In this episode, Dr. Slavin hosts Dr. Tin-Yun Tang, a current hematology and oncology fellow at MD Anderson Cancer Center. Together, they discuss what programs and training can look like for physicians interested in genetics research and Dr. Tang’s efforts in genomic research during his combined internal medicine and clinical genetics and genomics residency at Case Western Reserve University.
0:00:11.7 Dr. Thomas Slaven: Hi, I'm Dr. Thomas Slaven, chief medical officer for Myriad
Genetics. Welcome to Inside The Genome. Hi, everyone. Welcome back to the podcast. Today we
have Tim Yun Tang. He is a resident doctor at Case Western Reserve School of Medicine. We are
so happy to have you on the podcast today Tang. Thank you for coming on.
0:00:33.9 Tim Yun Tang: Yes, thank you for inviting me onto the podcast TJ. Happy to be here.
0:00:38.8 DS: Yeah, no, this is great. You know I think this is a great time that we can highlight
what's going on on the clinician side on educating our future workforce in genetics. So I wanted to
definitely talk about that. And then there's some exciting research going on at Case Western
Reserve. But before we get into all that, tell the audience a little bit about your background, and
how you got into genetics, what drove that passion, where you're going, 'cause you're still you
know, you're just starting out your career.
0:01:08.1 TT: Yep, so, I guess a little bit about myself, went to medical school at Thomas Jefferson
University in Philly. And that is actually kind of where I got interested in medical genetics. I ended
up joining a research lab at Children's Hospital of Philadelphia. I worked on Hemophilia gene
therapy initially. This was under Dr. Katherine Highs lab, when she was still running the, I believe
it was the Molecular Medicine Institute at Children's Hospital of Philadelphia. I subsequently went
to do a formal bench research year, through Howard Hughes Medical Institute, medical research
fellows program, where I actually worked on micro RNAs and neurodegenerative disorders. So I
kind of got really drawn into this kind of Medical Genetics world of how do I intervene? Gene
therapy, genome editing, because of course, around that time, that's when a lot of the bench labs
were really starting to focus on the power of CRISPR, as opposed to zinc fingers or TALENs,
which are older technology, still have their usages, but just older technologies. So that is kind of
how I got interested in medical genetics.
0:02:19.6 DS: Yeah, so you were doing some CRISPR research, then as part of your training?
0:02:24.3 TT: I wouldn't say I was fully focused on using CRISPR in a former project, just kind of
playing around with it a little bit, at most is what I would say, most of my work... Go ahead.
0:02:36.4 DS: Well, I was gonna say too just because some people might not know what CRISPR
is, I mean, do I give like a quick lay person's description?
0:02:45.4 TT: In the gene therapy world, there's always been a goal of potentially fixing a gene,
whether it's a point mutation, or some silencing or deletion, there's always been a goal of trying to
deliver a gene itself or otherwise delete a gene, CRISPR, and I know I'm going to muck this up. It's
a long acronym, but it's derived from a bacterial immune response system, actually, and it
recognizes bits of DNA, and it cuts DNA up. The power really, of CRISPR came in, because of
how easy to use it is. Zinc fingers and TALENs, those require by and far protein engineering. Every
time you want to target a different portion of the genome for any sort of double strand break, which
is, forms the backbone to allow for editing. Although there are newer technologies now that don't
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require double strand breaks, but what CRISPR allows you to do is almost a copy and paste, hey,
this is the portion of the genome I want to target; you copy and paste it into this system and you can
use it out of the box almost.
0:04:02.9 DS: Yeah, for genome editing. That's really amazing. Yeah.
0:04:05.7 TT: So it's really powerful. And I remember, when it first came out, kind of a number of
years ago, a lot of the research labs were, especially the ones that were doing zinc finger work, and
TALENs work, were kind of looking at it very critically and thinking kind of deeply, sort of, would
this be the next wave of technology, just because of the fact that there have always been a lot of
limitations with zinc fingers and TALENs?
0:04:31.7 DS: Yeah, well, you've you've proven to our audience that you are a bonafide researcher,
in the last two minutes, no, that's great. So what have you been doing at Case Western Reserve in
terms of training and where are you going with all this?
0:04:49.6 TT: Yeah, so because of my interest in really kind of gene therapy, genome editing, I
thought a very logical extension for when I finished medical school would be something that's
called a combined residency in Internal Medicine, and Medical Genetics and Genomics. And this is
a combined track training, perhaps those in the medical world would be more familiar with med
peds, medicine pediatrics or pediatric genetics. It's a similar idea. For your program, a combined
training, really trying to tie the two worlds together. Internal medicine, there's so much going on
now with what is precision medicine? How do you use polygenic risk scores? How do you use
genetics in a more intelligent manner?
0:05:39.4 DS: How does the program work then? Do you do like a year in internal medicine to start
and then kind of flip flop between the two for a while?
0:05:48.4 TT: Yeah, I finished my intern year at Case Western Reserve University School of
Medicine, University Hospitals school and medical center programs. So I did a full Internal
Medicine intern year. And then years two, three and four, I've been kind of splitting my time and
trying to crossover of both residencies, dispersed throughout years two, three, and four.
0:06:10.8 DS: Yeah. And then, as part of that you sprinkle in some research as well, some... It
sounds some dedicated research months.
0:06:18.3 TT: As one would expect for a person with interest in medical genetics, I have a strong
interest in different kinds of research endeavors. Most of the bench research time comes out of
Medical Genetics. I'm wrapping up my time right now actually finishing on a personal project that
is focused on mosaicism in TP53. But beyond that, there is a very heavy emphasis, as one would
expect for this kind of training on staying current with the medical literature, trying to figure out
original lines of research and discovery.
0:06:56.5 DS: Yeah, yeah, and what other kind of training programs are out there right now, to
your knowledge? 'Cause it is a pretty fast moving field even since I went through training.
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0:07:05.4 TT: I think it still remains rare. I think the Associate Board of Internal Medicine and the
Medical Genetics and Genomics boards, they have a very nicely written joint statement. There are
not very many programs out there right now which combines internal medicine and medical
genetics. I believe there are five in the country.
0:07:25.4 DS: Oh, really? Okay, 'cause when I started, there were zero and I think the case was... I
could be wrong but I think we were the first to have the internal medicine, also maybe the first to
have the peds, and that's part of the reason I always had an interest in adult genetics. But I went into
peds genetics because that was actually the only offered combined program at the time where you
could do, just like you, a mix of the dual residencies and then... I did a dedicated year of research. I
did five years at the time, so they've now changed that program a little bit. I don't know if that one
actually still exists anymore on the peds or the internal medicine side but...
0:08:11.2 TT: I believe that my year, and I'm graduating in year 2021 from the fouryear
was actually the first person to go through the fouryear
0:08:21.4 DS: That's what we're gonna title this podcast, First Person.
0:08:25.2 TT: My senior, who I'm graduating with in two weeks, he just finished the fiveyear
track, and everyone else moving forward. Our pipeline here at case is full. We have been very
fortunate to recruit very talented physician scientists throughout all the years. Our pipeline is full.
We have someone coming in from a PGY1
year and we have years two, three, four.
0:08:50.9 DS: So it sounds like they're all moving to fouryear
programs, and I think that was part
of the initiative by the genetics board to really try to make it easier maybe in the long run to get
people trained up in genetics, so yeah, that's good. You're also unique in the sense that you have a
heavy... You just wrote about TP53, you also have a heavy hand in the cancer world. Where do you
see yourself going? Are you furthering your education in that regard?
0:09:20.7 TT: Yeah, so I was very fortunate to mash this year to hematologyoncology
through an internal medicine group. I'll be continuing on my training at MD Anderson Cancer
0:09:32.9 DS: Yeah, I've heard of it. It's a good place. No, that's very exciting.
0:09:36.7 TT: It's a big place out here. [chuckle]
0:09:38.3 DS: So yeah, you will be part of that new guard then that's really gonna have a good
handle on not only internal medicine, so taking care of adult patients for anything, but also genetics
and then layering on top of real expertise then in oncology. Where do you see genomics fitting into
the everyday medical oncology? Because you're really gonna come at this from a very trained
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0:10:03.2 TT: Yeah, I'm glad you brought up specifically the phrase genomics, TJ, because it did
not escape my notice that a couple of years ago, the Associate Board of Medical Genetics renamed
themselves to Medical Genetics and Genomics. And of course, this is a personal opinion but I do
think a lot of where medicine is going really is in the genomic world, particularly in oncology. I
think there's an emphasis on somatic sequencing now to the point where it's almost near standard of
care, and I think there's a growing appreciation too, that, for somatic sequencing, that time point is
important. The genomics of the cancer itself changes across time and I know there's a number of
different industrial offerings where they offer to repeat genomic sequencing if you acquire a
different tissue sample after different treatment courses, after relapse and so forth. I think from pure
old school medical genetics side, which is how I think of single gene disorders, BRCA1, BRCA2,
these are genes that are becoming actionable on the germline side.
0:11:17.3 TT: I believe the OlympiA trial time of recording was reported out only a couple of
weeks ago in New England Journal of Medicine and that is the study that demonstrates a benefit to
using Olaparib for patients with breast cancer in the adjuvant setting with BRCA1 and BRCA2.
Yeah. And those are used as longterm
maintenance adjuvant. It also did not escape my notice that
certain... For metastatic prostate cancer that is castration resistant, there was a study published
around last year, I forget the name of this phase three at this point.
0:12:00.0 DS: PROfound.
0:12:00.4 TT: PROfound, there we go. But that study is notable in that it focused on somatic. To
qualify for that study, you did not even need a germline BRCA1 or BRCA2. And of course, there's
the big pancreatic cancer study a year ago too but basically, all of these genes, these genomics, all
these aspects, they're becoming clinically actionable very, very quickly. I think since I started
residency, all of these trials have come out and been published, large phase one, two, phase three
trials. So I think for practicing medical oncologists in the future, having some a grasp for these
concepts is going to be necessary and I think there is a role for oncologists with a particular
emphasis on trying to, whether it's direct research or direct clinical trials, figure out how best to use
all this powerful technology that is now available to us.
0:13:04.6 DS: Do you have a sense of how much standard genetics training is part of now new
0:13:13.3 TT: I think there is just interacting with the oncologist here at Case Western Reserve
University, which would, of course, be Siteman Cancer Center, as well as the current fellows that
are encountering in the wards and the current residents. I think there's a little bit of a area that
requires just some more, whatever you wanna call it CME, Continuing Medical Education, or we're
gonna phrase it. I think the genetics and genomics world has really changed.
0:13:44.1 DS: Yeah.
0:13:45.1 TT: I think it's advanced at a breakneck pace and that it can be challenging for some of
the attendings and professors and fellows residents at all levels of training to keep a grasp and a
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hold and a pulse on what exactly is going on, in the genetics and genomics world.
0:14:03.4 DS: Yeah, it is just so hard. You brought up mosaicism. It's something in the germline, is
it in the tumor? Now we do liquid biopsies.
0:14:12.4 TT: Yeah.
0:14:12.8 DS: Amd what does that mean 'cause that's in the blood, but it's not germline, it's tumor
and there's things that might be pre leukemia. It's a very complex world. If you don't have some
good background about what all these things mean in your own head and how to differentiate them.
0:14:28.7 TT: Yeah. And that's before even bringing up these gnarly concepts of, can you even
calculate cancer cell fraction? Does that matter? All these numbers that are reported out in a lot of
different industry, Somatic Sequencing Reports, where some of the attendings may not be aware of
all of the foundational science behind those that helps with the interpretation.
0:14:52.5 DS: Yeah, yeah. Well, hopefully, you're part of the new guard and help with some of the
educational needs at your new center. And beyond that as all this goes forward. And one of the
reasons I even, I got in touch with you, I would say is, because some of the work that was going on
at Case Western Reserve, I know there's a discordant family history study. I was just hoping you
could kind of explain a little bit about that or any other exciting projects going on there just for the
0:15:21.0 TT: Yeah. So this study, I believe it's formerly called family history of discordant
cancers, or something similar in the ct.gov listing. The goal of this study was really to almost readdress
this very old question of, is there such thing as a general cancer susceptibility gene? For the
benefit of the listeners, if they're not aware, there's concordant cancers, which is the cancers that we
think of that run along with known genetic syndromes, colorectal cancers or Lynch syndrome, for
instance, or in the Hereditary Breast and Ovarian Cancer syndromes, the HBOC syndromes, breast
cancer, ovarian cancer. What happens though when you have a family that colloquially, we would
say, has far too much cancer in it?
0:16:14.9 DS: Yeah.
0:16:15.1 TT: There's been these... There's a number of families in our practice here in the Medical
Genetics Department. And patients that have been noticed, in the cancer center. This study was
initiated really by Dr. Stanton Gerson, who is our interim dean at this point, for the Case Western
Reserve University, as well as the director of Siteman Cancer Center. He had a number of patients,
that he had accumulated over the decades. He's been in practice where they just have so much
cancers, and they, on routine medical genetics, what we'd call at this point standard of care, these
patients do not have any identifiable mutations. So in kind of our canonical, whether it's different
industrial companies, of course, have different genes on their multi cancer panels, but we can't find
any in kind of the lowest hanging, most well described genes. So what does that mean, though?
When you have a family where you're just like, "Wow, that's a lot of cancer across multiple
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0:17:26.4 DS: Yeah. Yeah.
0:17:27.4 TT: We arbitrarily set our cutoff for inclusion at five, that is kind of based on some
studies in different communities in Utah and some different Bayesian probability studies that really
kind of focus on at what points are you likely to find...
0:17:44.6 DS: So five cancers in the immediate family, is that what you're...
0:17:48.4 TT: Yeah. Five cancers, we're focused really on kind of one to two generations of a
family, I would say. So we're looking for at least five different cancers within kind of one degree of
separation. And a lot of the times these families that we're identifying have far more than five. I
consented the first family for inclusion in the trial just about a week ago, recording for this podcast.
They are more near six or seven cancers across a small family and then, of course they...
0:18:29.0 DS: And this is any type of cancer.
0:18:31.0 TT: Any type.
0:18:31.9 DS: Like even skin cancer and things like that.
0:18:33.7 TT: Skin cancer, leukemias, lymphomas.
0:18:37.3 DS: Yeah.
0:18:37.8 TT: Skin cancer is an interesting one. I think people are finding different, rarer, of
course, susceptibility genes to even melanoma, that comes to mind. But yeah, it's interesting,
because some of these families still, of course, there are family members that have zero cancers. So
that kind of, I think it brings up a lot of very interesting potential scientific questions.
0:19:01.3 DS: Yeah. And what are you doing now with these families? You're enrolling them in a
study and you're doing some sequencing.
0:19:07.0 TT: We're enrolling them in a study and we're going for Genome sequencing? Right
now, the study is set up for whole exome sequencing.
0:19:14.7 DS: Oh, whole exome.
0:19:16.0 TT: My expectation is that it will probably expand to a whole genome sequencing after
some of the technology becomes a little bit more accessible. Not that the technology is not
acceptable. I think right now, the main issue is the bioinformatic analysis. It can be a little
challenging right now to manipulate whole genome sequencing easily.
0:19:40.2 DS: Probably an understatement.
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0:19:42.2 TT: Yes, it is very challenging. Let's put it that way. But, that is the goal right now, and
you know, we're going to assess for whether or not there are genes that are overlooked, that
potentially could be explaining some of these cancers then, and we'll also be kind of trying to take a
look at the polygenetic
one. Is there an accumulation, of small SNPs, SNVs, insertions, deletions,
what have you. Is there a statistically significant difference between what we see as.
0:20:13.5 DS: These SNVs and SNPs, so.
0:20:19.0 TT: Yes, so of course.
0:20:19.6 DS: And it's mutations, genome markers and things.
0:20:23.1 TT: Yes, sorry, I should probably define some of the jargon I'm using, but yes, I tend to
use SNVs instead SNPs just, but, that's a entire discussion in on of itself.
0:20:34.4 DS: Yeah, you may be the first person I've ever heard use the term SNV.
0:20:37.6 TT: Okay.
0:20:37.7 DS: But I love it.
0:20:39.1 TT: Well, then, maybe, I'm the one going blank.
0:20:39.9 DS: I'm gonna keep it going. That's good. And how do people... Do you have to be a
patient at Case Western? I mean, can you access this trial otherwise? Are there any like, major
things you already have to have genetic testing to... That's negative to enroll.
0:20:58.8 TT: Yeah, right now we are, it is... We're enrolling mainly out of University Hospitals.
And also from Siteman Cancer Center, so right they're very least, it would be most helpful for those
interested in this study to try to establish care one way or another, through the medical genetics
department, the Center for Human Genetics at University Hospital Cleveland Medical Center,
where the main clinical branch for Case Western Reserve University. That would be the easiest way
to get entry into the study, is what I would say. And it's always standard of care...
0:21:34.1 DS: And do people need genetic negative genetic testing prior?
0:21:38.4 TT: Negative genetic testing will be a part of the inclusion criteria, but I would just
suggest everyone for, especially if you are encountering patients with such significant family
histories to undergo a routine standard of care, clinical grade, what we would call right now whether
it's a multicancer,
a panel, some sort of formal assessment, by a medical geneticist.
0:22:02.8 DS: Yeah. Yeah.
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0:22:03.1 TT: Before you go down the road of a clinical study because they may not be necessary.
0:22:08.1 DS: Yeah, or a genetics professional or, yeah, whatever is like available, yeah, yeah.
0:22:10.7 TT: Yeah, some sort of genetics profession.
0:22:12.7 DS: Getting back to even some of the beginning of discussion, I mean, we know that a lot
of more... At point of care, medical oncology, breast surgeons, they're, a lot of the time now, they
are seeing some of these patients right up front to in addition to some of the other formal genetic
professionals, but it sounds like, yeah, at least the message is trying to get a thorough standard of
care work up, at least in your area before maybe accessing the next step, which would be something
like this study.
0:22:46.9 TT: Yes, exactly, TJ, standard of care is very important, despite, I think the enthusiasm
in myself certainly, but in the larger medical genetics, in the larger medical oncology world, there's
something to be said for standard of care, certainly NTCA guidelines are always evolving, I think
BRCA1 and BRCA2, genetic testing for pancreatic cancers is a very new addition to that, but, just
the... There's something to be said for standard of care, and I think that also helps patients not get
0:23:24.2 DS: Yeah. Absolutely. Yeah.
0:23:27.2 TT: I think everyone gets worried when they say, "Oh, you're such a rare case." I think
maybe in the medical professional community, we get enthused and excited about rare cases, but
from the patient side, they never want to hear, "Oh, you're very unusual."
0:23:40.7 DS: Right. Yeah. It's the last thing people wanna hear.
0:23:43.3 TT: Yeah.
0:23:44.9 DS: Yeah.
0:23:45.2 TT: So I think it helps reassure patients and like, "Hey, we know what we're doing, we've
been doing this for a very, very long time." You may be hearing, this is maybe the first time that a
lot of patients hear about medical genetics, I think in recent years, but it's a long historic field, and
it's been around for a very long time.
0:24:02.0 DS: Yeah, yeah, and it sounds like, yeah, with the newer, some of the streamlined
training program options and things like that, we're... We have a big future ahead of welltrained
individuals like yourself entering subspecialty
fields which is fantastic. I just wanna say thank you
so much, Dr. Tang, for coming on and spending your time, I think this was, hopefully, it will be
very useful for our audience in terms of genetics education, what are some of the studies going on,
particularly for hereditary cancer that could be sought after. This was fantastic, so I really do
appreciate it. Thank you so much.
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0:24:41.6 TT: Thank you for the invitation, TJ, it's been an absolute pleasure...
0:24:44.7 DS: Yeah.
0:24:44.7 TT: To be on this podcast.