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Cultural Barriers to Genetic Testing

Source: Cell Press
Date: 6/7/2022
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As prices for genetic testing go down and awareness of what these tests can do goes up, more and more people are choosing to have their DNA analyzed. The underrepresentation of non-European ancestry groups in genomic databases, however, complicates the interpretation of their genetic test results.

In a commentary published on June 2 in the American Journal of Human Genetics(link is external and opens in a new window), researchers examine how “variants of uncertain significance” (VUS)—a genetic change whose impact on the individual’s disease risk is not yet known—are more likely to be identified in populations underrepresented in genetic databases, as well as ways to reduce their incidence.  

“A great deal of effort goes into broad-based projects that aim to recruit diverse segments of the population,” says first author Paul Appelbaum, MD, director of the Center for Research on Ethical, Legal & Social Implications of Psychiatric, Neurologic & Behavioral Genetics at Columbia University. “What’s different about our contribution here is the recognition that broad-based recruitment will need to be complemented by more focused efforts that take group concerns into account.”

There are practical and ethical reasons that VUS are important to address. Tests that yield a VUS fail to generate information that is useful clinically. Additionally, although current guidelines discourage clinicians from making treatment decisions based on a VUS, many clinicians and patients may feel compelled to act on them anyway. Discovery of a VUS can lead to anxiety, distress—especially variants in genes known to increase the risk of diseases like cancer—and, in some cases. even drastic interventions like prophylactic surgery.

Cultural Concerns

In this paper, the investigators focused on cultural issues among two ancestry groups, as well as culturally informed ways to address and overcome those issues.

For the first group—the Sephardi Jewish community in New York—they focus on the Dor Yeshorim project, an effort created to reduce the incidence of genetic diseases in the Jewish community, with an initial focus on Tay Sachs. The second group was the Silent Genomes Project, an effort housed at the University of British Columbia that aims to reduce healthcare disparities and improve diagnostic success for children with genetic diseases from Indigenous populations in Canada.

The two communities have very different concerns about contributing to genomic research and datasets. Sephardi concerns focus on the possible negative effects of genetic findings on the marriage prospects of family members. Canadian Indigenous populations seek control over the research uses to which their genetic data would be put.

“Both groups have specific cultural reasons for being hesitant to provide genetic data,” says Dr. Appelbaum, who is the Elizabeth K. Dollard Professor of Psychiatry, Medicine and Law at Columbia. “By working with them to find ways to address their concerns, we can overcome these hesitations.” 

Dr. Appelbaum acknowledges challenges in scaling up these kinds of efforts to reach other underrepresented populations and the lack of a one-size-fits-all approach. “For each of these groups, we need to recognize the reasons for their underrepresentation and work with them to find ways to address those concerns,” he says. He adds that it’s vital to obtain more funding for targeted recruitment efforts and to develop a governance structure that involves the relevant communities in an ongoing fashion.

“It’s crucial to know the frequency of variants in the population,” Dr. Appelbaum says. “And given differences in variant frequency across population groups and the prevalence of population-specific variants, comparisons with reference data from a specific ancestral group may be crucial. That’s true in both clinical settings and in research.”

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Distinct biological ages across individuals’ various organs and systems

Source: Cell Press
Date: 3/8/2022
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It’s common to say that someone looks either younger or older than their chronological age, but aging is more than skin deep. Our various organs and systems may have different ages, at least from a biological perspective. In a study published March 8 in the journal Cell Reports, an international team of investigators used biomarkers, statistical modeling, and other techniques to develop tools for measuring the biological ages of various organ systems. Based on their findings, the researchers report that there are multiple “clocks” within the body that vary widely based on factors including genetics and lifestyle in each individual.

“Our study used approaches that can help improve our understanding of aging and — more importantly — could be used some day in real healthcare practice,” says co-corresponding author Xun Xu of the Beijing Genomics Institute (BGI) and China National GeneBank (CNGB) in Shenzhen, China. “We used biomarkers that could be identified from blood and stool samples plus some measurements from a routine body checkup.”

The concept of evaluating people’s biological aging rates has been around since the 1970s, but earlier studies were focused either on developing methods for estimating one centralized aging index or studying the molecular aging biomarkers using tissues and cell cultures outside the body.

“There has been a lack of practical applications in a population-based sample for precisely estimating the aging rates of live people’s organs and systems,” says co-corresponding author Xiuqing Zhang, also of BGI and CNGB. “So we decided to design one.”

To do this research, the investigators recruited 4,066 volunteers living in the Shenzhen area to supply blood and stool samples and facial skin images and to undergo physical fitness examinations. The volunteers were between the ages of 20 and 45 years; 52% were female and 48% were male. “Most human aging studies have been conducted on older populations and in cohorts with a high incidence of chronic diseases,” says co-corresponding author Brian Kennedy of the National University of Singapore. “Because the aging process in young healthy adults is largely unknown and some studies have suggested that age-related changes could be detected in people as young as their 20s, we decided to focus on this age range.”

In total, 403 features were measured, including 74 metabolomic features, 34 clinical biochemistry features, 36 immune repertoire features, 15 body composition features, 8 physical fitness features, 10 electroencephalography features, 16 facial skin features, and 210 gut microbiome features. These features were then classified into nine categories, including cardiovascular-related, renal-related, liver-related, sex hormone, facial skin, nutrition/metabolism, immune-related, physical fitness-related, and gut microbiome features.

Because of the difference in sex-specific effects, the groups were divided into male and female. The investigators then developed an aging-rate index that could be used to correlate different bodily systems with each other. Based on their findings, they classified the volunteers either as aging faster or aging slower than their chronological age.

Overall, they discovered that biological ages of different organs and systems had diverse correlations, and not all were expected. Although healthy weight and high physical fitness levels were expected to have a positive impact, the investigators were surprised by other findings. For example, having a more diverse gut microbiota indicated a younger gut while at the same time having a negative impact on the aging of the kidneys, possibly because the diversity of species causes the kidneys to do more work.

The investigators also used their approach to look at other datasets, including the National Health and Nutrition Examination Survey from the US Center for Disease Control and Prevention and the Chinese Longitudinal Healthy Longevity Survey, which includes data on more than 2,000 centenarians with matched middle-aged controls. In addition, they looked at single nucleotide polymorphisms (SNPs) to determine whether differences could be explained by genetic factors. There, they did find certain pathways that could be associated with aging rates.

The researchers plan to regularly follow up with the study participants to track the development of aging and validate their findings. Future studies will use additional approaches for classifying features of aging and studying the interactions between organ systems.

They also plan to use single-cell technology to look at programmed aging in more detail. “It’s important to capture the cell-to-cell variation in an aging individual, as this will tell us important information about the heterogeneity within cell types and tissues and provide important insights into aging mechanisms,” says co-corresponding author Claudio Franceschi of Lobachevsky State University in Russia.

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The impacts from using genetic testing to track down relatives

Source: Cell Press
Date: 2/24/2022
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Genetic genealogy has become a popular hobby over the past several years, thanks to direct-to-consumer (DTC) genetic testing and relative-finder services offered by some DTC genetic testing companies. In a paper published February 24 in the American Journal of Human Genetics, researchers report results from a survey that asked people who had participated in these services what effect the discovery of previously unknown relatives had on their lives.

Among the most important findings were that identifying a genetic relative appeared to be somewhat common. Additionally, those discoveries were generally experienced as neutral or positive and didn’t appear to have a big impact on participants’ lives. However, some participants learned things that could be considered significant and destabilizing — such as that their biological parent wasn’t who they thought. These participants were especially vulnerable to negative outcomes.

“Everyone on our team is involved in studying the ethical, legal, and social implications of DTC genetic testing, and we’ve been paying attention to stories in the media about individuals who’ve made surprising family discoveries from these tests and relative-matching services,” says lead author Christi Guerrini of the Center for Medical Ethics and Health Policy at Baylor College of Medicine. “We wanted to understand if these and other kinds of discoveries are common, how they’re experienced by those making the discoveries, and what people are doing as a result.”

The investigators sent the survey to about one million DTC genetic testing customers and genetic genealogy database participants; more than 26,000 responded. The final sample for analysis consisted of 23,196 completed or substantially completed surveys. Among the reasons that respondents said they chose to participate in this type of testing were to learn more about their family or build their family trees; to search for a biological parent, child, or other relative; or to investigate a suspicion that they might not be genetically related to family members.

“It seems that many — perhaps most — are just curious about their families and interested in building out their family trees, but it’s clear that quite a lot of participants are looking for someone or hoping to confirm something in particular,” Guerrini says. “It might be that they’re adopted and looking for a biological parent, or that they’ve always felt out of place in their family and want to see if there’s something to that feeling. Or they might be looking for information about a branch of their family tree that’s unknown to them, or to confirm a family story that’s been passed down over the years.”

Most respondents (82%) reported that they learned the identity of at least one genetic relative. Among this subpopulation, 10% identified a biological grandparent, 10% identified a full or half- sibling, and 7% identified a biological father. The survey asked whether the participant had chosen to contact any of their newly identified relatives and, if so, the reasons for doing so. It also asked whether their discoveries resulted in any life changes, including changes in health-related behaviors.

Guerrini says that the high number of people overall who identified an unknown genetic relative was not unexpected, because many of those relatives could be very distant ones. But she acknowledges that the high number of participants who found close relatives could be skewed by the type of people who choose to undergo relative matching in the first place. “Unfortunately, we can’t answer that question with our data, but I’m very interested in trying to do so in future research,” she says.

She adds that although these experiences appear to be interesting and enjoyable to a large number of people, it’s clear that some who are participating in these services have experienced negative outcomes. “In future research, we’d like to better understand those outcomes and what resources could be helpful in managing them,” she says.

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Ancient DNA reveals clues about how tuberculosis shaped the human immune system

Source: Cell Press
Date: 3/4/2021
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COVID-19 is only the latest infectious disease to have had an outsized impact on human life. A new study employing ancient human DNA reveals how tuberculosis has affected European populations over the past 2,000 years, specifically the impact that disease has had on the human genome. This work, which publishes March 4 in the American Journal of Human Genetics, has implications for studying not only evolutionary genetics, but also how genetics can influence the immune system.

“Present-day humans are the descendants of those who have survived many things — climate changes and big epidemics, including the Black Death, Spanish flu, and tuberculosis,” says senior author Lluis Quintana-Murci of the Institut Pasteur in France. “This work uses population genetics to dissect how natural selection has acted on our genomes.”

This research focused on a variant of the gene TYK2, called P1104A, which first author Gaspard Kerner had previously found to be associated with an increased risk of becoming ill after infection with Mycobacterium tuberculosis when the variant is homozygous. (TYK2 has been implicated in immune function through its effect on interferon signaling pathways.) Kerner, a PhD student studying genetic diseases at the Imagine Institute of Paris University, began collaborating with Quintana-Murci, an expert in evolutionary genomics, to study the genetic determinants of human tuberculosis in the context of evolution and natural selection.

Using a large dataset of more than 1,000 European ancient human genomes, the investigators found that the P1104A variant first emerged more than 30,000 years ago. Further analysis revealed that the frequency of the variant drastically decreased about 2,000 years ago, around the time that present-day forms of infectious Mycobacterium tuberculosis strains became prevalent. The variant is not associated with other infectious bacteria or viruses.

“If you carry two copies of this variant in your genome and you encounter Mycobacterium tuberculosis, you are very likely to become sick,” Kerner says. “During the Bronze Age, this variant was much more frequent, but we saw that it started to be negatively selected at a time that correlated with the start of the tuberculosis epidemic in Europe.”

“The beauty of this work is that we’re using a population genetics approach to reconstruct the history of an epidemic,” Quintana-Murci explains. “We can use these methods to try to understand which immune gene variants have increased the most over the last 10,000 years, indicating that they are the most beneficial, and which have decreased the most, due to negative selection.”

He adds that this type of research can be complementary to other types of immunology studies, such as those performed in the laboratory. Moreover, both researchers say these tools can be used to study the history and implications of many different genetic variants for multiple infectious diseases.

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Researchers simulate privacy leaks in functional genomics studies

Source: Cell Press
Date: 11/12/2020
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The functional genomics field, which looks at the activities of the genome and levels of gene expression rather than particular gene mutations, generally relies on aggregating information from many samples for its statistical power. This means that broadly sharing raw data is vital; however, sharing these data currently is challenging because of the privacy concerns of individuals within those datasets, leading to these data being largely inaccessible behind firewalls.

In a study publishing November 12 in the journal Cell, a team of investigators demonstrates that it’s possible to de-identify those data to ensure patient privacy. They also demonstrate how these raw data could be linked back to specific individuals through their gene variants by something as simple as an abandoned coffee cup if these sanitation measures are not put in place.

“The purpose of this study is to come up with practical ways to broadly share the raw data without creating undue privacy concerns,” says senior author Mark Gerstein, a professor of bioinformatics at Yale University.

Functional genomics research is frequently tied to a specific disease. For example, an investigation into a particular psychiatric condition might look at the expression of certain genes in a type of neuron. And, by nature of having their genetic material included in such a study, an individual’s medical status with regard to that condition could inadvertently be revealed.

This can happen through what’s known as a quasi-identifier. The way a quasi-identifier works is that if someone has enough individual data points about you, even if those data on their own are not sensitive or unique, they can be combined to create an identifier that is unique to you. In a non-genetic setting, this means if someone has your zip code, birthday, the model of car you drive, and other similar data that might not be considered private or sensitive on their own, they might eventually be able to combine them and create a unique profile that would link you to other data that you wouldn’t want public — data like financial records that were collected when you applied for a car loan. The same thing could happen if someone were able to obtain some of your genetic variants and link those variants to the presence of your genetic material in a study on a particular disease. This could in turn reveal a diagnosis, such as HIV status or an inherited cancer predisposition, that you would prefer to keep private.

In their study, the researchers constructed a “linkage attack” scenario to demonstrate how someone could make these kinds of connections from functional genomics studies’ data by using DNA obtained from a discarded coffee cup. After adding samples from two consenting participants to a functional genomics database, the researchers gathered used coffee cups from the same individuals. They sequenced genetic material left on the cups and were able to successfully match that material to the samples in the database and infer sensitive health information about the participants. The researchers were also able to use DNA information “stolen” from a genotyping database to match the identities of 421 people with phenotypic information found in a test functional-genomics dataset that the researchers constructed for 436 people.

However, the researchers also identified steps that can be taken to thwart these kinds of linkage attacks and safeguard participants’ health information when functional genomics datasets are shared. “Functional genomics is special because variants are usually not needed for data processing,” says first author Gamze Gürsoy, a postdoctoral researcher at the Gerstein lab. “Because of this, we can sanitize the variants to prevent data being linked back to the private information connected to the phenotypes included in these studies, while still retaining the utility of the data.”

To achieve this balance between privacy and data usefulness, the researchers propose a file-format manipulation that will allow raw functional genomics data to be shared while largely reducing sensitive information leakage by generalizing information about phenotypic variants. The file format is based on a widely used standard file-format system, is compatible with a range of software and pipelines, and when tested, showed little loss of utility. The researchers have also developed a framework with which other researchers can tune the level of privacy and utility balance they want to achieve with the file format based on the policies and consents of the donors.

“As more data are released for these kinds of functional genomics studies, concerns about security and privacy shouldn’t be lost,” Gerstein says. “At the dawn of the Internet, people didn’t realize how important their online activities would become. Now that type of digital privacy has become so important to us. If we move into an era where getting your genome sequenced becomes routine, we don’t want these worries about health privacy to become dominating.”

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Why the ‘wimpy’ Y chromosome hasn’t evolved out of existence

Source: Cell Press
Date: 8/17/2020
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An Opinion paper co-authored by a UNSW scientist – published online this month in the journal Trends in Genetics – outlines a new theory, called the “persistent Y hypothesis”, to explain why the Y chromosome may be more resilient than it first appears. 

Much smaller than its counterpart, the X chromosome, the Y chromosome has shrunken drastically over 200 million years of evolution. Even those who study it have used the word “wimpy” to describe it, and yet it continues to stick around even though sex chromosomes in non-mammalian vertebrates are known to experience quite a bit of evolutionary turnover.

“The Y chromosome is generally thought to be protected from extinction by having important functions in sex determination and sperm production, which, if moved to somewhere else in the genome, would signal its demise,” says co-author Paul Waters, an Associate Professor at the UNSW Sydney. “However, we propose that the future of the Y chromosome is secure because it carries executioner genes that are critical for successful progression of male meiosis–and unlike other genes on the Y, these executioners self-regulate.”

During meiosis, sexually reproducing organisms form haploid gametes (eggs and sperm), each of which contains only one copy of each chromosome. They do this through one round of genome replication followed by two consecutive rounds of cell division. This meiotic process is tightly regulated to avoid infertility and chromosome abnormalities. 

One step of meiosis requires the silencing of both the X and Y chromosomes during a specific window. “Importantly, the Y chromosome bears genes that regulate this process, a feature that has been known for years now,” says co-author Aurora Ruiz-Herrera, a professor at Universitat Autònoma de Barcelona in Spain. “We believe that bearing these genes is what protects the Y chromosome from extinction. The genes that regulate the silencing process, the Zfy genes, are called ‘executioner’ genes. When these genes are turned on at the wrong time and at the wrong place during meiosis, they are toxic and execute the developing sperm cell. They essentially act as their own judge, jury, and executioner, and in doing so, protect the Y from being lost.”

The Y chromosome is present in all but a handful of mammalian species. Important contributions to understanding the Y chromosome have come from looking at the rare mammals that don’t follow the rules–for example, a handful of species of rodents. “I’ve always been a firm believer that the comparison of unusual systems is informative to other systems,” A/Prof. Waters says. “Determining the common prerequisites for rare Y chromosome loss enabled us to build a hypothesis for how Y chromosomes persist in most species.”

The collaboration between Waters and Ruiz-Herrera–based half a world apart–began to bear fruit during the COVID-19 pandemic. “Earlier this year, we put together a grant application to examine aspects of X chromosome silencing during meiosis,” says Waters. “After the shutdown of our labs, we decided to massage our discussions into a review article. We had no idea we would essentially stumble onto such an intuitive mechanism to explain why the mammal Y chromosome has persisted in most species.” Going forward, the researchers plan to take a closer look at how the executioner genes evolved, and how they are regulated from evolutionary and functional perspectives.

“The mammalian Y has been taken as a symbol of masculinity, not only in popular culture but also in the scientific community,” Ruiz-Herrera says. “Despite that, many have projected that, given enough time, it will be eventually lost. However, we propose the Y chromosome can escape this fatal fate. So our male colleagues can breathe easy: the Y will persist!”

Paul Waters is supported by the Australian Research Council. Aurora Ruiz-Herrera is supported by the Spanish Ministry of Science and Innovation.

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Inherited Cancer Risks: New Insights from MSK Presented at 2023 ASCO Meeting

Source: Memorial Sloan Kettering - On Cancer
Date: 06/05/2023
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Researchers from Memorial Sloan Kettering Cancer Center (MSK) revealed new findings about hereditary cancers and genetics at the recent 2023 American Society of Clinical Oncology (ASCO) annual meeting.

Genetic mutations that are passed down through families cause a significant percentage of cancers — between 5 and 10%, and as high as 15 to 20% in people with advanced cancers. Patients with certain hereditary cancers may especially benefit from many of the latest cancer treatments, including targeted drugs and immunotherapies. Their families also may benefit from being monitored for early signs of cancer.

Among the recent advances in MSK’s research into understanding how inherited DNA mutations affect cancer development and treatment, four presentations at the ASCO meeting highlighted new analysis of early-onset disease, hereditary cancers in transgender people, a new gene linked to lung cancer, and the importance of genetic testing for younger people with gastrointestinal cancers.

What Defines Early-Onset Cancers and How Should They Be Treated?

Amid growing concern about an increase in cancers occurring in younger people, clinical geneticist and gastrointestinal oncologist Zsofia Stadler, MD, presented research that found the age for so-called “early-onset” cancer can vary widely depending on the type of cancer. Dr. Stadler stressed the need to have clear criteria to define early-onset cancers, because her research also found these cancers are more likely to be linked to an inherited genetic mutation. Knowing whether a cancer is caused by a hereditary mutation is important because it can make a difference in choosing the right treatment. It’s also a signal that members of a patient’s family should consider genetic testing.

“We know the incidence of early-onset cancer is increasing for some tumor types, but when we think about what early onset means, we realize it’s actually poorly defined,” says Dr. Stadler, Clinical Director of MSK’s Clinical Genetics Service. “These cancers are usually defined as those arising before the age of 50 for any type of solid tumor. But the fact is, there is a dramatic variation in the average age of onset across different tumor types.”

The research had two aims: The first was to determine what age should be considered early onset for a variety of solid tumors. The second was to determine how often different types of early-onset cancers were likely caused by inherited genetic mutations.

First, the investigators used a National Cancer Institute database to determine the average age at which patients typically developed 32 types of solid tumors. Based on those ages, researchers then used a formula to calculate what age would be considered early onset for each of these cancers. That age ranged from the late 30s for cervical and thyroid cancers to about 60 for mesothelioma and bladder cancer. “If we considered 50 the cutoff age for every type of solid tumor, there are a lot of early-onset cancers that we would miss,” Dr. Stadler explains.

To answer the study’s second major question, the researchers then used these new classifications to analyze how often early-onset cancers were linked to an inherited genetic mutation. (This is an alteration in DNA that is passed on by a parent and present in every cell in the body.)

Overall, researchers found that early-onset cancers were much more likely to be linked to hereditary mutations — 19% versus 15.5% in people whose cancers developed at an average age. For hereditary mutations defined as “high penetrance” (meaning they were extremely likely to cause cancer), the difference was even more dramatic: 13% of early-onset cancers were linked to inherited mutations versus 5% of cancers occurring at an average age.

Researchers arrived at this conclusion using data from about 29,000 patients whose DNA was analyzed with MSK-IMPACT®, a test that identifies genetic mutations linked to cancer. It can find mutations that are only in tumors as well as inherited mutations that may increase the risk of developing cancer.

“The diagnosis of an early-onset cancer is an impetus for doing genetic testing to look for inherited risk factors,” Dr. Stadler says. “The findings from this study illustrate how important it is that early-onset cancers be correctly classified.”

Caring for Transgender Patients With Hereditary Cancer Syndromes

Genetic counselor Megha Ranganathan, MS, CGC, participated in a panel discussion focused on caring for transgender patients with inherited mutations in the BRCA1 and BRCA2 genes. Mutations in these genes can increase the risk for several cancers, including breast, ovarian, and prostate cancer.

“There are more than 1.6 million people in the United States who identify as transgender, and that number is likely an underestimate,” Ranganathan says. “The data is so limited that many providers are often unsure how to best manage cancer risk in these people, especially those at higher risk due to an inherited genetic predisposition.”

Ranganathan and her co-presenters discussed two cases demonstrating the challenges for these patients. The first case involved a transgender woman (a person who is assigned male at birth but identifies as a woman). After her mother was diagnosed with ovarian cancer, genetic testing revealed the transgender woman had a BRCA2 mutation. “At that point, the patient had already been receiving gender-affirming estrogen therapy for about 10 years,” Ranganathan said. “We know that prolonged estrogen exposure is a risk factor for breast cancer, but it is unknown how much it increases her risk, especially because she has a BRCA2 mutation.

“Despite the lack of reliable data, increased breast cancer surveillance or risk-reducing surgery may be reasonable options,” she added. “We encourage these patients to talk to their doctors to determine the best option for them depending on their gender-affirming goals.” Another issue for this patient: Because she was assigned male at birth, she has a prostate, and this gene mutation puts her at increased risk for prostate cancer as well.

The second case involved a young transgender man (a person who is assigned female at birth but identifies as a man). He had a BRCA1 mutation and was considering top surgery (surgery to remove breast tissue and make the chest look more masculine). Would having top surgery reduce his risk for breast cancer? The panel suggested more extensive surgery such as a full mastectomy could be considered to prevent breast cancer in this situation.

Ranganathan and her co-presenters also discussed several ways healthcare providers can create a more inclusive environment for gender-diverse people. The panelists explained key concepts and terms, how to represent someone’s gender and sex assigned at birth on family trees, and how to request a patient’s chosen name and pronouns.

“Many transgender people avoid the healthcare system altogether because they fear discrimination and stigmatization. Research is lacking on how best to care for them,” says Ranganathan. “As an institution that is dedicated to reducing healthcare disparities, we at MSK want patients to be aware that this is something we’re thinking about and that we aspire to provide excellent care for all patients, regardless of gender identity.

A New Gene Potentially Linked to Inherited Risk of Lung Cancer

Pediatric oncologist and clinical geneticist Michael Walsh, MD, presented new research that found for the first time that mutations in the cancer predisposition gene POT1 are associated with increased rates of lung cancer. Previously, mutations in POT1 have been associated with sarcoma, certain types of leukemia, and clonal hematopoiesis, a blood condition linked to aging.

“Compared with other cancers like breast, ovarian, and prostate cancers, we know less about the inherited risks of lung cancer,” Dr. Walsh says. “We know that lung cancer is strongly linked to environmental causes like smoking. These findings shine a light on potential inherited factors that may also play a role in causing lung cancer.”

Dr. Walsh and his team were able to make this discovery thanks to the cancer genetic test MSK-IMPACT. In addition to sequencing patients’ tumors, MSK-IMPACT can also analyze the genetics of normal tissue, so experts can determine whether a cancer is linked to an inherited genetic mutation or developed at random. In this case, a study of data from patients’ normal DNA allowed investigators to undercover new findings about inherited mutations in POT1.

“POT1 has been added to the list of genes detected by MSK-IMPACT relatively recently, so it hasn’t been studied as well as some other cancer genes,” Dr. Walsh explains. “But when we looked at data for about 7,000 patients, we found that the incidence of lung adenocarcinoma in people with this inherited mutation was much higher than expected.”

After the MSK-IMPACT analysis, Dr. Walsh and his colleagues found that other large databases of cancer genes supported their findings. They will continue studying the link.

Dr. Walsh says one day this discovery might provide insights leading to new treatments for cancer.

Increasing Genetic Testing for Younger People with Gastrointestinal Cancers

In response to the alarming increase in colorectal cancer cases in younger people, MSK clinical geneticist and family medicine physician Alicia Latham, MD, MS, urged more testing to determine possible inherited risks of cancer.

“As MSK offers genetic testing to more of our patients, we’re finding that some of these gene mutations are more common than we previously believed,” says Dr. Latham, who spoke at an ASCO session focused on gastrointestinal (GI) cancers. “But there are questions about whether these mutations are truly related to the cancer or are instead incidental findings.”

Dr. Latham specializes in treating people with Lynch syndrome. This hereditary condition carries an increased risk of certain types of cancer, including colon cancer and rectal cancers. Lynch syndrome cancers are characterized by a feature called microsatellite instability, which makes them especially responsive to immunotherapy drugs called checkpoint inhibitors.

Because these mutations have important implications for treatment, there is a move toward testing more patients with GI cancers for these genes, especially younger patients, Dr. Latham explains.

“This is a real change from what we’ve done in the past,” she says. “But because findings from these tests can have such important implications for treatment, we want everyone to be aware of these connections and the importance of testing.”

She adds that several collaborative advisory groups in North America and Europe are also backing the recommendations to test more patients for inherited conditions.

Dr. Latham leads MSK’s Comprehensive Assessment, Treatment, and Prevention of Cancers with Hereditary Predispositions (CATCH) program, which provides surveillance and monitoring for people who have genes that are linked to inherited cancer predisposition syndromes.

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The Latest on Genetic Testing for BRCA Mutations in Breast Cancer

Source: Memorial Sloan Kettering - On Cancer
Date: 02/21/2018
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Last month, the US Food and Drug Administration approved olaparib (Lynparza®) for people who have certain types of breast cancer that has spread and who have been previously treated with chemotherapy. Olaparib was the first drug in a class called PARP inhibitors to be approved for breast cancer.

Medical oncologist Mark Robson headed the first multicenter phase III clinical trial of this drug for breast cancer. Results from that study, which were reported at the American Society of Clinical Oncology meeting last summer, led to the drug’s approval.

Dr. Robson, who was named Chief of Memorial Sloan Kettering’s Breast Medicine Service in November 2017, was recently part of a panel discussion held at New York City’s 92nd Street Y entitled “Knowledge Is Power: Understanding and Managing BRCA-Related Cancer Risk.” We spoke with him about what this drug approval means for people with breast cancer, as well as its implications for expanding the use of genetic testing for BRCA mutations.

How do we know whether someone’s cancer is caused by a BRCA mutation?

At MSK, everyone with advanced cancer is offered the opportunity to undergo testing with MSK-IMPACT™. In addition to looking for cancer mutations in the tumor itself, this test can scan the normal tissue for cancer mutations, if the patient agrees. Because BRCA mutations are carried in the germline, meaning all the cells in the body, they show up with this test.

There are other tests for inherited BRCA mutations that are available through a number of companies. But we don’t recommend taking these tests unless you speak with a genetic counselor.

Based on your findings, who do you think should get BRCA testing?

Now that olaparib is an approved therapy, I would recommend that anyone with advanced breast cancer get the BRCA test. It can help guide their treatment, and it may allow them to avoid getting chemotherapy for a longer period. Olaparib is taken at home as a pill, and it has relatively few side effects.

People with earlier-stage breast cancer as well as other forms of cancer that have been associated with BRCA mutations may want to consider getting tested if their personal or family history suggests they might be carrying a BRCA mutation. That is best determined through a consultation with a genetic counselor. Knowing that they have a mutation can help them plan ways to reduce their risk of developing another cancer. It also might tell them if there is a clinical trial that might help them.

These are genes that are inherited and run in families. Because of that, close relatives of people who are known to have BRCA mutations should strongly consider talking to a genetic counselor and getting tested.

Some people have suggested that because BRCA mutations are more common in people of Ashkenazi Jewish descent, the use of this test should be expanded to include this whole group. There is certainly the potential to benefit, since many people with mutations don’t have a family history that would prompt them to get tested. But there are also possible risks if people aren’t prepared to learn that they have a mutation. There are a number of studies that are trying to find the best way to get this information to people who want it. One of them is the BFOR study, which is being led by Kenneth Offit of the Clinical Genetics Service here at MSK.

How would a BRCA mutation affect my options for drug therapies?

PARP inhibitors work by blocking enzymes called poly (ADP-ribose) polymerases, or PARPs for short. Members of this family of enzymes help repair breaks in DNA. If DNA cannot be repaired, cells cannot divide and will die. An emerging strategy in cancer therapy has been to block the repair role of PARPs. Normal cells can overcome this type of attack, but certain cancer cells cannot.

In particular, mutations in the genes BRCA1 and BRCA2 are connected with the inability to repair this kind of damage. This weakness makes cancers linked to BRCA mutations good candidates for these drugs.

Besides breast cancer, what other cancers are BRCA mutations linked to?

BRCA mutations have been known to be associated with breast cancer and ovarian cancer for more than two decades. More recent studies have shown that they are also linked to many cases of advanced prostate cancer, as well as pancreatic cancer.

Olaparib was previously approved for treating BRCA-associated ovarian cancer. There are two other PARP inhibitors approved for ovarian cancer as well. Clinical trials at MSK and many other centers are looking at expanding PARP drugs to all cancers that are associated with BRCA mutations.

You have been studying BRCA for a long time. Is there anything that’s surprised you about recent developments?

It’s been an incredibly exciting and interesting time to be involved in this field. When the Human Genome Project was completed in 2003, there were all these theoretical ideas of how genetic information could be applied to human health. But none of them were very practical.

The ways that we are beginning to use genetic information now are what we always hoped we would be able to do, even though at that time we couldn’t envision the details. So I would not say that I’m surprised, even though I couldn’t have predicted exactly what we’d be doing today.

We have reached the place we’re at in this field because of investments in fundamental research. It’s been a privilege to help turn promise into reality.

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Testing for BRCA: What Is the Best Way to Screen for Cancer Genes?

Source: Memorial Sloan Kettering - On Cancer
Date: 04/25/2018
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In March 2018, the US Food and Drug Administration approved an at-home, mail-in kit that tests for some of the inherited mutations in the genes BRCA1 and BRCA2. These mutations are linked to an increased risk of breast cancer, ovarian cancer, and prostate cancer, and possibly others.

Storefront centers that conduct cholesterol checks, do thyroid panels, and screen for sexually transmitted diseases have made people more comfortable initiating their own medical tests. But many experts say that some types of testing — including for cancer genes — should continue to be done under a healthcare provider’s guidance.

“The developers of at-home genetic tests have said they should be as easy and available as a pregnancy test, which any woman can take at home alone in her bathroom,” says Kenneth Offit, Chief of MSK’s Clinical Genetics Service. “But that’s exactly what we’re worried about. For men and women, finding out that you’ve inherited a cancer gene can raise a lot of issues. We want to make sure that people who receive these results are getting the support that they need.”

To answer some of the questions about the best way for people to get this kind of health information, a team of clinical genetics experts has launched the BRCA Founder Outreach (BFOR) study. The study is being led by Memorial Sloan Kettering and three other cancer centers.

A Contrast to Recreational Genomics

“Thanks to new avenues of communication and education, we can enhance genetic counseling and widely share the knowledge of top experts when screening for cancer genes,” explains Mark Robson, Chief of the Breast Medicine Service and a co-principal investigator of the study. “BFOR is designed to help us do that.”

The purpose of the BFOR study is to evaluate how to best combine the convenience of direct-to-consumer genetic tests with guidance from a medical care provider. It will allow 4,000 women and men with Jewish ancestry to enroll in screening for the three most common BRCA mutations linked to increased cancer risk. These mutations are quite rare in the general population, but one in 40 people of Ashkenazi (Eastern European) Jewish descent carries at least one of them.

“This is not recreational genomics, which is what most home-testing kits have traditionally been,” says Dr. Offit, who is one of the principal investigators and head of the executive committee running the BFOR study. “The stakes for these kinds of cancer genetic tests are much higher than just looking at your ancestry.”

People who are age 25 and older and have one or more Ashkenazi Jewish grandparent can go to the BFOR website and fill out a questionnaire to determine whether they are eligible. Once they complete the online educational and consent process, they can go to a local Quest Diagnostics center to get a blood test. Quest is providing testing at no charge to the study participants.

Explaining Potentially Life-Changing Genetic Test Results

Under the BFOR model, participants receive the results from someone who can explain what the findings mean, rather than getting them in the mail. They can choose whether to get their results from a clinical genetics expert or their own doctor. Some of the issues raised by learning of an increased cancer risk include whether to consider risk-reducing surgery and how to inform other family members who may also carry the mutation.

Currently, the study is limited to people living in metropolitan areas that have participating centers, so they have access to genetics experts. In addition to MSK in New York City, the other sites involved are Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center in Boston, the University of Pennsylvania in Philadelphia, and Cedars-Sinai Medical Center in Los Angeles.

Another important note is that with both the BFOR study and the commercial genetic-testing service, only the three most common BRCA mutations are included. These three mutations account for about 95% of BRCA1 and BRCA2 mutations in Ashkenazi Jews. BRCA mutations overall explain only about a quarter of inherited breast cancers.

“Just because you test negative for these three BRCA mutations doesn’t mean you’re in the clear, especially if you have a strong family history. You may need to decide if you want to undergo additional testing,” explains Kelly Morgan, a genetic counselor dedicated to this study. “This is just another illustration of why working with a trained healthcare provider is so important.”

Founders in the Field of Cancer Mutations

The three mutations included in the study — two in BRCA1 and one in BRCA2 — are called founder mutations. A founder mutation is a genetic change that appears with high frequency in a small group of people who were geographically or socially isolated for a long time and had ancestors who carried that specific gene mutation. Because Ashkenazi Jewish populations were culturally separated for hundreds of years, these BRCA mutations, which initially occurred by chance, became more common in that group.

In 1996, Dr. Offit and his team discovered the most common BRCA2 mutation linked to breast and ovarian cancers. The mutation has since been linked to other cancers, including prostate cancer and pancreatic cancer. Around the same time, other research groups identified the two BRCA1 founder mutations.

Teaming Up with the Community

Dr. Offit emphasizes that as a National Cancer Institute–funded cancer center, MSK counts treating the community in which it’s located as one of its primary roles. About two million people of Jewish descent live in the New York City metropolitan area, most of them Ashkenazi, and 20% of people treated at MSK have Jewish ancestry, making this focus especially fitting.

However, he notes, the information gained from focusing solely on this group in the BFOR study can later be applied to the wider population, just as other BRCA-related findings have been more broadly applied in the past.

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Genomic Marker Is Associated with Lynch Syndrome, a Hereditary Cancer Condition, Across Many Different Cancers

Source: Memorial Sloan Kettering - On Cancer
Date: 06/02/2018
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Memorial Sloan Kettering researchers have found that the genetic condition Lynch syndrome may be associated with more cancers than earlier thought. Lynch syndrome runs in families. It was previously known to increase the risk mainly of colon cancer, rectal cancer, and endometrial (uterine) cancer. The MSK team has now linked Lynch syndrome to cancers that are rarely or not already associated with the syndrome. These include pancreatic cancer, prostate cancer, adrenocortical tumor, sarcoma, and many others. Results of the study were reported today at the annual meeting of the American Society of Clinical Oncology (ASCO).

The study looked at people with advanced cancer whose tumors carried a genomic biomarker called high microsatellite instability (MSI). The data showed that these patients had a one in six chance of having Lynch syndrome — regardless of what type of cancer they had. Lynch syndrome is currently believed to occur in about 1 in 300 people in the general population.

The findings have wide-ranging implications. They suggest that people whose tumors demonstrate high MSI should be tested for Lynch syndrome mutations. Those who are found to have Lynch can undergo more frequent screening for certain cancers. Family members can also be tested to see if they have the condition.

“Our findings suggest that anyone with an advanced solid tumor who is found to have high MSI should be tested for Lynch mutations, regardless of the location of the tumor or family cancer history,” says medical oncologist and clinical geneticist Zsofia Stadler, who led the study. The research was presented at the ASCO meeting by medical genetics fellow Alicia Latham Schwark.

“We expect that genetic testing of all people with high-MSI tumors will help identify additional individuals and families with Lynch syndrome,” Dr. Stadler adds.

Expanding Tumor Testing

The study focused on more than 15,000 people with many different types of cancer who were tested at MSK for MSI in their tumors. MSI is a genetic defect that occurs in about 5% of advanced cancers. It leads to the accumulation of hundreds or even thousands of mutations in a single tumor. In the past, testing for this biomarker has been limited. But thanks to the US Food and Drug Administration’s approval of pembrolizumab (Keytruda®) in May 2017 for any cancer that has a high level of MSI, many more people are now having their tumors analyzed for this defect.

In addition to tests for MSI, the people included in the study also had genomic testing with MSK-IMPACTTM. This tool looks for mutations in 468 cancer-associated mutations in tumors as well as a number of cancer-linked hereditary mutations found in normal tissues. These inherited mutations include those linked to Lynch syndrome.

“At MSK, because we sequence the tumors of so many people, we have a unique opportunity to make these kinds of discoveries,” says Dr. Stadler, who is clinic director of MSK’s Clinical Genetics Service and a member of the Robert and Kate Niehaus Center for Inherited Cancer Genomics. “This kind of research helps people with cancer and, in this case, also helps us provide predictive genetic testing for at-risk family members, who may then benefit from increased cancer surveillance and cancer prevention measures.”

A Cancer Syndrome That Runs in Families

Lynch syndrome is an inherited condition caused by a mutation in one of five genes known as mismatch repair (MMR) genes. When one of the MMR genes is mutated, cells are unable to repair errors that can occur when they divide — resulting in MSI.

Lynch syndrome has been known about for decades, but in the past, it has been largely associated with just a few cancers. MSK’s Clinical Genetics Service offers testing for Lynch syndrome to people who have multiple relatives with related cancers. However, the findings from this study suggest that many cases of Lynch syndrome could be going undetected.

Consequences for Future Research, and for Families

Knowing whether a cancer is due to Lynch syndrome has important implications for families. Lynch mutations are autosomal dominant, which means a person with Lynch has a 50% chance of passing it down to a child. MSK’s genetic counselors recommend that when someone is found to have Lynch syndrome, their parents, siblings, and children get tested too.

Experts also recommend more frequent screening for certain cancers if a Lynch-associated mutation is found. In particular, people with Lynch mutations should get regular colonoscopies to look for colon and rectal cancer.

Focusing on families with inherited cancer genes is a major part of the Precision Interception and Prevention (PIP) initiative. This MSK effort concentrates not only on catching cancer very early but also on preventing it from developing in the first place.

PIP is led by Luis Diaz, Head of MSK’s Division of Solid Tumor Oncology, and MSK Physician-in-Chief José Baselga. It was created to take advantage of all of the findings coming out of MSK-IMPACT.

“Dr. Baselga’s initiative of genomic analysis of a very large number of patients through MSK-IMPACT has been instrumental to this project,” Dr. Stadler concludes. “This test has been vital in making sure that people get the best treatments for their cancer and enabled us to do these kinds of important studies that can ultimately benefit whole families.”