E-cadherin gene mutations

Wow, Joanie, this is a heavy one! I know nothing about this, in fact never have heard about it.



Clearly you have had this test for a reason, like a family history and/or current stomach problems. I hope that you seek advice from at least two top notch geneticists/oncologists. Are there varying rates of penetrance of the gene mutation, even with the presence of the gene?



Nevertheless, my heart is heavy hearing this, as yours must be. No simple answer here for the gastric cancer. I might travel to Sloan Kettering and see what their doctors recommend.



I'm so sorry for your troubles. Hopefully another sister or brother will come by with more knowledge. Please let me know if you need the list of comprehensive cancer centers and by all means educate us by sharing your journey, should you be so inclined to do so.



I'm glad you've joined us at breastcancer.org. No one needs to travel such an unnerving and complex road alone. I will keep you close in my thoughts, and help you in any way I may.



Sincerely,

Tender

Here's some abstracts I found. I don't have this mutation, but maybe this would help. I don't know if these abstracts are representative of current thought.



Clin Gastroenterol Hepatol. 2006 Mar;4(3):262-75.
Hereditary diffuse gastric cancer: diagnosis and management.



Blair V, Martin I, Shaw D, Winship I, Kerr D, Arnold J, Harawira P, McLeod M, Parry S, Charlton A, Findlay M, Cox B, Humar B, More H, Guilford P.



Department of Surgery, University of Auckland, Auckland, New Zealand. vblair@auckland.ac.nz



Hereditary diffuse gastric cancer (HDGC) is a familial cancer syndrome defined by germline mutation of the E-cadherin gene (CDH-1). The cumulative risk for advanced gastric cancer in HDGC is 67% in men and 83% in women by 80 years of age. Early HDGC is characterized by multiple microscopic foci of intramucosal signet-ring cell carcinoma. The time to progression of these foci appears to be variable and currently is not predictable--the carcinoma foci may remain confined to the mucosa for many years. The management options for mutation carriers include prophylactic gastrectomy or surveillance gastroscopy. The only extensive published surveillance experience used chromogastroscopy, which detected early HDGC foci not visible on white-light endoscopy. The use of new techniques such as confocal microscopy, spectroscopy, or autofluorescence may prove useful, but have not been studied in HDGC. In patients up to 20 years of age, the risk for gastric cancer is less than 1%; this risk is outweighed by the mortality and morbidity associated with total gastrectomy. It is therefore recommended that genetic testing should occur at 16 years of age and that annual surveillance chromogastroscopy also should begin at age 16 in identified CDH-1 mutation carriers. After 20 years of age, delaying prophylactic gastrectomy carries significant risk, particularly if the alternative is surveillance by white-light gastroscopy. Surveillance chromogastroscopy (Congo red/methylene blue technique) should be considered for individuals younger than 20 years and patients unwilling to undergo prophylactic gastrectomy. Sufficient evidence for an increased risk for lobular breast cancer in CDH-1 carriers exists to justify breast screening in female carriers older than 35 years of age, however, evidence is insufficient to recommend prophylactic mastectomy.


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: Ann Surg. 2007 Jun;245(6):873-9. Links
CDH1 truncating mutations in the E-cadherin gene: an indication for total gastrectomy to treat hereditary diffuse gastric cancer.






Norton JA, Ham CM, Van Dam J, Jeffrey RB, Longacre TA, Huntsman DG, Chun N, Kurian AW, Ford JM.
Department of Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94035, USA. janorton@stanford.edu


BACKGROUND: Approximately 1% to 3% of all gastric cancers are associated with families exhibiting an autosomal dominant pattern of susceptibility. E-cadherin (CDH1) truncating mutations have been shown to be present in approximately 30% of families with hereditary diffuse gastric cancer (HDGC) and are associated with a significantly increased risk of gastric cancer and lobular breast cancer. METHODS: Individuals from a large kindred with HDGC who were identified to have a CDH1 mutation prospectively underwent comprehensive screening with stool occult blood testing, standard upper gastrointestinal endoscopy with random gastric biopsies, high-magnification endoscopy with random gastric biopsies, endoscopic ultrasonography, CT, and PET scans to evaluate the stomach for occult cancer. Subsequently, they each underwent total gastrectomy with D-2 node dissection and Roux-en-Y esophagojejunostomy. The stomach and resected lymph nodes were evaluated pathologically. RESULTS: Six patients were identified as CDH1 carriers from a single family. There were 2 men and 4 women. The mean age was 54 years (range, 51-57 years). No patient had any signs or symptoms of gastric cancer. Exhaustive preoperative stomach evaluation was normal in each case, and the stomach and adjacent lymph nodes appeared normal at surgery. However, each patient (6 of 6, 100%) was found to have multiple foci of T1 invasive diffuse gastric adenocarcinoma (pure signet-ring cell type). No patient had lymph node or distant metastases. Each was staged as T1N0M0. Each patient recovered uneventfully without morbidity or mortality. CONCLUSIONS: CDH1 mutations in individuals from families with HDGC are associated with gastric cancer in a highly penetrant fashion. CDH1 mutations are an indication for total gastrectomy in these patients. This mutation will identify patients with cancer before other detectable symptoms or signs of the disease.
PMID: 17522512 [PubMed - indexed for MEDLINE]

PMCID: PMC1876967

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: N Engl J Med. 2001 Jun 21;344(25):1904-9.
Comment in:
Adv Anat Pathol. 2002 Nov;9(6):329-37.
N Engl J Med. 2001 Jun 21;344(25):1942-4.


Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations.



Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C.
Hereditary Cancer Program, British Columbia Cancer Agency, Vancouver, Canada. dhuntsma@bccancer.bc.ca
BACKGROUND: Germ-line truncating mutations in the E-cadherin (CDH1) gene have been found in families with hereditary diffuse gastric cancer. These families are characterized by a highly penetrant susceptibility to diffuse gastric cancer with an autosomal dominant pattern of inheritance, predominantly in young persons. We describe genetic screening, surgical management, and pathological findings in young persons with truncating mutations in CDH1 from two unrelated families with hereditary diffuse gastric cancer. METHODS: Mutation-specific predictive genetic testing was performed by polymerase-chain-reaction amplification, followed by restriction-enzyme digestion and DNA sequencing in Family 1 and by heteroduplex analysis in Family 2. A total gastrectomy was performed prophylactically in five carriers of mutations who were between 22 and 40 years old. In each case, the entire mucosa of the stomach was extensively sampled for microscopical analysis. RESULTS: Superficial infiltrates of malignant signet-ring cells were identified in the surgical samples from all five persons who underwent gastrectomy. These early diffuse gastric cancers were multifocal in three of the five cases, and in one person infiltrates of malignant signet-ring cells were present in 65 of the 140 tissue blocks analyzed, representing in aggregate less than 2 percent of the gastric mucosa. CONCLUSIONS: We recommend genetic counseling and consideration of prophylactic gastrectomy in young, asymptomatic carriers of germ-line truncating CDH1 mutations who belong to families with highly penetrant hereditary diffuse gastric cancer.
PMID: 11419427 [PubMed - indexed for MEDLINE]http://www.ncbi.nlm.nih.gov/pubmed/11419427?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA



Please know we are thinking of you.

I've been to a few sites online looking for information on this, or someone who was going through the same thing.

First of HI to all of you, this is my first post here, I hope it finds you all feeling well.

I'm being tested for the cdh1 mutation, I go get my results on friday of this week.  We just found out at the beginning of this year that the gene is indeed in our family. We've had 2 family members test positive, and are awaiting the results on the rest of us.

My dad had already passed away when we discovered that the gene was in his family, both his parents died of stomach cancer, my dad however died of lung cancer and had previously battled cancer in a lymph node. I'm hoping that he didn't have it. His sister died a month after being tested for the gene, when her results came back positive the entire family was called in for testing. To put it into perspective... we've lost 5 out 9 people in my dad's immediate family to cancer. 4 of them were stomach cancer, but had previously battled other cancers (bladder, breast,lymph). 

I was tested over two months ago, so I'm looking forward to finding out once and for all if I have the gene. 

 Also, just food for thought here:  My uncle tested negative for the gene, but he has stomach cancer. There's just no telling with this dreadful disease.

E-cadherin is a protein that acts like glue, or maybe Velcro, making cells stick together. http://en.wikipedia.org/wiki/Cadherin

Classically, invasive ductal carcinoma is associated with being E-cadherin positive.  It is thought that this is why most ductal carcinomas are lumps.

Classically, invasive lobular carcinomas are associated with being E-Caderin negative, so the cells don't stick together.  Lobular carcinoma is associated with forming in sheets, not lumps.

The association of the tumor type with E-cadherin positive or negative is pretty strong.  Something like >90% of IDCs are positive and something like >90% of lLCs are negative.  (If I remember right, one article said they were more like 95 or 98% accurate.)

leaf- I have a question. You pointed out to invasive lobular carcinoma that is associated with E-cadherin being negative. My path report did not mention ILC but it did mention atypical hyperplasia, LCIS, classic type, and atypical lobular hyperplasia, multifocal. Is multifocal considered ILC?? Thanks,

I had a partial gastrectomy at 38 after being diagnosed with cancer,,,Stage 2 but the tumoor was grapefruit size and thru the serosa.  Not knowing that it was HDGC (althought my brother had died 10 years earlier of the same cancer at 36,,, I had adjunctive chemo and radiation. 5.5 years later I developed gastric ca once again but it was found due to my insistence of 2x yearly gastrectomies. I also had Barretts esophagus which was problematic.

The surgery was scheduled and although all the tissues looked normal I had dozens of difuse foci of signet cell carcinoma.  It wasn't until this spring that the lab doing research was able to locate the gene mutation in my blood tests and tissues.  I have the mutation.  so I have done pretty well so far with everything...Actualy I think I had more stomach trouble before my second surgery.

God Bless you and may he keep you safe for your surgery.  My breast cancer risk is a concern for me but I have been on tamoxofen and changed to evista but the side effects are not so much fun.  seeing a surgeon next week since I am 54. 

E cadherin is neither good nor bad.  It is a very common finding for DCIS and IDC. I think it would make it more likely that you indeed did have IDC and DCIS.

AFAIK,  ILC and LCIS are almost always E cadherin negative.

E cadherin is associated with cell adhesion.  This is one reason why they think that IDC usually forms lumps and ILC usually forms sheets.

http://en.wikipedia.org/wiki/Cadherin

Cribriform is a 'low grade' type of DCIS.  http://www.breastcancer.org/pictures/types/non_invasive/cribriform.jsp http://www.breastcancer.org/symptoms/dcis/type_grade.jsp

Hello all...if I can share my family's story, my father died of stomach cancer before we knew it was genetic.  When the CDH1 gene was discovered and we were tested, after noting several cousins dying of gastric cancer in their 40-50's it was also noted that there is a high occurrance of breast cancer with women with this mutation.  8 of 11 siblings have tested positve for this gene (I did not).  Of the 8, 3 are male, 5 female.  2 brothers and 3 sisters has had the total gastrectomies.  It has been life altering and I would strongly suggest nutritional and supportive counseling prior to going this route.  3 of the 5 had beginnings of gastric cancer so the decision was appropriate, but I strongly recommend support before, during and after surgery.  2 of the 4  positive sisters had already experienced breast cancer in one or both breasts prior to the genetic knowledge.   The other 2 sisters who had the TG (total gastrectomy) also decided to have prophylactic bilateral mastectomies. Both had negative mammo's; neg U/S and neg MRI's but decided to go ahead anyway.  Both ended up having BC after all.  I was one of the few that "dodged the bullet" yet 2 months ago I was dx with both ductal and lobular carcinoma....go figure. I chose a BM because I am a bit done with cancer if you can appreciate what the last 3 years have been like around my family, and as it turned out I truly feel like I made the right decision based upon my pathology report ...although I hate my TE's!!  Patience is the virtue that I still in need of developing, I know this too shall pass.

There is a wonderful website called HDGC@yahoo.com for support around this issue.  Although rare, the more we learn the more testing is being done, and more people are being found to have this genetic issue.  We are at the tip of the iceberg when it comes to genetic mutations....and right now although Total Gastrectomies and prophylactic BM seem draconian....it is the best we have to save our lives, extend time with family and loved ones and fight for more research and a cure.

There is info out there, try to get informed as much as possible...good luck to you and God Bless!

 Angel10