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Mount Sinai Thoracic Surgeon Studies microRNA Profiles in Esophageal Cancer

Name: Virginia Litle
Position: Assistant professor of cardiothoracic surgery, Mount Sinai Medical Center
Background: Cardiothoracic surgical resident, University of Pittsburgh Medical Center — 2002-2004
Visiting fellow, thoracic surgery, Memorial Sloan-Kettering Cancer Center — 2003
Fellow, thoracic minimally invasive surgery, University of Pittsburgh Medical Center — 1999-2001
Resident, surgery, University of California, San Francisco — 1990-1997
MD, Brown Medical School — 1990
BS, biology, University of Vermont — 1985

This month, Mount Sinai Medical Center surgeon Virginia Litle received a two-year grant, worth $84,739 in its first year, from the National Cancer Institute to investigate the expression of specific microRNAs in esophageal adenocarcinoma.
While this cancer affects only about 15,000 people each year in the US, it is becoming more common, according to the NCI.
According to Litle’s grant abstract, the “identification of unique miRNA profiles should be useful in molecular classification of pre-malignant esophageal lesions and [gastroesophageal junction] adenocarcinomas, and thus improve the current surgical treatment and outcome.”
This week, RNAi News spoke with Litle about the effort.
Let’s start with an overview of your work at Mount Sinai.
I’m a thoracic surgeon and I work in collaboration with our thoracic oncology lab here at Mount Sinai run by Tony Godfrey.
I’m very interested in the esophagus and studying esophagus cancer. This cancer, in particular [esophageal] adenocarcinoma, is significantly on the rise. There are not that many cases in the United States, but the incidence continues to climb dramatically [as it has] over the past three decades.
The main risk factors [for the disease are gastroesophageal] reflux disease and obesity. One of the big problems is that by the time those people are diagnosed with [esophageal adenocarcinoma], about half of them have metastatic … disease. That can be very discouraging from a clinical standpoint, so I became interested in trying to figure out how we can improve early detection of the disease.
[Another risk factor is] Barrett's esophagus, which is a pre-malignant change in the esophagus caused by reflux disease. But only about half a percentage of patients with Barrett’s will ever go on to get cancer, so the problem is … [figuring] out which of these patients [with Barrett’s] should be screened [for cancer] more rigorously or treated more aggressively with local therapies to prevent them from getting cancer.
What happens is that people [with Barrett’s] become, in my opinion, a little lackadaisical about it and don’t even [go for] follow-ups regularly. Then, by the time they’ve developed cancer, it’s too late.
Because our thoracic oncology lab is involved with a lot of molecular diagnostics and cancer genetics, and has done some work with … microRNAs … I was thinking that what we could do is subtype some of these Barrett’s [patients by looking for miRNA expression profiles in tissue samples that are associated with the development of] pre-malignant changes like dysplasia [and progression to cancer].
So you think that certain microRNAs could be linked to the kind of Barrett’s that advances to esophageal adenocarcinoma?
Exactly — in a subset of patients. We know that the majority of [Barrett’s] patients are not going to develop cancer, but the problem is knowing which ones you need to be more aggressive about because it’s such a deadly cancer and because we don’t have a lot of good way to make sure these patients get followed up more carefully.
There are other diseases that are sort of similar [to Barrett’s] like ulcerative colitis [for which] random biopsies are done by colonoscopy. That’s the same thing that is done for people who have Barrett’s — you do random biopsies of the esophagus, and there may be a lot of sampling error. You don’t know if you’re really even seeing any of the more malignant changes occurring in the esophagus.
The work that we’ve done so far has shown that there are microRNA expression profiles that are unique to adenocarcinoma of the esophagus. We also [found unique profiles for] some squamous cell carcinomas — even though we’re not going to study those in the long run — [in] Barrett’s, and one high-grade dysplasia, which is a progression from Barrett’s to cancer.
Is your role in the effort to collect sample and provide them to the other researchers for analysis?
We all work together. The bioinformatics part is very difficult [for me] to figure out, so I can’t take any credit for any of the bioinformatics analysis that’s been done. But I work [with the postdocs] on the experiments, and I’ve done a lot of lab research myself, actually.
So at this point, you’ve identified some microRNAs that appear to be particular to esophageal adenocarcinoma.
Yeah. We submitted this for publication, but it hasn’t been published yet. [But I can say] we found that there are certain ones that are unique to adenocarcinoma and squamous cell carcinoma. Some of those are common to other cancers, too, but you don’t find them in benign tissue. So there are certain ones we can say are more likely to be expressed or less expressed in malignancy versus normal tissue. Then, there are ones that can [be used to] distinguish adenocarcinoma from squamous cell carcinoma of the esophagus.
Now that you have these … findings, what is the next step?
Now that we have funding from the NCI, we are going to carry this out on a bigger [scale] with more Barrett’s cases, because we had a pretty small sample size [in the previous experiments].
About how many?
We had five Barrett’s [esophagus samples, in addition to normal tissue samples], so we have to look at more of those and do more arrays.
We also switched our array platform to a different company so we have to repeat a bunch of the experiments.
Which array platform are you using now?
We were using Ambion, now we’re going to be using Affymetrix.
Any reason for the change?
Just because we like it better, and they’re also less expensive.
So the idea now is to expand and confirm the earlier results?
Right, and also look at some dysplasia, too. That’s the first part.
The second part [concerns] cancers at what we call the gastroesophageal junction. Sometimes the pathologist reads [this kind of cancer] as being from the stomach and sometimes they’re read as being from the esophagus. Truly, from a surgical standpoint, you may want to do a different operation [in each case]. But the majority of the time, patients just get whatever the surgeon happens to do.
Another thing we’re going to be looking at is cancers in this area and try to see if some [miRNA profiles] are going to be more consistent with stomach cancers and some are going to be more consistent with esophagus cancers.

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