Ten children have already been diagnosed with cancer; 13 others carry gene requiring lifelong testing
Shocking news about a single sperm donor’s shared gene mutation has shed light on shortfalls in preventative clinical laboratory genetic screening.
The otherwise-healthy donor’s sperm has already led to various cancer diagnoses for 10 of the children he fathered, including Hodgkin lymphoma and brain tumors, CNN reported.
“Unlike in some cases of serial sperm donors, such as a Dutch man who was ordered to stop donating sperm after being found to have fathered between 500 and 600 children around the world, this man only donated to a single private sperm bank in Denmark named the European Sperm Bank,” CNN reported.
Though it may be an anomaly, this occurrence has generated calls for increased regulation on the use of donated sperm.
“At the heart of the problem seems to lie the regulation, or maybe the lack of regulation, of the number of births by a single donor,” said Edwige Kasper, PhD, oncogenetic biologist at Rouen University Hospital in France, at the annual conference of the European Society of Human Genetics in Milan, Italy, CNN reported. (Photo copyright: LinkedIn.)
Limits to Genetic Screening
“Preventative genetic screening is reaching its limits here,” Julie Paulli Budtz, vice-president of corporate communications at the European Sperm Bank, told CNN. Budtz noted that in this case, the donor was tested even above traditional standards.
“Every human being has about 20,000 genes, and it is scientifically simply not possible to detect disease-causing mutations in a person’s gene pool if you don’t know what you are looking for,” she told CNN.
At least in this situation, the need for improvement is evident and will likely inspire continued research and development in the genetic testing capabilities.
“The fact that the case in point is very rare does not mean that it will not reoccur,” Kasper noted in the ESHG press release.
Calls for Increased Regulation of Sperm Donations
At the European Society of Human Genetics (ESHG) annual conference in May, Edwige Kasper, PhD, an oncogenetic biologist and specialist in genetic predisposition to cancer at Rouen University Hospital in France, explained how one European man’s sperm donations spanning from 2008-2015 resulted in the birth of 67 children, 23 of whom have already been impacted by his cancer-causing genetic mutation, CNN reported.
“We need proper regulation at European level to try to prevent it happening again, and to implement measures to ensure a worldwide limit on the number of offspring conceived from the same donor,” she noted.
ESHG’s press release describes Li-Fraumeni as “one of the most severe inherited predispositions to cancer that is characterized by a broad spectrum of tumors at an early age.”
Additional Case Details
In addition to the 10 children with cancer diagnoses, another 13 he fathered are currently cancer-free but carry the gene, which now subjects them to invasive life-long testing including whole-body MRI scans to clinical exams and scans of the brain, breast, and abdomen, CNN noted.
“[The procedure is] heavy and stressful for carriers, but we have seen its effectiveness in that it has enabled early detection of tumors and thus improved patients’ chances of survival,” Kasper said in the ESHG press release.
The offspring of these 10 children will have a 50% greater chance of receiving the gene as well, CNN added.
Requirement reflects increasing worldwide focus on preventing genetic disorders through clinical laboratory genetic testing
In a significant move, Abu Dhabi’s Department of Health has established a new policy that requires engaged couples to get genetic testing done along with clinical laboratory blood testing before walking down the aisle.
Abu Dhabi, the capital city of the United Arab Emirates (UAE), is following an established public health policy of testing soon-to-be-married couples for specific disease conditions. Now, however, instead of just infectious diseases, it is testing for specific genetic conditions as well.
This marks a first for Arab nations and also demonstrates a shift in the standard of care for those regions.
“Abu Dhabi continues to set a global standard in proactive healthcare, marking a significant paradigm shift from traditional and reactive healthcare to informed and holistic health planning and decisions,” said Asma Al Mannaei, DrPH, Director of Health Quality and Executive Director of the Research and Innovation Center at Abu Dhabi Department of Health (DOH), in a press release.
Clinical laboratory managers and pathologists in the US will note that the move in Abu Dhabi mirrors a similar trend in this country. A growing number of children’s hospitals are using genetic testing such as rWGS (Rapid Whole Genome Sequencing) as a pro-active screen for newborns where family history indicates the value of such testing.
It appears the use of genetic testing as a way of predicting risk for genetic disorders is growing in popularity across the globe.
“The integration of genetic testing as part of the premarital screening program is a proud milestone for Abu Dhabi. It positions the Emirate at the forefront of leading healthcare destinations globally, harnessing the power of genomics and latest technologies to promote informed decisions,” said Asma Al Mannaei, DrPH (above), executive director of the Research and Innovation Center at Abu Dhabi’s Department of Health, in a press release. “This step aims to prevent the transmission of genetic diseases to children and elevate early intervention through different phases including diagnostic, tailored genetic counselling, and introducing reproductive medicine solutions for couples.” (Photo copyright: Global Medical Tourism Summit.)
Why Screen for Genetic Disorders?
Pre-screening betrothed couples isn’t a new concept. The US previously required blood tests prior to marriage primarily to spot diseases such as Rubella (a.k.a., German Measles). The nationwide program was eliminated in 2019 for a variety of reasons including the fact that “the mandated blood tests worked to discourage marriage while doing little to actually identify people with disease or improve public health,” the Mises Institute noted at the time.
However, things are different in Middle East nations where consanguinity—when a couple shares a blood relative—is a common cultural norm. It’s not unusual in those regions for first cousins to marry and have children, which can lead to genetic complications.
“If a couple are consanguineous (related) their children have a higher chance of being affected by autosomal recessive genetic disorders. These only occur if a child has a mutation (change) in both copies of a particular gene pair,” according to Top Doctors.
This is where Abu Dhabi’s new genetic testing requirement comes in.
Making Informed Decisions for Future Families
Just like in the US, Abu Dhabians have been blood screening couples for infectious diseases for decades. Genetic testing as part of premarital screening was added at the end of 2024, a report from the Abu Dhabi Public Health Center (ADPHC) noted.
Screening is available at 22 primary healthcare centers throughout Abu Dhabi and the Al Dhafra and Al Ain regions.
“The comprehensive genetic testing list includes 570 genes that cover 840+ genetic disorders. It is important because it can help couples assess the risk of having children with genetic disorders and support them in making informed decisions about family planning,” the ADPHC stated in its report.
Dark Daily in the Middle East
It seems inevitable that in time genetic testing for engaged couples would eventually become a requirement.
Abu Dhabi’s DOH partnered with Abu Dhabi Public Health Center (ADPHC) to launch a pilot of the genetic testing program back in 2022. It screened more than 800 couples and found that 86% showing “genetic compatibility.” The other 14% received test results that required them to obtain more advanced family planning and intervention, the ADPHC reported.
As consanguinity is a common practice in many areas of the Middle East, other nations and Emirates may follow Abu Dhabi in requiring couples to undergo genetic testing. In the US, it would be prudent for clinical laboratories to watch growing trends as more couples opt for extra testing to provide best possible outcomes for their future families.
Half of the people tested were unaware of their genetic risk for contracting the disease
Existing clinical laboratory genetic screening guidelines may be inadequate when it comes to finding people at risk of hereditary breast-ovarian cancer syndromes and Lynch syndrome (aka, hereditary nonpolyposis colorectal cancer). That’s according to a study conducted at the Mayo Clinic in Rochester, Minn., which found that about half of the study participants were unaware of their genetic predisposition to the diseases.
Mayo found that 550 people who participated in the study (1.24%) were “carriers of the hereditary mutations.” The researchers also determined that half of those people were unaware they had a genetic risk of cancer, and 40% did not meet genetic testing guidelines, according to a Mayo Clinic news story.
The discoveries were made following exome sequencing, which the Mayo Clinic news story described as the “protein-coding regions of genes” and the sites for most disease-causing mutations.
“Early detection of genetic markers for these conditions can lead to proactive screenings and targeted therapies, potentially saving lives of people and their family members,” said lead author Niloy Jewel Samadder, MD, gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center.
“This study is a wake-up call, showing us that current national guidelines for genetic screenings are missing too many people at high risk of cancer,” said lead author Niloy Jewel Samadder, MD (above), gastroenterologist and cancer geneticist at Mayo Clinic’s Center for Individualized Medicine and Comprehensive Cancer Center. New screening guidelines may increase the role of clinical laboratories in helping physicians identify patients at risk of certain hereditary cancers. (Photo copyright: Mayo Clinic.)
Advancing Personalized Medicine
“The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC (hereditary breast and ovarian cancer) and LS (Lynch syndrome),” the authors wrote in JCO Precision Oncology.
For the current study, Helix, a San Mateo, Calif. population genomics company, collaborated with Mayo Clinic to perform exome sequencing on the following genes:
BRCA1 and BRCA2 genes (hereditary breast and ovarian cancer).
Mayo/Helix researchers performed genetic screenings on more than 44,000 study participants. According to their published study, of the 550 people who were found to have hereditary breast cancer or Lynch syndrome:
387 had hereditary breast and ovarian cancer (27.2% BRCA1, 42.8% BRCA2).
163 had lynch syndrome (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM).
Participants recruited by researchers hailed from Rochester, Minn.; Phoenix, Ariz.; and Jacksonville, Fla.
Minorities were less likely to meet the NCCN criteria than those who reported as White (51.5% as compared to 37.5%).
“Our results emphasize the importance of expanding genetic screening to identify people at risk for these cancer predisposition syndromes,” Samadder said.
Exome Data in EHRs
Exomes of more than 100,000 Mayo Clinic patients have been sequenced and the results are being included in the patients’ electronic health records (EHR) as part of the Tapestry project. This gives clinicians access to patient information in the EHRs so that the right tests can be ordered at the right time, Mayo Clinic noted in its article.
“Embedding genomic data into the patient’s chart in a way that is easy to locate and access will assist doctors in making important decisions and advance the future of genomically informed medicine.” said Cherisse Marcou, PhD, co-director and vice chair of information technology and bioinformatics in Mayo’s Clinical Genomics laboratory.
While more research is needed, Mayo Clinic’s accomplishments suggest advancements in gene sequencing and technologies are making way for data-driven tools to aid physicians.
As the cost of gene sequencing continue to fall due to improvement in the technologies, more screenings for health risk factors in individuals will likely become economically feasible. This may increase the role medical laboratories play in helping doctors use exomes and whole genome sequencing to screen patients for risk of specific cancers and health conditions.
Clinical laboratory managers should note that this company’s new diagnostic offering involving screening embryos for specific genetic conditions is not without controversy
Is the world ready for whole genome sequencing (WGS) of preimplantation embryos to help couples undergoing in vitro fertilization (IVF) treatments know if their embryos have potential genetic health problems? Orchid Health, a clinical preimplantation genetic testing (PGT) laboratory that conducts genetic screening in San Francisco, believes the answer is yes! But the cost is high, and the process is not without controversy.
According to an article in Science, Orchid’s service—a sequencings of the whole human genome of preimplantation embryos at $2,500 per embryo tested—“will look not just for single-gene mutations that cause disorders such as cystic fibrosis, but also more extensively for medleys of common and rare gene variants known to predispose people to neurodevelopmental disorders, severe obesity, and certain psychiatric conditions such as schizophrenia.”
However, Science also noted that some genomics researchers “claim the company inappropriately uses their data to generate some of its risk estimates,” adding that the “Psychiatric Genomics Consortium (PGC), an international group of more than 800 researchers working to decode the genetic and molecular underpinnings of mental health conditions, says Orchid’s new test relies on data [PGC] produced over the past decade, and that the company has violated restrictions against the data’s use for embryo screening.”
There are some who assert that a whole genome sequence of an embryo—given today’s state of genetic technology and knowledge—could generate information that cannot be interpreted accurately in ways that help parents and doctors make informed prenatal testing decisions. At the same time, criticisms expressed by the PGC raise reasonable points.
Perhaps this is a sign of the times. Orchid Health is the latest genetic testing company that is looking to get ahead of genetic testing competitors with its diagnostics offerings. Meanwhile, knowledgeable and credible experts question the appropriateness of this testing, given the genetic knowledge that exists today.
“This is a major advance in the amount of information parents can have,” Orchid’s founder and CEO Noor Siddiqui (above) told CNBC. “The way that you can use that information is really up to you, but it gives a lot more control and confidence into a process that, for all of history, has just been totally left to chance.” Should Orchid Health’s analysis prove useful, pediatricians could order further clinical laboratory prenatal testing to confirm and diagnose potential genetic diseases for parents. (Photo copyright: General Assembly.)
Orchid Receives World-class Support
Regardless of the pushback from some genetic researchers, Orchid has attracted several world-class geneticists and genetics investors to its board of advisors. They include:
Jacques Cohen, PhD, embryologist, co-founder and former director for genetics laboratory Reprogenetics LLC (now CooperGenomics).
Anne Wojcicki, co-founder and CEO of direct-to-consumer genetic testing company 23andMe.
and others.
The WGS test, according to Orchid, detects genetic errors in embryos that are linked to severe illnesses before a pregnancy even begins. And by sequencing 99% of an embryo’s DNA, the test can spot potential health risks that could affect a future baby.
According to its website, the PGT lab company uses the WGS data to identify both monogenic (single-gene) and polygenic (multiple-gene) diseases, including:
Orchid is not without its critics. Knowledgeable, credible experts have questioned the appropriateness of this type of genetic testing. They fear it could become a modern-day form of eugenics.
Andrew McQuillin, PhD, Professor of Molecular Psychiatry at University College London, has concerns about Orchid’s preimplantation genetic testing. He maintains that it is difficult to control how such data is used, and that even the most accurate sequencing techniques do not predict disease risk very well.
“[Polygenic risk scores are] useful in the research context, but at the individual level, they’re not actually terribly useful to predict who’s going to develop schizophrenia or not,” McQuillin told Science. “We can come up with guidance on how these things should be used. The difficulty is that official guidance like that doesn’t feature anywhere in the marketing from these companies.”
McQuillin also stated that researchers must have an extensive discussion regarding the implications of this type of embryo screening.
“We need to take a look at whether this is really something we should be doing. It’s the type of thing that, if it becomes widespread, in 40 years’ time, we will ask, ‘What on Earth have we done?’” McQuillin emphasized.
Redefining Reproduction
It takes about three weeks for couples to receive their report back from Orchid after completing the whole genome sequence of a preimplantation embryo. A board-certified genetic counselor then consults with the parents to help them understand the results.
Founder and CEO Noor Siddiqui hopes Orchid will be able to scale up its operations and introduce more automation to the testing process to the cost per embryo.
“We want to make this something that’s accessible to everyone,” she told CNBC.
“I think this has the potential to totally redefine reproduction,” she added. “I just think that’s really exciting to be able to make people more confident about one of the most important decisions of their life, and to give them a little bit more control.”
Clinical laboratories have long been involved in prenatal screening to gain insight into risk levels associated with certain genetic disorders. Even some of that testing comes with controversy and ambiguous findings. Whether Orchid Health’s PGT process delivers accurate, reliable diagnostic insights regarding preimplantation embryos remains to be seen.
If further research confirms these findings, clinical laboratory identification of cancer cells could lead to new treatments for certain childhood cancers
Can cancer cells be changed into normal healthy cells? According to molecular biologists at the Cold Spring Harbor Laboratory (CSHL) in Long Island the answer is, apparently, yes. At least for certain types of cancer. And clinical laboratories and anatomic pathologists may play a key role in identifying these specific cancer cells and then guiding physicians in selecting the most appropriate therapies.
The cancer cells in question are called rhabdomyosarcoma (RMS) and are “particularly aggressive,” according to ScienceAlert. Generally, and most sadly, the cancer primarily affects children below the age of 18. It begins in skeletal muscle, mutates throughout the body, and is often deadly.
“Treatment usually involves chemotherapy, surgery, and radiation procedures. Now, new research by scientists at Cold Spring Harbor Laboratory demonstrates differentiation therapy as a new treatment option for RMS,” Genetic Engineering and Biotechnology News (GEN) reported.
For those young cancer patients, this new research could become a lifesaving therapy as further studies validate the approach, which has been in development for six years.
“Every successful medicine has its origin story,” said Christopher Vakoc, MD, PhD (above), a molecular biologist at Cold Spring Harbor Laboratory, who led the team that develop the method for converting cancer cells into healthy cells. “And research like this is the soil from which new drugs are born.” As these findings are confirmed, it may be that clinical laboratories and anatomic pathologists will be needed to identify the specific cancer cells in patients once treatment is developed. (Photo copyright: Cold Spring Harbor Laboratory.)
Differentiation Therapy
According to an article in the Chinese Journal of Cancer on the National Library of Medicine website, “Differentiation therapy is based on the concept that a neoplasm is a differentiation disorder [aka, differentiation syndrome] or a dedifferentiation disease. In response to the induction of differentiation, tumor cells can revert to normal or nearly normal cells, thereby altering their malignant phenotype and ultimately alleviating the tumor burden or curing the malignant disease without damaging normal cells.”
Vakoc and his team first pursued differentiation therapy to treat Ewing sarcoma, a pediatric cancer that forms in soft tissues or in bone. In January 2023, GEN reported that the researchers had discovered that “Ewing sarcoma could potentially be stopped by developing a drug that blocks the protein known as ETV6.”
“This protein is present in all cells. But when you perturb the protein, most normal cells don’t care,” Vakoc told GEN. “The process by which the sarcoma forms turns this ETV6 molecule—this relatively innocuous, harmless protein that isn’t doing very much—into something that’s now controlling a life-death decision of the tumor cell.”
The researchers discovered that when ETV6 was blocked in lab-grown Ewing sarcoma cells, the cells became normal, healthy cells. “The sarcoma cell reverts back into being a normal cell again,” they told GEN. “The shape of the cell changes. The behavior of the cells changes. A lot of the cells will arrest their growth. It’s really an explosive effect.”
The scientists then turned their attention on Rhabdomyosarcoma to see if they could elicit a similar response.
“In this study, we developed a high-throughput genetic screening method to identify genes that cause rhabdomyosarcoma cells to differentiate into normal muscle. We used this platform to discover the protein NF-Y as an important molecule that contributes to rhabdomyosarcoma biology. CRISPR-based genetic targeting of NF-Y converts rhabdomyosarcoma cells into differentiated muscle, and we reveal the mechanism by which this occurs,” they wrote in PNAS.
“Scientists have successfully induced rhabdomyosarcoma cells to transform into normal, healthy muscle cells. It’s a breakthrough that could see the development of new therapies for the cruel disease, and it could lead to similar breakthroughs for other types of human cancers,” ScienceAlert reported.
“The cells literally turn into muscle,” Vakoc told ScienceAlert. “The tumor loses all cancer attributes. They’re switching from a cell that just wants to make more of itself to cells devoted to contraction. Because all its energy and resources are now devoted to contraction, it can’t go back to this multiplying state,” he added.
Promising New Therapies for Multiple Cancers in Children
Differentiation therapy as a treatment option gained popularity when “scientists noticed that leukemia cells are not fully mature, similar to undifferentiated stem cells that haven’t yet fully developed into a specific cell type. Differentiation therapy forces those cells to continue their development and differentiate into specific mature cell types,” ScienceAlert noted.
Vakoc and his team had previously “effectively reversed the mutation of the cancer cells that emerge in Ewing sarcoma.” It was those promising results from differentiation therapy that inspired the team to push further and attempt success with rhabdomyosarcoma.
Their results are “a key step in the development of differentiation therapy for rhabdomyosarcoma and could accelerate the timeline for which such treatments are expected,” ScienceAlert commented.
Developing New Therapies for Deadly Cancers
Vakoc and his team are considering differentiation therapy’s potential effectiveness for other types of cancer as well. They note that “their technique, now demonstrated on two different types of sarcoma, could be applicable to other sarcomas and cancer types since it gives scientists the tools needed to find how to cause cancer cells to differentiate,” ScienceAlert reported.
“Since many forms of human sarcoma exhibit a defect in cell differentiation, the methodology described here might have broad relevance for the investigation of these tumors,” the researchers wrote in PNAS.
Clinical laboratories and anatomic pathologist play a critical role in identifying many types of cancers. And though any treatment that comes from the Cold Spring Harbor Laboratory research is years away, it illustrates how new insights into the basic dynamics of cancer cells is helping researchers develop effective therapies for attacking those cancers.
