Genetic mutations predispose to LE

kira66715

New abstract that shows that some of the risk is genetic--I've heard of the author, he's doing a lot of genetic research into LE, both secondary and primary, and Pat O'Connor--of lymphadema people strongly supports him:

http://clincancerres.aacrjournals.org/content/early/2012/02/18/1078-0432.CCR-11-2303.abstract

Connexin 47 mutations increase risk for secondary lymphedema following breast cancer treatment

David Finegold1,*, Catherine Baty2, Kelly Knickelbein3, Shelley Perschke3, Sarah Noon3, Diana Campbell3, Jenny Karlsson2, Diana Huang2, Mark Kimak3, Elizabeth Lawrence3, Eleanor Feingold3, Stephen Meriney4, Adam M Brufsky5, and Robert Ferrell3
+ Author Affiliations

1pediatrics/human genetics, university of pittsburgh
2cell biology and physiology, university of pittsburgh
3human genetics, university of pittsburgh
4neuroscience, university of pittsburgh
5Hematology and Oncology, University of Pittsburgh
↵* Corresponding Author:
David Finegold, pediatrics/human genetics, university of pittsburgh, 130 desoto st, Pittsburgh, PA, 15261, United States dnf@pitt.edu
Abstract

Purpose:Secondary lymphedema is a frequent complication of breast cancer associated with surgery, chemotherapy, or radiation following breast cancer treatment. The potential contribution of genetic susceptibility to risk of developing secondary lymphedema following surgical trauma, radiation, and other tissue insults has not been studied.

Experimental Design:To determine if women with breast cancer and secondary lymphedema had mutations in candidate lymphedema genes, we undertook a case - control study of 188 women diagnosed with breast cancer recruited from the University of Pittsburgh Breast Cancer Program (http://www.upmccancercenter.com/breast/index.cfm) between 2000-2010. Candidate lymphedema genes, GJC2 (encoding connexin 47 [Cx47]), FOXC2, HGF, MET, and FLT4 (encoding VEGFR3), were sequenced for mutation. Bioinformatics analysis and in vitro functional assays were used to confirm significance of novel mutations.

Results:Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment but not in breast cancer controls or normal women without breast cancer. These novel mutations are dysfunctional as assessed through in vitro assays and bioinformatics analysis, and provide evidence that altered gap junction function leads to lymphedema.

Conclusions:Our findings challenge the view that secondary lymphedema is solely due to mechanical trauma and support the hypothesis that genetic susceptibility is an important risk factor for secondary lymphedema. A priori recognition of genetic risk 1) raises the potential for early detection and intervention for a high risk group, and 2) allows the possibility of altering surgical approach and/or chemo- and radiation therapy, or direct medical treatment of secondary lymphedema with novel connexin modifying drugs.

Received September 22, 2011.
Revision received February 7, 2012.
Accepted February 8, 2012.
Copyright © 2012, American Association for Cancer Research

carol57

Kira, This is really terrific, because it suggests an actionable pathway of pre-treatment screening and modification. Isn't there already the 'reverse mapping' technique to identify susceptible lymphatics and help guide surgery or rads to avoid them when possible?  Not sure I have the straight story on reverse mapping, and I have wondered if it's widely performed. But if a woman had proven genetic susceptibility, it would be unconscienable not to treat with that in mind.  

What are 'novel connexin modifying' drugs? 

Carol 

kira66715

Carol, I'll send you the whole article--they're drugs that are being developed for cardiac problems.

I'd heard about this researcher from Pat O'Connor, and actually, he was in desperate financail straits to keep his primarly LE study going--and I hope that's been resolved.

I always had a sense I had inherent risk, and there's a questionairre that goes with his study, and it discusses swelling history.

Kira

carol57

Thank you, Kira. I'll look forward to reading the study.

toomuch

KIRA - This is truly fabulous. It gives us HOPE that there will be a treatment in our lifetimes! . Two years before my BC dx my dad had an excisional biopsy of a singe epitrochlear node. He developed significant LE within a week which stunned his surgeon. I was worried about my genetic risk prior to treatment but went forward with the AND and radiation anyway. I hate LE but I hate BC more!

kira66715

Toomuch, I had a sense I was at risk as I come from a family of "swellers"--you dad's LE really shows how predisposition can cause it. A single epitrochlear node!

We had to do what we had to do.

I emailed Dr. Finegold to congratulate him, and tell him how much this means to us.

Kira

kira66715

Another article by Dr. Finegold, and in that journal, Stanley Rockson wrote an editorial that the line between primary and secondary LE is blurred as some people will get LE with minimal provocation--and likely have a predisposition, while others require a lot of provokation.

http://www.ncbi.nlm.nih.gov/pubmed/18564920

Lymphat Res Biol. 2008;6(2):65-8.
HGF and MET mutations in primary and secondary lymphedema.
Finegold DN, Schacht V, Kimak MA, Lawrence EC, Foeldi E, Karlsson JM, Baty CJ, Ferrell RE.
Source

Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 130 Desoto Street, Pittsburgh, PA 15261, USA. david.finegold@hgen.pitt.edu
Abstract
BACKGROUND:

Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes.
METHODS AND RESULTS:

The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals.
CONCLUSIONS:

The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.

Rockson's editorIal:

Taken together, these two manuscripts shed important
light upon the genetic substrate of lymphedema, both pri-
mary and secondary. In fact, it is likely that the distinction
between primary and secondary lymphedema will progres-
sively blur. Continued emphasis upon the genetic investi-
gation of lymphedema is likely to provide additional insights
into the mechanisms of lymphatic health and its perturba-
tion through heritable and acquired disease.

So, when is all this research going to translate into 1) identification of people at risk and 2) TREATMENT???

Kira

Suzybelle

Can I just say that, rather than LE, I would like to have a genetic mutation that enhances my spidey sense or enables me to be telepathic.

Is that too much to ask?  I think not.

kira66715

Suzy!!!!!!

Maybe it confers those powers as well.....

I just want to know when the scientific understanding of the human genome is going to benefit me--like on a concrete, treat my problem level. Is that too selfish?

Thought of you as I figured out how to download David Sedaris onto the Nook I got for the holidays--and how Amy Sedaris yelled back at him, as she left him on a crowded subway train:  "Hope you beat that rape charge!" And then the doors closed.....

I do not think that is too much to ask. Afterall we put up with this "krappe" on a daily basis.

Suzybelle

Just finished "The Night Circus" by Erin Morgenstern - it was fantastic. 

carol57

Suzy, if it's going to be a genetic mutation that makes us telepathic, I'd prefer to think of it as a genetic 'enhancement.'  'Mutation' belongs to LE.  'Enhancement' would aptly describe a special genomic twist that enables us to use mental powers to will away extra pounds, or just to remember where the car keys are. 

Marple

My g'mother developed LE but that was back in the day when they did rad. mast. followed by rads.  The poor woman, what she had to endure........there was absolutely nothing available to help her back then.  But when she did die at 102 it was not from b.c.

I guess I always felt LE was in the cards for me too.  Darnit, I should have had more positive thoughts.

The genetic component is very interesting for sure.

cookiegal

I think this is brillant.

carol57

My mother had radical mx with full axillary dissection 43 years ago, and no LE whatsoever-she's still here. No stories to say whether her sisters and mom and grandma had LE after their mx's, and they all lived less than a year after diagnosis, so hard to say what might have happened afterward.  I had 5 measly nodes removed, and wham- LE, although mild, fortunately.  There's no figuring this out, so I hope those researchers got the telepathic gene enhancement and can find an answer soon.

Suzybelle

Carol, you are so genius...I severely need a genetic mutation to enable me to lose weight while still eating chocolates and lounging around watching "Downton Abbey" reruns.

crystalphm

I am fascinated, my mom has lymphedema severely due to one lymph node in her groin...so I gues this means I may have that gene.

I was disappointed to know this, but I can also be more careful with prevention now, always wearing my sleeve and gauntlet as needed.

Does anyone think, considering this new gene research, that I need to sleeve and gauntlet my good arm, where I had a mastectomy, no lymph nodes removed, and no radiation?

kira66715

Crystal--preventive use of compression has never, to my knowledge, been shown to help prevent LE, the exception is the use of it with air flight--which is controversial.

The Nicole Stout study measured women with perometry, which is super sensitive, and if their arms went up 3%, she put them in a sleeve and gauntlet and most got better. But these were women with proven low grade, latency LE.

There is no study to prove that putting compression on a limb that is not symptomatic will prevent LE, and poorly fitting compression can trap fluid. Some researchers--one in particular--are actually against compression. 

I'll ask Binney to weigh in, but personally, I think you should just exercise precaution in the arm and be sensitive to changes in it. I really don't know about wearing a sleeve on that arm when you fly--it would be very debatable.

Kira

Binney4

Crystal, technically both arms are at risk because you've had bilateral surgeries. For flying (or any travel where change of altitude would be a factor) a low-compression sleeve and gauntlet or glove would be advisable for that arm as well, but it would be important to be sure the fit was good. It's a controversial issue in the LE world, but in my case my LE started on the prophylactic side, with a plane trip, so I take a pretty conservative view of precautions.

On the other hand, I don't think this new study shows that if your mom has LE from a single groin node removed that proves a genetic link. Some primary lymphedema is genetic, some is not, so even if her lymph system is less than adequate, it doesn't prove yours is.  So caution yes, but despair, no.

Hugs!
Binney

sushanna1

Sharon50 et. al.

My grandmother also had lymphedema as a result of a Halsted radical mastectomy.  I went into the cancer experience (for lack of a better word) hoping to avoid a fat arm like my grandmother's.  I got a fat hand instead!

Sue 

Leah_S

Neither of my aunts who had bc got LE. However, it's possible to inherit the LE weakness from one parent, the BC  mutation from the other.

So I don't know where I got the fat arm from. The fat tush, on the other hand....

Leah

Marple

LOL @ the fat tush comment Leah.

kira66715

bump

Anonymous

This is all very interesting. My mother had a uni-mast 30 years ago and never developed LE. She was always very active and used her arm just as much as prior to surgery. No LE on father's side. I had such a hard time during expansion process for implants, and I did a lot of stretching trying to get relief from the intense pressure and pain. The implants were too large for my size, I developed capsular contracture and one implant poked through the pectoral muscle. I used to blame the sentinel node biopsy entirely for my truncal LE, but I have it slightly on non-node side as well. Considering the difficulty I had with recon, I really think it's the primary cause. Obviously, the SN biopsy and the six other biopsies I had during the testing phase put me at greater risk.




Suzy, thanks for "The Night Circus" recommendation. Just downloaded and will read next.

Outfield

Interesting.

I have myself been thinking about how the purported pathogenesis of post-treatment lymphedema in breast cancer just doesn't make sense.  I see lots of posts from women with one part of their upper extremity more obviously involved than other parts, like Sue's hand.  If this were simple mechanical disruption at the axilla, I would expect us all to have similar fluid distribution if we had extra fluid in the upper extremity.   

kira66715

Outfield, Andrea Cheville MD is a great doctor who is now at the Mayo Clinic: I heard her lecture at the NLN conference, and she wrote a great piece for lymphadivas on the importance of hand protection with a sleeve, and she talked about the "patchy" nature of LE

http://lymphedivas.com/lymphedema/gauntletandsleeve/Importance of Compression Sleeve and Gauntlet Combination

USE OF GAUNTLETS AND COMPRESSION SLEEVES IN LYMPHEDEMA MANAGEMENT AND PREVENTION

Dr. Andrea Cheville, Associate Professor of Physical Medicine at the Mayo Clinic

Controversy persists regarding the benefits of compression garments in preventing lymphedema. A key stumbling block is the possibility of triggering hand lymphedema when wearing a sleeve without a glove or gauntlet. Compression applied to the arm may reduce lymph flow from the hand. Even a normal lymphatic system works harder to drain lymph from the hand than other parts of the arm. This fact explains why hand lymphedema is often the most challenging to treat and why lymphedema specialists take great pains to prevent it. Concern that compression sleeves may inadvertently trigger hand lymphedema underlies the recommendation to always wear a compression gauntlet or glove with a sleeve.

Most women at risk for lymphedema who have not noted increased arm volume, symptoms, or other indicators of early lymphedema wear their sleeves during activities that increase lymph production. Examples include airplane travel, vigorous aerobic or resistive exercise, and repetitive activities performed in an intense fashion. It is important that women using preventative compression sleeves combine their sleeve with either a gauntlet or glove during such activities. Particular attention should be paid to constriction at the shoulder band, elbow, and wrist crease. Sometimes overlap of a gauntlet and sleeve at the wrist can cause excessive pressure.

For women with established lymphedema the decision to use a gauntlet or glove is based on slightly different considerations. Lymphedema of the upper limb may be distributed in a surprisingly patchy manner. For example, lymphedema may be restricted to the underside of the upper arm or the back of the hand. It goes unsaid that lymphedema is a very individual phenomenon. Many women with lymphedema never note hand involvement despite use of an arm compression sleeve for many years. However, even these women should remain watchful for hand swelling since lymphedema is a dynamic process with the potential to change over time. A quick check for hand edema after engaging in the activities listed above is always warranted. Differences in skin texture or the visibility of bones, veins and tendons may indicate lymphedema. These changes suggest a need to consider some form of hand compression.

Of particular concern are women with lymphedema that plan to begin an exercise program or to significantly increase their activity and do not use hand compression. For these individuals use of hand compression during exertion is crucial until a stable level has been established. At that point a woman may carefully experiment with using a sleeve alone. However, it is always prudent and appropriate to use hand compression during vigorous arm activity. As previously noted, hand lymphedema is more difficult to control than arm lymphedema. The hand's irregular shape, its critical role in daily activities and the difficulty inherent in precisely fitting a gauntlet/glove all contribute to this problem. It is vital that early signs of hand lymphedema be taken seriously and that appropriate modifications are made to a patient's lymphedema maintenance program.

In summary, a gauntlet or glove should be used in conjunction with compression sleeves when used for lymphedema prevention. Women with established lymphedema who have not required hand compression should consider adding a glove or gauntlet in situations that may increase lymph production in their arms. Many patients with lymphedema spend their entire lives well-controlled with use of a sleeve alone. A good comparison to the decision to wear a gauntlet/glove with a sleeve is that it is like buying insurance. The risk of having hand lymphedema is present in all women with arm lymphedema and those at risk. Adding a gauntlet buys some protection against this event and like all insured risk, we do not know who will be helped by the insurance and who might not even need it. Working with physicians and therapists skilled in lymphedema management will ensure that each woman develops a safe and effective compression plan tailored to her unique needs.

 

Marple

Kira, thank you for posting this.  A very interesting read for sure. 

Marple

I am kind of sheepish to admit I only wear a sleeve w/o hand compression.  I do wrap routinely.

kira66715

Sharon, Andrea Cheville said that if it's only been in your arm, and you watch your hand, than it's okay to do that.

Personallly, I haven't worn a compression sleeve in years. But I do wrap to the axilla every night. My gloves go to the mid-forearm.

We cover the area that swells. I know it seems like over-kill to wrap to the axilla every night, but I do swell at night, and when I wrapped to the elbow--I got a pocket above it. Love to stop wrapping, but also really appreciate the vision of a "normal' hand in the morning, and the ability to not wear compression much during the day.

kira

Outfield

I was really only using the hand as an example. Seems a lot of women who post here have different areas of trouble.  

What I was thinking was that if we all have an insult to the axilla, if this were solely mechanical from loss of lymphatic pathways - just something akin to a clogged tub drain - then we should all have similar patterns of swelling.  Like the predictable level of water in the tub.  It wouldn't make sense that some people have problematic hands, some have problematic upper arms, etc.  

That has made me wonder about what goes on beyond that injury and loss.  There has to be tissue remodelling, and I wonder if the injury and response to injury can effect upstream tissues as well.  

I guess the other factor could be local anatomy.  Maybe the only place where my own lymphedema never goes away is in the middle of my forearm beause of the particular relationship between the muscles and lymphatics there, which might be different for someone else. 

lago

Outfield we are all different. That's why we don't all swell the same. I'm in the lower arm  just below the bend but initally it was in my lower arm just above my hand. The woman in my building that is a 35+ survivor has it in her entire arm and hand.

Suzybelle

Tina - I think you will love the book.  It's sort of a cross between Ray Bradbury and Alice Hoffman.  It was just fantastic.

Kira, thanks so much for starting this topic and posting the Dr. Cheville article:  I am not wearing my gauntlet anymore except to do strenuous work.  It works well for me doing this, but it's only because I have no swelling anywhere below my elbow.  My LE is confined entirely to my upper arm and side.  I am watchful w/regards to my hand, but just being able to go without the gauntlet is a huge relief.

Iago - so good to see you!  Hope you're doing well.