Posts (9)

Wed, Oct 23 5:22pm · Finding the needle in the haystack: a tool for rare inherited diseases

Individualized medicine has had notable success in identifying DNA mutations that cause cancer. But rare inherited diseases pose an even bigger challenge. Like a needle in a haystack, the cause of a rare inherited disease is often deeply buried, in the DNA that comprises genes or controls their expression. Now however, Mayo Clinic’s Center for Individualized Medicine  has developed a tool to pinpoint RNA aberrations that underlie rare inherited diseases, paving the way for increased diagnosis.

“Individuals
with these diseases have usually been through a years-long odyssey of
traditional medical testing and profiling without success,” says Gavin Oliver, a Mayo Clinic informatics
specialist. “Identifying a specific cause offers the patient and family
the potential for treatment options, reproductive counselling and — not least —
the peace of mind of knowing a cause with certainty.”

Gavin Oliver

Current
genomic testing for rare inherited diseases compares a patient’s DNA to the DNA
of family members and to databases of healthy individuals’ DNA. Those
comparisons might uncover a difference in the patient’s DNA that can be tied to
the physical characteristics of his or her disease.

“But
DNA sequencing yields a diagnosis in only about 25% of rare disease
patients,” Oliver says. “The addition of RNA-based testing has been
shown in some studies to improve that rate to as much as 60%. DNA tells us a
lot, but the ability to actively profile what the DNA produces — that is, the
RNA transcripts — offers us a whole new perspective.”

Filtering RNA’s noise

Mayo’s
new tool focuses on an RNA aberration known as fusion transcription. Although
fusion transcripts have been linked to blood and solid tissue cancers, they
haven’t been widely investigated in rare genetic diseases. Identifying these
RNA errors, which result in individual genes being abnormally joined, is
daunting.

“RNA
is very noisy data,” Oliver says. “When we analyze it, we see a lot
of artifacts from random occurrences. Much of this noise is due to imperfections
of the computer programs, errors caused by laboratory protocols or perhaps
biological events that aren’t relevant to the patient’s disorder.”

Mayo researchers
succeeded in filtering that noise, to isolate verifiable fusion transcripts. In
a study of the new approach, 47 people
with undiagnosed, suspected inherited disease had RNA sequencing performed. The
results were analyzed using an existing fusion transcription algorithm originally
designed for cancer data, with all the filters aimed at cancer data turned off.

The initial result was large haystacks — roughly 31,000 candidate fusion events per study participant. But after creating their own filters aimed at rare genetic diseases, the researchers reduced that number to about 12 candidates per patient.

Eleven
candidates with the highest potential relevance to the patients’ conditions
were then investigated in the laboratory. Eight of the 11, or 75%, were
confirmed as genuine RNA fusion transcripts. Two were judged clinically
diagnostic of the patients’ conditions.

“Initially,
we had to consider everything, including the noise, as a fusion transcript
candidate. But we were able to reduce the noise and obtain a manageable number
of events to investigate in the lab,” Oliver says. “The two cases we
solved using fusion transcript analysis had gone unsolved for years, despite
wide-ranging clinical and research testing. More follow-up is required to
confirm the role of the remaining nine events.”

“Fusion transcript detection definitely won’t solve every case of rare inherited disease, but it can contribute. Every patient diagnosed is a huge victory. The true goal is 100% diagnosis.”

Gavin Oliver

The
study represents the first systematic application of fusion transcript
detection in people with undiagnosed, rare inherited diseases. The patients in
the study had a wide range of rare conditions, including neurological, immune,
muscular, digestive, connective tissue and skeletal disorders. The new method
of fusion transcription analysis will be used routinely at Mayo Clinic for
every patient with an undiagnosed rare disease whose RNA is sequenced.

“Fusion
transcript detection definitely won’t solve every case of rare inherited
disease, but it can contribute,” Oliver says. “Every patient
diagnosed is a huge victory. The true goal is 100% diagnosis.”

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Wed, Sep 25 8:49am · The BEAUTY of it: award recognizes personalized medicine approach for breast cancer

The BEAUTY team
Back row (from left): Sarah McLaughlin, M.D.; Vera Suman, Ph.D.; Richard Gray, M.D.; Alvaro Moreno-Aspitia, M.D., and Krishna Kalari, Ph.D.
Front row: Liewei Wang, M.D., Ph.D.; Matthew Goetz, M.D.; Judy Boughey, M.D., and Richard Weinshilboum, M.D.

A
Mayo Clinic research team supported by the Center for Individualized
Medicine
is
making significant breakthroughs — and gaining recognition for them. The Breast
Cancer Genome-Guided Therapy (BEAUTY) project has received the 2019 Mayo Clinic
Team Science Award, given for interdisciplinary work that substantially
advances Mayo’s research. The award cites BEAUTY’s discoveries about breast
tumor biology and the group’s development of lab models, which already are
helping to uncover new treatment options for chemotherapy-resistant disease.

Chemotherapy
is a standard breast cancer treatment, used for aggressive biology breast
cancer to shrink tumors in the breast and lymph nodes before surgery, assess
response and destroy any undetected cancer cells elsewhere in the patient. But some
breast tumors don’t respond well to chemotherapy, putting patients at high risk
of recurrence and early death.

Matthew Goetz, M.D.

New
treatments are needed for chemotherapy-resistant breast cancer. But the stunning
complexity of breast cancer at the cellular level makes it tough to find alternatives
that can target an individual’s tumor.

“BEAUTY
is a paradigm shift not only in terms of how the trial was designed, but the
clinical and research findings that continue to emanate out of the study. We
are working to change the standard of care,” says Matthew Goetz, M.D., a Mayo medical
oncologist who co-leads the project.

Liewei Wang, M.D., Ph.D.

The goal is to determine why some patient’s tumors respond to chemotherapy while others don’t, and to use that knowledge to develop personalized medicine therapies.

“Breast cancer is not a single disease,” says Liewei Wang, M.D., Ph.D., PI of Mayo’s Pharmacogenomics and Drug Targets Laboratory and a member of BEAUTY’s executive team. “Breast tumors are highly heterogeneous. Every patient experiences a different disease process, so naturally we shouldn’t treat every patient the same.”

Launched in 2011, BEAUTY
has impact beyond Mayo Clinic. The wealth of clinical, genomic and imaging data
gathered by the project is being used in multiple collaborations across the nation
to guide cancer research. BEAUTY has generated four clinical trials, two
patents, multiple NCI and DOD grants, as well as a methodology for
incorporating molecular sequencing data into clinical trial results.

“BEAUTY works predominantly to
further treatments for breast cancer, however there have also been advantages
for some of the individuals enrolled in the study,” says Judy Boughey, M.D., a Mayo breast
surgeon who co-leads BEAUTY. “We’ve been able to achieve that because we
have a huge multidisciplinary team of clinicians and basic scientists with everyone
working together for the greater good.”

Judy Boughey, M.D.

Germline
screening for genetic mutations was performed on blood samples from study participants
in BEAUTY.

“In
the 124 women, we identified 28 deleterious mutations across 26 patients. That was
a lot higher than we expected because this wasn’t a group of women with a
strong family history of breast cancer,” Dr. Boughey says. “In
addition to BRCA1 and BRCA2, we found some lesser- known mutations, some of
which weren’t specific to breast cancer.”

Participants with clinically actionable mutations were referred to genetic counselors. “Some of these patients have gone on to get screening for other malignancies that they are at elevated risk of developing in the future,” Dr. Boughey says. “That’s been an unanticipated benefit of patients’ participation in the study.”

A chemotherapy-resistant model of success

BEAUTY
has resulted in a series of further laboratory and clinical studies of women
with invasive breast cancer who qualify for chemotherapy before surgery.

Tissue
samples were obtained from BEAUTY participants through minimally invasive
needle biopsy. In addition to performing exome and RNA sequencing of the
tumors, the researchers achieved a milestone: the successful implantation of
patient tumor tissue in laboratory mice to create a living model of an
individual’s disease, known as a patient-derived xenograft (PDX).

PDXs provide
opportunity to further interrogate the tumors, studying the impact of new drugs
and drug combinations, and facilitate preclinical studies of new therapies. The
BEAUTY team created PDXs from tumor tissue biopsies taken throughout the breast
cancer treatment process. That allows the researchers to study the molecular
evolution of cancer over the course of treatment and to identify mechanisms of
resistance to chemotherapy.

“It’s
really fortuitous to have PDXs from not only the tumor that’s never been
exposed to chemotherapy, but also the tumor collected at surgery that continued
to remain viable despite being exposed to 20 weeks of chemotherapy. That’s
truly a chemotherapy-resistant model” Dr. Goetz says. “These are the
models that will provide some of the most useful information when it comes to
prioritizing new drugs”

BEAUTY’s
comprehensive genomic and PDX data has led to several discoveries — including a
potential treatment for triple negative breast cancer, one of the most
aggressive and lethal forms of the disease. “Triple negative” means
the tumor lacks the three most common proteins known to respond to existing therapies.

The
BEAUTY team found that a drug already approved for treating certain blood
cancers can significantly inhibit the growth of some chemotherapy-resistant triple
negative breast tumors. The Mayo researchers are now collaborating with the
National Cancer Institute to refine the existing drug and plan to launch a
clinical trial in women with triple negative breast cancer.

“These new discoveries can lead to more clinical trials that will provide additional choices for personalized care,” says Dr. Wang.

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Thu, Aug 29 2:07pm · Gerstner awards boost research into rheumatoid arthritis, breast cancer

Creating tools to identify optimal treatments for rheumatoid arthritis and breast cancer are focuses of the 2019 Gerstner Family Career Development Awards.

This year’s awardees are Elena Myasoedova, M.D., Ph.D., a rheumatologist at Mayo Clinic’s Minnesota campus and Bhavika Patel, M.D., a radiologist at Mayo’s Arizona campus. Both researchers seek to apply data centric approaches to medical care, sparing patients unnecessary complications and providing enhanced disease treatment.

Elena Myasoedova, M.D., Ph.D.: Predicting response to rheumatoid arthritis therapy

Elena Myasoedova, M.D., Ph.D.

For
Dr. Myasoedova, rheumatology care is a family tradition. “My grandfather
and mom were both professors of rheumatology,” she says. “This is how
I became interested in improving outcomes for rheumatoid arthritis treatment.”

Rheumatoid
arthritis is a chronic autoimmune disorder that causes irreversible joint and
organ damage. Early, effective treatment is needed to avoid severe disability
and even death. The most commonly used rheumatoid arthritis medication,
methotrexate, is ineffective in 30% to 40% of patients. Methotrexate also must
be taken for three to six months before doctors can determine if it’s working,
and — if it isn’t — try something else, which imposes a costly delay for
patients.

“The
window of opportunity for early treatment is about three months,” Dr.
Myasoedova says. “Without timely and effective intervention, we lose a lot
of momentum in attacking the disease.”

Using
artificial intelligence, Dr. Myasoedova is building an algorithm that can
predict an individual’s response to methotrexate. The algorithm incorporates genomic,
clinical, sociodemographic and blood test data from people with early rheumatic
arthritis who have been treated with methotrexate.

“Analyzing
and synthesizing all this information into a model is beyond the capabilities
of a regular statistical model,” Dr. Myasoedova says. “Artificial
intelligence is able to streamline that process and create a model to predict
the likelihood of therapeutic response.”

This work, undertaken in conjunction with the Center for Individualized Medicine Pharmacogenomics Program, is a pilot project that can potentially provide a foundation for studies of emerging rheumatoid arthritis treatments, including biologics and small molecule therapies.

“Eventually, I hope we will be able to create an artificial intelligence platform where, based on the patient’s bloodwork, we can match that patient’s characteristics to the medication that would be most beneficial,” Dr. Myasoedova says.

Bhavika Patel, M.D.: Shifting the paradigm for breast cancer treatment

Bhavika Patel, M.D.

Treatment
for early stage or locally advanced breast cancer generally involves
chemotherapy or other medical treatment, followed by surgery and additional
medical therapy. Currently there is no precise way to determine whether each
additional treatment benefits an individual patient.

For
some patients, presurgical treatment kills all cancer at the tumor site — so it’s
unclear what benefit the surgery provides. After surgery, however, patients
whose tissue tests cancer-free might have residual tumor DNA in their bodies and
may benefit from additional treatment.

“Patients
with breast cancer are often overtreated and sometimes under-treated, due to
the lack of biomarkers that could help personalize treatment plans,” Dr.
Patel says. “In recent years, overall survival for breast cancer has
improved tremendously. But we need biomarkers to accurately identify patients
with residual disease after surgery while sparing others who can safely skip
postoperative treatment.”

Dr.
Patel’s research team is utilizing two such biomarkers. The first is a blood
test to detect residual tumor DNA circulating in patients’ blood after breast
cancer treatment. This state-of-the- art blood test — developed in
collaboration with the University of
Cambridge

and TGen, a translational genomics
research institute in Phoenix — was recently described in Science Translational Medicine. The second utilizes quantitative image analysis tools
to identify patterns and metrics detectable on breast cancer patients’ contrast-enhanced
imaging studies before, during and after treatment.

“Combined with imaging and clinical assessments, measurements of circulating tumor DNA can help guide treatment strategies in individual breast cancer patients, with the use of a fusion biomarker. We can potentially change the paradigm for breast cancer treatment,” Dr. Patel says. “Ultimately, the goal is that these biomarkers can inform personalized therapies, to improve breast cancer patients’ quality of life and avoid unnecessary treatments.”

Funding for the Gerstner Family Career Development Awards in the Center for Individualized Medicine is provided by The Louis V. Gerstner, Jr. Fund at Vanguard Charitable.

The awards are given each year to early-stage investigators to advance individualized therapies. Another goal is to promote a specialized workforce capable of moving individualized medicine from discovery into patient care.

The latest advances in cancer care

Join us for Individualizing Medicine 2019 Conference: Precision Cancer Care through Immunotherapy and Genomics on Sept. 20-21, in Scottsdale, Arizona. 

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Other key conference themes include:

  • CAR-T cell therapy
  • Clonality
  • Pharmacogenomics
  • Lineage Plasticity
  • National Cancer Institute match

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Tue, Aug 13 10:34am · An artificial intelligence tool to improve pancreatic cancer outcomes

Only 9% of people with pancreatic cancer live for five years after diagnosis. “That is an abysmally low number, probably the worst in human cancers,” says Michael Wallace, M.D., a digestive disease specialist and a researcher within the Center for Individualized Medicine at the Mayo Clinic campus in Florida. “We want to get that rate substantially higher.”

Artificial intelligence is providing a way to do just that. In collaboration with computer scientists from the University of Central Florida, Mayo Clinic radiology and gastroenterology experts have developed an algorithm that can identify pancreatic cysts that are at higher risk of developing into pancreatic cancer. (Read about the research in a recent publication). Typically, pancreatic cancer is found when it’s too advanced for curable surgery. But people who are identified as high risk can be monitored to catch cancer early.

“Outcomes
from other cancers — colon, breast, prostate and lung — have improved
dramatically in the past decades, largely through early detection programs such
as colonoscopy and mammograms,” Dr. Wallace says. “We are applying
that model to pancreatic cancer.”

Michael Wallace, M.D.

Mayo Clinic is committed to a personalized medicine approach to assessing disease risk. These efforts are led by the Center for Individualized Medicine, in collaboration with other groups within and beyond Mayo Clinic. Artificial intelligence is key to evaluating the risk of pancreatic cancer because screening for that disease is challenging.

“The only effective screening modalities for pancreatic cancer are very expensive and somewhat invasive. We wouldn’t want to screen the general population,” Dr. Wallace says. “But identifying individuals who are at above-average risk for pancreatic cancer allows us to apply that screening only to them.”

A first in artificial intelligence

Artificial intelligence is increasingly used to assist in image analysis. But the Mayo Clinic-University of Central Florida work is the first to address pancreatic cancer.

Recent studies have found that pancreatic cancer often starts with a precancerous cyst known as an intraductal papillary mucinous neoplasm (IPMN). Like a skin mole, an IPMN is capable of remaining harmless or developing into cancer. Pancreatic cysts are commonly seen on abdominal MRIs and CTs that people have performed for another purpose.

“About
40% of people have some sort of pancreatic cyst. The vast majority are
benign,” Dr. Wallace says.

Radiologists who analyze scans of pancreatic cysts look for certain imaging features such as a cyst’s size and enhancement. But those factors aren’t very accurate at predicting cancer risk. “If you sent people to surgery based on the existing criteria, only about half would turn out to have pancreatic cancer or an advanced precancerous cyst,” Dr. Wallace says.

Like the human brain, Mayo Clinic’s artificial intelligence tool learns from experience. The researchers fed into the algorithm MRIs of individuals who’s IPMNs progressed to cancer, and MRIs from a control group who’s IPMNs remained benign for many years. Once the algorithm was “trained,” its classifications of high-risk and low-risk cysts were compared to classifications made by Mayo Clinic radiologists.

“We
found that the algorithm reads a scan — which is about 1,200 images — in
roughly half a second, versus the 20 to 30 minutes an average radiologist would
need,” Dr. Wallace says.

Candice Bolan, M.D.

“The algorithm is able to call attention to cysts that may be of higher risk, bringing it to the attention of the radiologist for detailed review,” says Candice Bolan, M.D., chair of the Division of Body MRI in Florida, who helped in the development of the software.

“This artificial intelligence has the potential to provide high-quality image interpretation to people anywhere in the world,” Dr. Wallace says.

The next step is further enhancing the algorithm’s accuracy. Dr. Wallace, Dr. Bolan and their UCF colleagues recently received National Institutes of Health funding that will allow them to feed more pancreatic cyst scans into the algorithm.

“The more cases we have, the better we can train and refine the algorithm,” Dr. Wallace says. “It’s like an online photo collection — the more times you tag someone’s face on your photo app, the better the app is at detecting that person on unknown photographs. An algorithm that is as good as our best radiologists isn’t good enough. We want the algorithm to be better than that.”

More tools for earlier cancer detection

Kristin Clift

In
addition to applying artificial intelligence to imaging, Mayo Clinic is using
patient questionnaires and genetic DNA testing to better characterize
pancreatic cancer risk. Both approaches can help patients through earlier
detection and treatment of cancer.

The patient questionnaire — designed in a multidisciplinary collaboration of the Center for Individualized Medicine and the Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, and supported by the Florida Pancreas Cancer Coalition and Champions for Hope — seeks to identify individuals with genetic syndromes that can increase the risk of pancreatic cancer. People who see Dr. Wallace for any gastrointestinal issue complete the questionnaire before their appointments.

“Although
this tool is low-tech, it has already helped us direct people to genetic
counseling and to identify individuals with pathogenic variants associated with
pancreatic cancer,” says Kristin Clift, who coordinates research for the
Center for Individualized Medicine.

The
questionnaire goes beyond pancreatic cancer to ask about a family history of
other diseases, including breast cancer. “Many people understand that the
BRCA1 and BRCA2 mutation can increase your risk for breast and ovarian cancer.
But those mutations also increase risk for pancreatic cancer,” Clift says.

Among
430 people who completed the questionnaire, 25% met National
Comprehensive Cancer Network

guidelines for referral to genetic counseling and testing. Three individuals
were found to have pathogenic variants associated with pancreatic cancer,
including one who was found to have the disease.

“The
genetic testing helped determine the best treatment option for that individual.
Her sister also came in for genetic testing and was found to have the
variant,” Clift says. “We were able to put the sister on a screening
regimen so that we can catch the cancer earlier if it develops.”

For Dr. Wallace, genetic testing and artificial intelligence are critical to improving pancreatic cancer outcomes. “They both allow for early detection. There is a strong need for better classification of individual risk, and we are committed to it.”

In addition to providing expertise in survey design and
implementation, the Mayo Clinic Kern Center for the Science of Health Care
Delivery leads Mayo Clinic’s artificial intelligence strategy. And as Dr.
Wallace mentions, radiology plays a critical role in many of the projects
underway in AI. This work is an example of the team collaborations that exist
across Mayo Clinic, and which are essential to Mayo’s efforts to provide the
best possible care to patients.

The latest in cancer care

Join us for Individualizing Medicine 2019 Conference: Precision Cancer Care through Immunotherapy and Genomics on Sept. 20-21, in Scottsdale, Arizona. 

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Other key conference themes include:

  • CAR-T cell therapy
  • Clonality
  • Pharmacogenomics
  • Lineage Plasticity
  • National Cancer Institute match

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Fri, Jun 28 10:58am · Can BioBanks Help Close Gaps in Health Outcomes?

By definition, personalized medicine requires diversity. One-size-fits-all doesn’t work for every individual, especially members of groups that are medically underserved.

In collaboration with Arizona State University and Mountain Park Health Center (MPHC) in Phoenix, Mayo Clinic’s Center for Individualized Medicine has created a biobank to enhance the diversity of Mayo’s medical research. Sangre Por Salud (Spanish for Blood for Health) contains samples and health information from 3,756 people who self-identify as Latino and receive care at Mountain Park. As a Federally Qualified Health Center, MPHC provides comprehensive health services to underserved populations, including Latinos and African-Americans, independent of their immigration status.

Giovanna Moreno Garzon

“To practice individualized medicine, we need to understand all individuals. We cannot generalize that whatever is discovered in Caucasians is applicable to Latinos or other populations. Our intent is to close these gaps,” says Giovanna Moreno Garzon, Mayo Clinic’s senior research coordinator for Sangre Por Salud.

Sangre Por Salud is more than a biobank. “With the consent of participants at Mountain Park, we collected blood samples, plasma and DNA, as well as responses to health questionnaires,” Moreno Garzon says. “We have access to the participants’ electronic medical records at Mountain Park and permission to contact the participants again if needed for research. This is a great resource for investigators to add diversity to their current research activities.”

When Mayo Clinic launched its biobank in Rochester, Minnesota, most of the samples were from Caucasians. Only 0.4% came from Latino donors. Mayo Clinic is now at the forefront of efforts to increase research in minority populations, to address health disparities.

“A lot of patients in the population we serve are disease-burdened. Obesity, diabetes, high blood pressure and the risk of heart problems are common,” says Valentina Hernandez, director of integrated nutrition services at MPHC. “We started working with Mayo Clinic to create the biobank so that these patients could contribute to the science of genomics. We hope these patients will be better represented in research to help ease the burden of disease in this population.”

Data from Sangre Por Salud is available to Mayo Clinic researchers and their collaborators. The Center for Individualized Medicine reviews all requests for data. Among the research projects using Sangre Por Salud data is a study led by Richard Caselli, M.D., involving APOE4, a form of a gene that increases the risk of Alzheimer’s disease.

Valentina Hernandez

In addition to facilitating diversity in medical research, Sangre Por Salud is directly benefitting Mountain Park patients. Samples from 500 of the donors were genetically sequenced to detect mutations associated with various conditions.

“We were able to identify 10 individuals who have a gene mutation that could be a predictor of a future disease — such as the BRCA gene and breast cancer,” Hernandez says. “We could then counsel these individuals on their risks and how they might help prevent the development of disease.” Both MPHC and Mayo Clinic are committed to developing further strategies and infrastructure for patients’ follow-up care.

Beyond those specific findings, information from the biobank is changing clinical practice at Mountain Park. “We learned a lot about our patients from the lab work that was done to get baseline measures from the donors,” Hernandez says. “Although these donors were young and nondiabetic, many of them had high cholesterol or prediabetes. We wouldn’t have known that without the lab testing.”

Prediabetes means that blood sugar levels are higher than normal but not yet high enough to be type 2 diabetes. With prediabetes, the long-term damage of diabetes to the heart, blood vessels and kidneys might already be starting.

“We had a lot of our patients see a dietitian to talk about diet and lifestyle,” Hernandez says. “We’re more aware that a seemingly healthy person might have something we can catch early, and prevent bigger problems later. Sangre Por Salud has really changed medical practice in our clinic.”

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  • Clonality
  • Pharmacogenomics
  • Lineage Plasticity
  • National Cancer Institute match

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Tue, Apr 30 11:20am · Sudden Cardiac Death: Defining the Risk for Surviving Relatives

A young person’s sudden death from cardiac arrest is doubly devastating. Just when family members are mourning the unexpected loss, they might also be wondering if the cause was inherited heart disease — and if they too are at risk.

Often there’s no easy answer. Unlike certain cancers with strong links to a single gene abnormality, cardiovascular disease is associated with complex genetic factors. Blood relatives of people who experienced sudden cardiac death can face a lifetime of uncertainty and annual medical imaging to detect any signs of heart disease.

With support from the Center for Individualized Medicine, Mayo Clinic is conducting research to find answers.

Joseph Maleszewski, M.D.

“Surviving family members don’t know if they are at risk for a heart condition, if they should change their lifestyle such as not engaging in certain types of athletics— they’re just stuck,” says Joseph Maleszewski, M.D., a Mayo Clinic pathologist specializing in cardiovascular disease. “We’re trying to elucidate the underlying genetic implications for these family members. We want to help them manage diagnostic screening and get the care they need right now.”

Sudden, unexpected death from cardiac arrest accounts for 12% to 15% of natural deaths. Up to half of people under age 35 who experience sudden cardiac death had no family history of it and no warning signs of heart disease, according to the National Society of Genetic Counselors.

Conducted in partnership with the Windland Smith Rice Sudden Death Genomics Laboratory & Long QT Syndrome Clinic, Mayo Clinic’s research involves postmortem analysis of the hearts from people under age 40 who died suddenly of presumed cardiac causes, and genetic testing of first-degree relatives—parents, siblings and children. “We believe it’s absolutely necessary to combine these two approaches in order to give the family information that’s much more useful than what they would get from either approach alone,” Dr. Maleszewski says.

Subtle signs that lead to answers

One common challenge for family members is incomplete information about the cause of a relative’s sudden death. An autopsy might establish that the person died of natural causes but fail to identify a specific cardiac disease or its genetic underpinning.

“We believe some cases of sudden cardiac death are very subtle manifestations of cardiomyopathy, or heart muscle disease. The features of cardiomyopathies are sometimes very difficult to detect, even by experienced medical examiners and coroners,” Dr. Maleszewski says.

The postmortem examinations conducted by Mayo Clinic cardiovascular pathologists will evaluate each heart’s overall appearance and analyze tissue sections under the microscope. If cardiomyopathy is suspected, genetic testing will be recommended for first-degree relatives.

Relatives who test negative for genetic variants associated with heart disease can avoid routine imaging. For family members who do have a genetic variant, risk-management plans can be developed. “

We think this is a much more scientific and comprehensive approach to cases of sudden death,” Dr. Maleszewski says. “Instead of a 20th-century screening paradigm, we want a 21st-century pairing of postmortem examination and genetic testing.”

That pairing is key. “There’s a lot of nuance in the understanding of cardiovascular disease. Our interpretation of the genetic tests is completely contingent on establishing with our eyes that there is some type of underlying pathology in the heart,” Dr. Maleszewski says. “We can then give information to the family that empowers them to obtain efficient screening and to have complete closure.”

Another common challenge is a lack of genetic information about the deceased relative. Postmortem blood samples are stored for a limited time — due to cost and space constraints experienced by medical examiners — and so often aren’t available for genetic testing.

Mayo Clinic has developed a unique genetic test that uses tissue samples preserved in paraffin. Unlike blood samples, those tissue samples are often kept by medical examiners for several years to meet accreditation requirements.

“We use this tissue-based genetic testing routinely. It opens up a lot of older cases for possible interrogation,” Dr. Maleszewski says. “For example, if a Mayo cardiologist sees a patient whose father had cardiac death at a young age, we can obtain the father’s tissue samples, examine them and then determine if genetic testing should be done to assess the son’s risk.”

Data accumulated will also provide insight into the complex genetic variations that can cause heart disease.

“Ultimately, we hope that for every case of sudden cardiac death, there can be a complete workup of the heart and the genetics,” Dr. Maleszewski says. “We’d like to help educate medical examiners and coroners on how to perform a thorough cardiovascular exam to look for these subtle signs of disease, and to give them access to expert consultation when they need it.”

Mayo Clinic’s study is being conducted through medical examiners and coroners who refer new cases of sudden death in which a cardiac cause is strongly suspected.

###

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Key conference themes include:

  • CAR-T therapy
  • Clonality
  • Pharmacogenomics
  • Lineage Plasticity
  • National Cancer
    Institute.

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for Individualized Medicine
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Tue, Mar 19 8:00am · Not the end of the road: Delivering the diagnosis of sex-chromosome trisomy

Even if you’ve never heard the word “trisomy,” you probably know someone with the condition. March is Trisomy Awareness Month, a time to raise awareness about trisomy conditions and the challenges they can pose to individuals and families.

Trisomy means having three copies of a chromosome instead of two. Down syndrome, or trisomy 21, is the best-known trisomy. Certain less-known types occur for other chromosomes, including the sex chromosomes. The traits, or phenotypes, associated with sex-chromosome trisomy vary widely among individuals—which poses significant challenges for discussions between health care providers and families. Research supported by Mayo Clinic’s Center for Individualized Medicine (CIM) highlights how providers might better deliver the diagnosis of sex chromosome trisomy.

Megan Allyse, Ph.D.

“It’s much easier to give prospective parents a clear vision of what life would be like for a child with Down syndrome because it’s well documented, and the perspective is very positive,” says Megan A. Allyse, Ph.D., a researcher in the CIM Bioethics Program who co-authored the study. “Whereas we can’t necessarily give a clear picture for a child with sex chromosome trisomy. The child may be indistinguishable from most other children, or may struggle with social and educational factors. The uncertainty is frustrating for both parents and counselors.”

Trisomy is usually caused by a genetic mutation. Most people have either XY or XX sex chromosomes. Individuals with sex-chromosome trisomy can have XXX (known as trisomy X), XXY (Klinefelter syndrome) or XYY (Jacob’s syndrome). Often sex chromosome trisomy isn’t diagnosed until adolescence or even adulthood. Increasingly, however, the diagnosis is made before birth, as parents opt for early prenatal screening to determine whether they’re having a boy or girl. The new genetic testing that provides that answer can also detect evidence of extra X or Y chromosomes.

“The parents aren’t thinking about screening for an X- or Y-chromosome trisomy,” Dr. Allyse says. “But genetic testing can indicate a high risk of sex chromosome trisomy, which additional diagnostic tests might confirm. Most parents going into this process of prenatal genetic screening aren’t expecting that outcome. We find that their minds generally go to the worst possible scenario.”

Kirsten Riggan

That anxiety might be fueled by misinformation. Studies conducted decades ago of individuals in institutional settings found many examples of sex chromosome anomalies. “Conclusions were made that if your child has a diagnosis of XYY, he’s more likely to become a criminal. But broader population studies have found that this is absolutely not true,” says Kirsten Riggan, a research coordinator in Mayo Clinic’s Biomedical Ethics Research Program who also co-authored the CIM study.

Parents and individuals surveyed for the CIM study expressed almost unanimous interest in more optimistic portrayals of their condition from their providers, even when the outlook is uncertain. The study participants—who were recruited nationwide with help from the Association for X and Y Variations (AXYS), a patient-advocacy group—also noted a need for greater coordination of their children’s medical care and direction in accessing follow-up care and support.

“What families want to hear is that this diagnosis is something we know about, other people have had this experience, and we can help you get through this,” Dr. Allyse says. “Lots of children live with this condition. It may mean some adjustments. But it’s not by any stretch of the imagination the end of the road.”

Wide variation in traits

It’s difficult to generalize about the traits of sex chromosome trisomy. Many individuals have mild symptoms, but some have significant health problems needing specialty care.

Females with trisomy X tend to be tall but often have no physically distinguishable characteristics. Symptoms may be mild, usually involving minor motor development and language delays. Sex development and fertility are frequently normal. “Typically, the phenotype isn’t as noticeable with trisomy X,” Ms. Riggan says.

Similarly, individuals with XXY or XYY may be taller than average. They may have a predisposition for weight gain that can lead to diabetes, and experience delays in development and learning. But not all do.

“There are plenty of men who grow up, graduate from college, get married and find out they have Klinefelter syndrome only when they try to have children,” Dr. Allyse says. Men with Klinefelter syndrome generally have impaired fertility, although Mayo Clinic has experience helping men with the condition to father children through in vitro fertilization. Men with Jacob’s syndrome generally have normal sexual development and fertility.

The biggest challenge is a correlation in males between sex chromosome trisomy and impaired executive function, or the thinking processes that control behavior. “Sometimes these boys have a misdiagnosis of attention deficit/hyperactivity disorder, antisocial behavior or autism,” Dr. Allyse says. “The finding of a genetic trisomy—which we often see when boys are ages 10 to 15—comes as a huge relief to the family because they finally have an underlying cause for the behavior, and can get support.

“We need more education among non-genetic health providers about the phenotypic signs of sex chromosome trisomy, so children can be diagnosed earlier,” she adds. “What we hear from these families is, ‘I just wish somebody had told us when we got the diagnosis that it was possible for us to have a great life.’ ”

 

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Mon, Jan 21 11:12am · Test offers hope for people with severe kidney disease

Optimal treatment requires knowing what caused a medical condition. If your arm is broken because you fell, a simple cast might be enough. But if a tumor in your bone made it brittle, you need very different treatment.

For people with a rare kidney condition—known as focal segmental glomerulosclerosis (FSGS)—identifying the cause is critical. Patients with an FSGS lesion identified through kidney biopsy have abnormal amounts of protein in their urine. As a result, over time the kidney’s filtering units become scarred, leading to permanent kidney damage and even kidney failure.

There are three main types of FSGS—primary, secondary and genetic—and each requires a different treatment approach. The wrong approach can lead to inappropriate and perhaps harmful therapy.

A pilot study funded by Mayo Clinic’s Center for Individualized Medicine has found a higher-than-expected proportion of people with FSGS have a genetic cause for the disease. Pinpointing a genetic cause paves the way to individualized treatment that can eliminate unnecessary drugs and make kidney transplantation more successful.

Fernando Fervenza, M.D., Ph.D.

“Until recently, a genetic variation contributing to the disease was found in only about 10 percent of FSGS patients lacking a clinically identifiable cause. In our pilot study, we found a potential genetic explanation in about 50 percent of cases,” says Fernando Fervenza, M.D., Ph.D., director of Mayo’s Nephrology Collaborative Group. “These are very exciting results. We believe genetic causes of FSGS are much more common than we once thought. Physicians have just not been looking for the exact cause of these renal diseases with the right technology.”

Mayo Clinic researchers used a testing panel that involves 50 genes known to cause FSGS. Patients who tested positive were given a diagnosis of genetic FSGS. Patients who tested negative were given whole exome sequencing, which looks for all genes in an individual’s DNA blueprint, hoping to discover new genes causing the genetic type of FSGS.

In primary FSGS, the increase in urinary protein is due to the presence of a circulating factor or factors that are toxic to the kidney’s filtering units. The origin or type of these factors is unknown. In secondary FSGS, scarring occurs when a kidney is forced to overwork for some reason, such as obesity, loss of one kidney or low birthweight that may result in abnormally small kidneys. Certain drugs and viral infections can also cause FSGS.

Ladan Zand, M.D.

“Unlike people with secondary FSGS, patients with the genetic FSGS generally don’t have an obviously identifiable cause that explains the presence of protein in their urine,” says Ladan Zand, M.D., a nephrologist in Mayo’s Nephrology Collaborative Group who worked on the pilot study.

In the past, the lack of easily accessible genetic testing may have contributed to genetic causes being overlooked. As a result, many patients have often been misdiagnosed as having primary FSGS—and been prescribed steroids or other immunosuppressive treatments commonly used for primary FSGS.

“Of course, these patients didn’t respond to steroid or other forms of immunosuppressive treatment because their disease was genetic,” Dr. Fervenza says. “Treatment with high-dose steroids or other forms of immunosuppression has significant side effects. Finding a genetic cause for FSGS can spare patients from taking these medications unnecessarily.”

Because primary FSGS frequently recurs, people with that diagnosis sometimes aren’t eligible for kidney transplant. “But transplant centers are more willing to take patients whose FSGS is due to a genetic mutation. The donor kidney will lack the genetic mutation, so the disease would not recur,” Dr. Fervenza says.

The results of Mayo Clinic’s pilot study indicate that genetic testing might be usefully performed in any adult who has what appears to be a primary FSGS lesion—but who doesn’t respond to immunosuppressive therapy. “We believe the results of this research will significantly inform clinical practice and change the standard of care for patients with FSGS,” Dr. Fervenza says.

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