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Notre Dame partners with Mayo Clinic on cancer research

What if science had the ability to dip into past genes to investigate a current ailment?

The results of a recent study, a collaboration between researchers at the Notre Dame genomics & bioinformatics core facility (GBCF) and the Mayo Clinic, mean that science might be headed in that direction for breast cancer and other diseases.

The paper, titled “Quality control recommendations for RNASeq using FFPE samples based on pre-sequencing lab metrics and post-sequencing bioinformatics metrics,” was published in BMC Medical Genomics online Sept. 16 and has 18 contributors from the two organizations.

Humble beginnings

The years-long project started with a cohort of patient samples from Amy Degnim, a specialized breast cancer surgeon and researcher at the Mayo Clinic. Degnim, a graduate of Notre Dame herself, had old benign samples from a subset of her patients that later developed breast cancer.

“Our interest is in looking back at these benign biopsies [the women] had years before they ever developed the cancer and comparing the biopsies of the women who did get cancer to those who didn’t,” she explained. “What are the differences, the molecular differences in the tissue that would give us some clues?”

Degnim added that having samples from the same person at two different time periods can give insights into possible somatic mutations, instead of hereditary, germline mutations that are commonly studied such as the BRCA 1 and 2 in breast cancer.

“Most women who get breast cancer don’t have a BRCA mutation or another genetic mutation. Most women who get breast cancer have, we think, somatic mutations — cumulative errors in genome that then translate into errors in cell proliferation genes and cause certain cells that have these mutations to proliferate out of control.”

Degnim said she realized that she had a very unique opportunity to almost literally look back in time to a period before the cancer developed; however, the samples were formalin-fixed and paraffin-embedded, a kind of preservation technique that allowed for the degradation of the DNA and RNA molecules needed for sequencing.

Degnim brought her problem to a colleague, who connected her to the Notre Dame GBCF. There, director Michael Pfrender, assistant director Melissa Stephens and technical scientist Brent Harker were up to the challenge.

“They were willing to take this project to push the limits of how successfully we can do RNA sequencing on these really, really old tissues,” Degnim said.

The legwork

According to Stephens, the partnership started in 2017, took a small break during the COVID-19 pandemic and the work for the paper was finally finished in 2021. She also noted that the GBCF worked closely with Derek Radisky, another collaborator on the paper and a cancer biology researcher at the clinic.

While Degnim, Radisky and others dealt with larger brainstorming and clinical applications, the collaborators at the GBCF did a majority of the legwork on the project — including RNAseq, a specialty of the center.

Stephens explained that RNAseq is a technique used to quantify the amount of RNA transcribed using next generation sequencing.

“Using RNAseq allows you to look at differences — what’s turned on, what’s turned off in these genes — and get information about the function of the genes,” she said. “[RNAseq] allows you to better understand the underlying biology of, in this case, a particular disease.”

The issue, Stephens said, was not with the archived preserved (FFPE) samples themselves but with the method of RNA extraction and the manner of enriching, or marking, the strands of interest.

“You have to use these other methods to try and get the coding transcriptome out [of the samples] without using the traditional approaches,” she said.

Stephens outlined two main methods that she and Harker used in the paper: the ribosomal depletion method or the exome sequence capture approach. The conclusion drawn in the paper was that the exome capture approach yielded better enrichment results than the depletion method.

At the end of a long trial and error period to figure out the best method, Pfrender explained that there was a need to figure out which samples’ data was reliable or “trustworthy.”

“In a whole range of samples, some were in pretty good shape, and some were in really rough shape. So, the big challenge for us was to try to figure out how to quantify that so we know which ones were safe to move forward,” he said. “The statisticians really took a harsh look at the data to try to figure out ‘what’s the roadmap? where are those cut offs?’”

The paper’s conclusion consisted of method recommendations on how to get usable data and guidance of how to judge good and bad samples.

Pfrender also took the opportunity to talk up the work ethic and patience of the center’s researchers.

“It’s really quite an accomplishment, and it’s completely up to their expertise and infinite patience trying to work through this project. I think most facilities would have just given up,” he said. “You lose a lot of potentially very important information … these kinds of samples are quite rare and really precious.”

Although the samples were localized to breast tissue and the study about breast cancer, Stephens said she believed the recommendations they created are viable for all FFPE samples.

Pfrender added in his belief that the standards and methods developed could be used to go back and study FFPE samples from 30 years into the past and beyond.

Into the future

Moving forward, Degnim told The Observer that they are currently in the process of analyzing the results of the RNAseq.

“The first step was just, ‘Can we trust this data?’” she explained. “Now we’re analyzing the data in those samples that pass the quality metrics to find out what the differences are in gene expression in women who develop cancer in the future and the women who did not.”

Degnim said she hopes to identify some biomarker, causative of the cancer or otherwise, that she can incorporate into future research endeavors and more studies.

“[This research] is a discovery effort to try to find new factors that either may predispose to breast cancer or will tell us that if a woman is expressing these changes in their RNA, they will be at an increased risk to get a breast cancer,” Degnim mentioned.

A graduate of Notre Dame herself, Degnim noted that she was really excited to work with the University on this project.

“It’s been really very thrilling and very endearing for me to be able to circle back now and have this collaboration with my alma mater,” she said.

Contact Bella Laufenberg at ilaufenb@nd.edu

‘Mickey was our leader’: Notre Dame journalism program benefactor dies after battle with cancer

“There isn’t a single story. I can’t give you a single instance that I would say sums him up for me,” Notre Dame graduate Anne Thompson said. “When I think of Mickey Gallivan, that’s what I think – commitment.”

Michael Dennis Gallivan, known to friends and family as Mickey, died Aug. 22, 2022, after a long battle with cancer.

Thompson, chief environmental affairs correspondent for NBC News, said she knew Gallivan through her work on the advisory board of the Notre Dame John W. Gallivan journalism, ethics and democracy (JED) program.

The program, which students can take to earn a minor, bears the name of Mickey’s late father, John “Jack” W. Gallivan. Both Mickey and Jack Gallivan were graduates of Notre Dame in 1967 and 1937, respectively.

As a gift to his father’s journalistic legacy with the Salt Lake Tribune, Mickey and other family members endowed the JED program with large financial gifts in 1999. He expressed that this endowment was meant to inspire young journalists.

“For more than 60 years, Jack Gallivan has defined what journalistic excellence should be in the communities of America. He approaches his profession as a responsibility. Fairness, a pure heart, and rational leadership have been his life’s tools. His family hopes that by this endowment the John W. Gallivan Program in Journalism, Ethics & Democracy can inspire like-minded leaders in the world’s news media,” Mickey Gallivan said in a 1999 press release written by University spokesperson Dennis Brown.

Brown said the University is thankful for the contributions made by Mickey to Notre Dame and to journalism.

“The Notre Dame journalism program supported by Mr. Gallivan and his family has educated scores of students who are making a difference in the field and our country. The University community joins with his family and friends in mourning his passing while celebrating a life so very well lived,” he wrote in an email.

The JED community within the University and beyond has expressed gratitude for Mickey’s continued presence in the program and sympathies for his loss.

Jason Kelly, the interim director of the JED program, said he enjoys using the colloquial term “Gallivan program” to describe both Jack and Mickey’s contributions to the program.

“The shorthand as we refer to it is the Gallivan Program because, for us, that means [Mickey’s] name is on it too. We’re thinking as much of Mickey as John, and that’s a testament to the impact he had,” Kelly said. “[Mickey] wasn’t someone who wanted a lot of credit for things.”

Although Kelly said he had only recently met Mickey, he explained how impactful his generosity and interest were to students.

“The thing that really stands out [about Mickey] is just how he was just a really nice guy, really generous guy in every sense of the term,” Kelly said. “It was really important to him to stay involved and to stay up to date on what was happening. He loved hearing about what students were doing.”

Kelly also said he believed Mickey was a great role model for JED students.

“He’s the kind of person that we all really aspire to be and certainly someone who represents what we want our students to become – a successful person, but also someone who’s contributing broadly to the community in valuable, beneficial ways and doing it with a lot of humility,” he said.

Thompson said the lasting impact Mickey made on her was his leadership style and commitment to everything he loved.

“[Robert Schmuhl] led the advisory board, but certainly I always thought of Mickey as a leader of that board. He would not thump his chest or speak the loudest or speak the longest, but it was his passion and commitment that made him a leader in that group,” she explained.

Thompson noted that working with Mickey inspired her to be a better journalist.

“[Mickey] could make me want to go out, go chase stories again,” she said. “If I was in a lull, he certainly had enthusiasm and passion, and when mine was waiting, just talking to him would inspire me.”

Robert Schmuhl, the founding director of the John W. Gallivan program, wrote an in memoriam remembrance of Mickey. In the piece, Schmuhl describes Mickey as “wise and merry.”

“Mickey’s personal commitment to Notre Dame’s Gallivan Program encompassed more than two decades. He served as an original — and continuing — member of the Advisory Board, faithfully participating in all the regular meetings. He brought wise, worldly suggestions to the discussions along with a smiling measure of Irish merriment,” Schmuhl said in the remembrance.

Schmuhl wrote in an email to The Observer that Mickey Gallivan was an advocate for ethical journalism.

“Mickey Gallivan understood the important role journalism plays in American democracy, and he became a champion of Notre Dame’s approach that puts ethical considerations central to all journalistic work,” Schmuhl said in an email.

Mickey Gallivan will be laid to rest on Aug. 31, 2022, in his hometown of Salt Lake City, Utah.

Bella Laufenberg

Contact Bella at ilaufenb@nd.edu