.8% were BAP1 positive, and the balance were unclear.  After 8.3 years of following patients (Notice how long it can take to get GOOD data.), 1,092 patients were alive, and 252 had ccRCC specific death.  Those patients who had BAP1-negative tumors were at a threefold increase risk of death compared to those with BAP1-positive tumors.

Thus, the researcher advocate using BAP1 staining, or analyses, post surgery, to monitor those patients at greater risk of recurrence and death from this subset of ccRCC patients who are likely at greater risk.

All the nagging that kidney cancer patients do to one another to be monitored, despite having had small tumor which was supposedly completely excised is not as effective as it should be.  Neither is the “Don’t worry, we got it all” attitude that too often impedes a proper monitoring.  This new tool is more objective and should be part of the post ccRCC surgery monitoring.

Just to stir up extra trouble, there may be a case for getting a biopsy to use for this testing, when the small, incidentally found tumor is “slated to be ablated”.  Would a biopsy be appropriate, in order to see the level of this protein and the aggressiveness of the tumor?  Stay tuned.




Filed under Uncategorized

Radiation for RCC? What Really Works?

Is kidney cancer really so resistant to radiation?  Many studies indicate that kidney cancer is far more resistant to radiation therapy than many other cancers. RCC just doesn’t behave as other cancers do, so the most knowledgeable doctors use radiation very carefully.  The typical wider damage that comes with general radiation is not balanced by a good response in RCC.  To be effective, a more specialized radiation is needed.

One of my most knowledge SmartPatients/friend has provided important information about radiation and RCC. The following is a link to  videos, and is followed by advice to a fellow patient trying to understand her options.  SBRT is Stereotactic Body Radiation Therapy, and not at all the same as general radiation, as is explained..

“For right now let me sort of define whats important about SBRT and why it works on RCC. SBRT is all about high daily dose needed for radioresistant cancers.

What is important is the high daily dose for RCC used in SBRT. For example, an SBRT plan for a lung met will use 3 fractions x 15 Gy/day or 5 fractions x 10 Gy/day. Fields will be very conformal to the tumor (but usually not by using shaped fields)

Forget shaped. Conformal small fields–yes.

An IMRT (Intensity-modulated radiation therapy) or shaped conventional plan might use 25 fractions x 10 Gy/day.

And to give daily doses of 15 Gy you need excellent imaging and mechanical capability that not every machine has.

Does it matter? Yes! The recurrence rate for RCC is much higher with low daily doses. The SBRT dose regimes will give about 90% local control (meaning that met never comes back-if you get cancer, it is a new spot.) Standard dose regimes give more like 60% long term local control.

SBRT typically uses dose modulation(which may or may not involve shaping beams ) to control where dose goes.

MLC or block shaped beam IMRT IMRT/IGRT-all use shaped beams but are not SBRT.

Cyberknife and Gammaknife, for example, use no beam shaping-they use hundreds of tiny identical circular pencil beams to build dose covering the tumor.

ANALOGY: Let’s say you have a huge thistle in your lawn. And you have a cup of Roundup. You can go outside 3 days in a row and put 1/3 of a cup on it. Or you can go out every other day for a month and put a spoonful on it. You are more likely to kill it for good with the first method. We want a quick thorough cell kill.”

This SmartPatient does not mince words.  We all want a quick through cell kill, which may bring a met under control permanently.  Not mentioned in this article, is that the body can also have an immune response in the area of the radiation, and deliver a burst of its own cancer-fighting proteins to the area.  This can have an additional effect in countering those super-tiny mets that may be invisible, or just trying to establish themselves in the neighborhood.

Just as there are a range of antibiotics, and we know that the choice of each is dependent up the infection, its location, and the individual’s system, so it is with radiation therapy.  Properly chosen, delivered correctly and to the exact place, with an understanding of the person’s disease, it may be a very effective tool to fight RCC, and not just clear cell.



Filed under Uncategorized