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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

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University, city enters into flu season

Over 6,000 free vaccinations were administered exclusively for students during the first flu blitz, University Health Services (UHS) director Edward Junkins told The Observer. Faculty, staff and dependents are eligible to make appointments for the second blitz.

The UHS orchestrated its annual flu vaccine blitz in the Stepan Center on Sept. 20 and Sept. 21. The secondary blitz takes place this week on Oct. 11 and Oct. 12.

Junkins supplied the rationale: influenza is a highly communicable infectious disease that consistently causes morbidity. 

Influenza, Junkins said, is an illness that can quickly overwhelm the resources the University has in place in the event of a widespread outbreak.

“[Morbidity] means loss of time from work, significant symptoms, so body aches, high fever, dehydration and putting people at risk who have chronic illness,” he said.

Though Notre Dame has a primary care clinic located on campus in Saint Liam Hall that takes care of urgent needs, Junkins said that the University does not have the resources to take care of hundreds of students.

“Even though we have a high vaccination rate, we still get breakthrough infections and that very quickly overwhelms our clinic, our pharmacy,” he said.

In agreement with Junkins, St. Joseph County Deputy Health Officer Mark Fox said he thinks Notre Dame’s flu blitzes are advantageous to the community because of the congregate living on campus.

“It is obviously important for the campus community because there is a lot of congregate living,” Fox said. “So, the risk of spreading any respiratory illness is significant. So, any opportunity to reduce that is beneficial.”

Aside from the congregate living, Fox said he regards Notre Dame to be a well-protected, heavily vaccinated community. Fox underscored the blitz’s effect on South Bend.

“And while much of the campus lives in congregate living settings, you know, it’s not a closed campus,” he added. “There’s a lot of interaction with Notre Dame students, faculty and staff out in the community, or volunteering or going to Martin’s or going to Finnies or wherever.”

The COVID pandemic’s third flu season beginning this fall, Fox pointed out the growing importance of flu vaccinations in 2022 than in direct years past.

“Over the last couple of years in general, the flu rates have been lower because there were a lot of COVID mitigation strategies in place and people who were sick were likely staying home or staying in their dorm,” he said.

Fox predicts that flu cases will increase now that pandemic era practices have gone away.

“Now that most of the community is following virtually no mitigation strategies, I expect that this will be probably a more normal flu season,” Fox said.

With these risks, last year saw over 90% student compliance with the flu vaccine mandate, Junkins said. The 6600 student-dedicated appointments at the first blitz were all taken.

“Shots in arms,” he said. “We still have about another 5000 or so students who still need to meet the requirement. I would predict about 3000 of those students will come back through during this next Blitz.”

Some students will get the vaccination over fall break but the University said they plan to set it up so that students can receive their vaccine for free before they travel home and back, Junkins said.

“Of course,” Junkins said, “[the flu vaccine] is required in order to be able to register for the spring semester.”

Contact Peter Breen at pbreen2@nd.edu