2013-09-30 21:27:29 UTC

AGA Perspectives Vol9Num5: Seminal CRC Research was a Family Affair

Oct. 1, 2013


C. Richard Boland, MD, AGAF

Chief, Division of Gastroenterology, Baylor University Medical Center, Dallas, TX


Everyone has some motivation behind whatever they do. Sometimes, the activity is an abstract means to a higher end. At other times, it’s a job, and perhaps you are just following orders. But there are occasions when you can see a target in front of you, and you know exactly what you are doing. The intensity and focus of such an activity can be quite unique and obscure all distractions for some period of time. An experience of this last sort occurred to me in the summer of 2001, when we were searching for the genetic basis of a familial cluster of colorectal cancers (CRCs).

When my own father died of colon cancer in 1970, I did some family history-taking and realized that he was the third consecutive generation to develop early-onset colon cancer. My father and his father both developed colon cancers in their 20s, which they survived with surgery, only to succumb to a second cancer in their 40s. My father’s siblings suffered from cancers of the colon, uterus, ovary, stomach and other organs in a way that seemed non-random, both in terms of the proportion of the family involved, and the ages at which the tumors occurred. In most instances, they died from the tumors. There was no known disease or syndrome that explained this. Certain common tumors — such as cancers of the prostate and breast — hadn’t occurred in the family. As a medical student, I consulted with the resident experts on the subjects, and the best explanation anyone offered was “bad luck.”

I pursued a career in academic gastroenterology in greatest part to be in a position where I could someday solve the problem. However, in the 1970s, there was no reason to believe that the solutions to these genetic problems would ever occur in my lifetime. In 1979, I joined the laboratory of Young S. Kim, MD, at University of California, San Francisco, determined to learn the art of scientific inquiry and to read everything I could about CRC. By the middle of the 1980s, I had moved to the University of Michigan and the molecular biology revolution was changing the face of biomedical research. I joined the laboratory of Andy Feinberg, MD, for a sabbatical to learn the burgeoning field of tumor genetics. By chance, I chose to study microsatellite sequences in the human genome as they were among the most powerful tools for genomic mapping at the time. By the middle of 1993, when my lab had done thousands of microsatellite analyses from neoplastic tissues in the colon, microsatellite instability (MSI) was identified as a novel pathway for CRC development and was linked to the hereditary colorectal cancer syndrome that I was stalking from a distance.1 Good luck this time.

We immediately determined that my father’s CRC tissues had MSI, as did the tumor of one of his siblings. At the same time, one of my cousins (Trudy) had developed sequentially cancers of the uterus and stomach. Guessing that she might be the only living carrier of the “familial mutation,” I drew blood from her and developed a lymphoblastoid cell line. The tools for detecting germ-line mutations in the DNA mismatch repair genes were primitive at the time. However, we were collaborating with Bert Vogelstein, MD, from Johns Hopkins, and he sequenced the two best characterized Lynch syndrome genes — MSH2 and MLH1 — and could find no mutation in Trudy’s DNA. He then did an experiment on her cell line to separate the two copies of each chromosome into separate “carrier” cell lines. Chromosome 2 contains the MSH2 gene; and Bert’s lab separated Trudy’s two chromosomes in separate mouse cell lines. One chromosome made the MSH2 protein, and the other didn’t; he had isolated the mutation-bearing chromosome. Furthermore, he reported that the putative mutated MSH2 gene was missing several exons, giving us a clue where to look for the mutation. He sent the line back to us at the end of 2000.

At that time, my nephew, Matt Yurgelun, was a junior at Dartmouth College and had expressed interest in a career in medicine. He applied for a summer student research grant through the AGA Research Foundation, which was funded. He came to University of California, San Diego, where I was at this time, to find the mutation in Trudy’s MSH2 gene, and had just eight weeks to do it. We knew that the rewards for getting this right would be immense for the family, since the information we had on the mutated MSH2 gene could not be used to test family members for its carriage.

Matt immediately dove into the laboratory and, before the end of the first day, he was performing experiments under the guidance of Jennifer Rhees, the lab manager, who has exceptional insight into genomics. We had developed an initial plan of attack, but had to discard it. The Human Genome Project released its first iteration just a few months earlier, and the part of the chromosome we were going to study was essentially “unsequencable.” Bad luck again. So, a second approach was developed, and Matt worked very effectively on that for two weeks. No luck. We tried to circularize the region of chromosome 2 surrounding the area of interest so we could clone the region, but this failed. So, Matt disappeared into the library for a couple of days, and came back with a new plan. This time, it worked, and Matt was able to isolate a piece of DNA that included sequences that flanked an area of chromosome 2 that contained the deletion mutation in the MSH2 gene. One fateful evening, about 7 p.m., Matt and Jennifer were reading DNA sequences out loud and Matt calmly declared “that’s it, we have it.” He and Jennifer found the “breakpoint” in the gene that contained flanking sequences on either side of a mutation in which 39,000 base pairs of DNA were deleted from the genome and ligated back together. We knew from the nature of the DNA sequences that large deletions of MSH2 were a possibility, but we proved that this occurred in Lynch syndrome. It has been shown subsequently that this is a common type of Lynch syndrome mutation in MSH2. It was not a matter of luck this time.

We had a nice celebration that night, but I mentioned to Matt that he still had two weeks to go, and we did not yet have a clinically usable test for the mutation. Not deterred for a moment, Matt went back to the lab and, in about 10 days, developed a diagnostic test which we used to test the entire family. Incidentally, Matt is now on the faculty of the Dana Farber Cancer Institute in Boston and is a GI oncologist.

The key to the story is that a relatively small student summer research grant from the AGA Research Foundation led to an important laboratory-based discovery, and permitted us to develop a diagnostic test for this mutation to our family — a very good example of highly “personalized medicine.” The grant provided Matt with just enough to test his interest in biomedical research, and permitted him to find novel skills that he was able to more fully develop over the next few years. He continues to study familial GI cancer syndromes. We sometimes wonder where the next generation of researchers and discoverers will come from. The AGA Research Foundation is a good place to start placing your bets. With a little luck, we can have a big payoff.

Dr. Boland has no relevant conflicts to disclose.


1. Boland CR, Lynch HT. The History of Lynch Syndrome. Fam Cancer 2013.

More on Colorectal Cancer

Principles of GI for the NP and PA

Aug. 10, 2018

Hear from the experts as they provide you with critical updates on treating and managing patients with a variety of GI disorders.

2018 AGA Postgraduate Course

June 2, 2018

Secure your spot for this clinically focused, multi-topic course that offers immediately applicable information. Held in conjunction with DDW®. Save $75 when you register by April 18.

Advocate CMS, close the colonoscopy loophole

March 8, 2018

AGA urges CMS to address the cost sharing problem that arises when screening colonoscopies become diagnostic for Medicare patients.