ILC and Stomach Cancer

Dear Judy,
I've read that there is one gene (that I believe can be tested for) that can be responsible. I just read a story in the news about a family that had the gene and there are ways to screen, act proactively. Please speak with your oncologist, genetecist about your concerns. They should be able to answer your questions.

I could be wrong, but perhaps you are referring to the CDH1 gene mutation. All comprehensive BC genetic tests look for the CDH1 mutation. It is rare and most will test negative for it. Like the well known BRCA gene, CDH1 is a "tumor suppressor gene". Without this gene, a cell has a higher chance of mutating into cancer.

In regards to E-cadherin. The hallmark of lobular cancer is the lack of E-cadherin. It's the sticky glue-like substance that holds cells together allowing the tumor to grow in a cohesive way, essentially forming a clump. Without E-cadherin, the cells tend to form little lines and are harder to find compared to ductal cases, which also explains why folks tend to discover ILC at later stages (although that is changing, as diagnostic / detection systems improve).

The E-cadherin protein is encoded by the CDH1 gene. A recent study (derived from a subset of the TCGA project) presented at SABCS Dec 2014 discussed the molecular events associated with ILC. The study looked at 127 Lobular cases and revealed that CDH1 gene changes were observed in 63% of the ILC tumors. Not sure what this means clinically though. My wife has ILC, but tested negative for the CDH1 mutation. Regardless, if she tested positive, I don't believe they have a drug that targets this mutation yet (this may be changing though, per research news out of the University of Otago in New Zealand. See this link: "Bright new hope for beating deadly hereditary stomach and breast cancers").

Clearly, lobular can metastasize in a slightly strange way to unusual locations of the body (Many attribute this to the lack of e-cadherin). One of those "unusual" areas I commonly read about is stomach metastasis.

My grandfather died of stomach cancer, but my mother always claimed this was environmental--he was a WWI soldier, exposed to gas, and also worked in copper mines for years as a driller. So should I be concerned? He died in 1944.

Claire

What's the PROMPT url?

Very informative post, John, thank you. I don't know yet whether I'm LCIS or ILC (not had surgery yet) but my biopsy report stated I had 'total lack of expression of e-cadherin'. I'm not sure whether it's the gene is absent or just hypermethylated (covered by methyl groups) and cannot be read, and whether the loss of e-cadherin is just in the malignant cells or in the other cells as well. No story of stomach cancers (or any cancers) in my family (and most of them died in their 80's or 90's), however, many cases of stomach ulcers, and a couple of partial gastrectomies, which might have cut out an undiagnosed stomach cancer in an early stage. My malignant cells are pleomorphic too  

Another forum member just sent me this research news article published last month. Very interesting.
Bright new hope for beating deadly hereditary stomach and Lobular breast cancers

Any ILC experts care to discuss it?

@Fizz... Yes, I was initially confused too. Like Lobular, E-Cadherin can be "lost" in gastric cancer, particularly in Hereditary Diffuse Gastric Cancer (HDGC), which Dr. Guilford studies.

Like the well known BRCA gene, CDH1 is a "tumor suppressor" gene. The CDH1 gene is responsible for encoding the cell-to-cell adhesion protein E-cadherin (Ecad). The genetic hallmark of Lobular is the lack (or "loss") of Ecad. Without the sticky Ecad protein, the cancer cells do not clump together very well and often grow if single file lines.

I emailed Dr. Guilford in New Zealand to get some clarification on the March 2015 article: "Bright new hope for beating deadly hereditary stomach and breast cancers".
I specifically asked: "Is this news relevant for the lobular cohort that tested negative for CDH1 gene mutations?"
He replied saying it is relevant for Lobular. It does not matter if you tested positive or negative for CDH1 gene mutation. This applies regardless of whether they are somatic or germline mutations. [Somatic mutations are not transmitted to children, but germline mutations may be transmitted to some or all children. Somatic mutations develop after conception in any cell in the body, and are passed down only to descendants of that particular cell, not to future generations. Germline mutations are passed from generation to generation; they are present at conception and therefore are passed down into every cell in the body.]

Anyway, Dr. Guilford emphasizes that their research results which exploit the targeting of "G-protein coupled receptor (GPCR) signalling proteins" to kill cancer cells, are based on "cell line observations", which may not hold in whole tumors... that's the next stage of their research.

Here's the good news... It's not mentioned in the article, but it's the new class of drugs called: "HDAC inhibitors" that may be useful against GPCR proteins which are over-expressed in Lobular, especially for those that experience AI & Tamoxifen resistance. HDAC inhibitors deal with Epigenetics, which looks at ways genes are turned on and off other than just through mutations. DNA methylation is an epigenetic mechanism used by cells to control gene expression. This could be big news. HDAC inhibitors are already on the market for lymphoma, multiple myeloma and others, per wikipedia, here. Clinical trials are underway to determine if they should be used for breast cancer. Researchers think they might add significant value, especially when dealing with ER+ drug resistance.

This new info warrants a new thread. Otherwise it will be lost in the sea of comments. Give me time to create the post as I collect more data.

So if you test positive for this gene, is there a drug available to prevent stomach cancer? I'm already high risk because of my node status and see my MO for CBC panels, etc. every 4-6 months. My grandfather on my mother's side and my aunt (I just remembered) both had the disease. However my grandfather died in the early 40s, and my mother said it was because of gas in WWI and the environmental exposure to copper mining. My aunt died in 2011, but she (as I am) is a downwinder--we were in the path of the fallout from above ground nuclear testing in the 50s/early 60s in Nevada, and were higher risk for cancers like stomach and breast because of our radiation exposure. Does most insurance in the US pay for genetic testing if it's ordered by a physician?

Claire in AZ

Thanks John Smith, that is very exciting news. I look forward to hearing more about HDAC inhibitors.

I have ILC and tested positive for CDH1 mutation, but have been told that the testing is too dangerous to monitor for gastric cancer? Endoscopies can't see it and biopsies are too invasive. Very interested in any developments on this front. There must be away to stay ahead of this!