Genetics

Invitae Partners with BridgeBio Pharma to Harness Genetic Insights for the Discovery of Rare Disease Therapeutics – PR Newswire

SAN FRANCISCO, Jan. 30, 2024 /PRNewswire/ -- Invitae(NYSE: NVTA), a leading medical genetics company, today announced a partnership with BridgeBio Pharma, Inc. (Nasdaq: BBIO), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, designed to advance genetics-based drug discovery for rare diseases. The goal of the collaboration is to generate new insights focused on genetic modifiers and the discovery of novel therapeutic targets for rare diseases and other unmet medical needs.

The agreement expands upon the longstanding partnership between the two companies to combine the strengths of BridgeBio's deep expertise in rare disease research and development of therapeutics, and Invitae's rare disease enriched dataset and analytical capabilities. Invitae has provided clinical testing for more than 4 million patients, generating an extensive dataset that is uniquely positioned to deepen insights on patients with genetic-driven disease.

"Invitae is on a mission to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. By leveraging de-identified genetic information from patients, our researchers can gain a much deeper understanding of the genetic basis of a disease," said W. Michael Korn, M.D., chief medical officer at Invitae. "Through this partnership, we aim to support the development of novel therapeutic targets and advance transformative medicines for patients with rare disease."

Access to large genetic and clinical datasets are needed to advance research and discover novel drug targets and are often hard to find for researchers.

"We chose to partner with Invitae because of the unique scale and depth of their dataset on affected populations. Patients with severe and highly penetrant dominant disorders are not represented in general population studies, making it nearly impossible to find data anywhere except a disease-focused cohort like Invitae's," said Sun-Gou Ji, Ph.D., vice president of computational genetics at BridgeBio. "These rich data sources will continue to offer researchers a mechanism to get a much deeper understanding of genetic variations and their effect on diseases."

Together Invitae and BridgeBio will translate genetic and phenotypic data into insights to improve therapeutic discovery and design for patients with rare disease. Invitae will analyze longitudinal medical phenotypes in linked genetic and clinical datasets, in order to understand the burden of disease in a real-world setting. Harnessing BridgeBio's disease expertise, Invitae will leverage AI-based phenotypic clustering to identify subgroups of patients based on their genetic and phenotypic profiles. Invitae will also conduct association testing to identify potential genetic modifiers of disease phenotype, severity, onset and progression.

For more information about Invitae's solutions for biopharma partners, visit https://www.invitae.com/en/partners/biopharma.

About InvitaeInvitae (NYSE: NVTA) is a leading medical genetics company trusted by millions of patients and their providers to deliver timely genetic information using digital technology. We aim to provide accurate and actionable answers to strengthen medical decision-making for individuals and their families. Invitae's genetics experts apply a rigorous approach to data and research, serving as the foundation of their mission to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people.

To learn more, visit invitae.comand follow for updates on Twitter, Instagram, Facebook and LinkedIn@Invitae.

About BridgeBioBridgeBio is a biotechnology company on a mission to discover and deliver transformative medicines for patients with genetic diseases and cancers with clear genetic drivers.

Safe Harbor StatementThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relatingto the company's goals with respect to the partnership; the intended structure and potential benefits of the partnership; the company's beliefs regarding its dataset and analytical capabilities; and the company's belief that the partnership may support the development of novel therapeutic targets and advance transformative medicines for patients with rare disease. Forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially, and reported results should not be considered as an indication of future performance. These risks and uncertainties include, but are not limited to: the company's ability to grow its business in a cost-efficient manner; the company's history of losses; the company's ability to maintain important customer relationships; the company's ability to compete; the company's need to scale its infrastructure in advance of demand for its tests and to increase demand for its tests; the risk that the company may not obtain or maintain sufficient levels of reimbursement for its tests; the applicability of clinical results to actual outcomes; risks associated with litigation; the company's ability to use rapidly changing genetic data to interpret test results accurately and consistently; security breaches, loss of data and other disruptions; laws and regulations applicable to the company's business; and the other risks set forth in the company's filings with the Securities and Exchange Commission, including the risks set forth in the company's Quarterly Report on Form 10-Q for the quarter ended September 30, 2023. These forward-looking statements speak only as of the date hereof, and Invitae Corporation disclaims any obligation to update these forward-looking statements.

Invitae PR contact:Renee Kelley [emailprotected]

SOURCE Invitae Corporation

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Invitae Partners with BridgeBio Pharma to Harness Genetic Insights for the Discovery of Rare Disease Therapeutics - PR Newswire

Genetics

The Born in Guangzhou Cohort Study enables generational genetic discoveries – Nature.com

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The Born in Guangzhou Cohort Study enables generational genetic discoveries - Nature.com

Genetics

Rare disorder causing extra fingers and toes identified – EurekAlert

image:

The foot of one of the children in the study, showing an extra toe

Credit: University of Leeds

A rare disorder which causes babies to be born with extra fingers and toes and a range of birth defects has been identified in new research co-led by the University of Leeds.

The disorder, which has not yet been named, is caused by a genetic mutation in a gene called MAX. As well as extra digits polydactyly - it leads to a range of symptoms relating to ongoing brain growth, such as autism.

The research marks the first time this genetic link has been identified. It has also found a molecule that could potentially be used to treat some of the neurological symptoms and prevent any worsening of their condition. However, more research is needed to test this molecule before it can be used as a treatment.

Published in the American Journal of Human Genetics, the paper focuses on three individuals with a rare combination of physical traits, namely polydactyly, and a much larger than average head circumference known as macrocephaly.

The individuals share some other characteristics, including delayed development of their eyes which results in problems with their vision early in life.

The researchers compared the DNA of these individuals and found they all carried the shared genetic mutation causing their birth defects.

The latest research was co-led by Dr James Poulter from the University of Leeds; Dr Pierre Lavigne at Universit de Sherbrooke in Qubec and Professor Helen Firth at Cambridge University.

Dr Poulter, UKRI Future Leaders Fellow and University Academic Fellow in Molecular Neuroscience, said: Currently there are no treatments for these patients. This means that our research into rare conditions is not only important to help us understand them better, but also to identify potential ways to treat them.

In this case, we found a drug that is already in clinical trials for another disorder meaning we could fast track this for these patients if our research finds the drug reverses some of the effects of the mutation.

It also means that other patients with a similar combination of features can be tested to see if they have the same variant we have identified in our study.

The study team has highlighted the importance of interdisciplinary research into rare diseases in giving understanding and hope of a treatment to families who often face many years of uncertainty about their childs condition and prognosis.

Dr Poulter added: These are often under-represented conditions that have a huge impact on patients and their families. These families go through a long and complex diagnostic odyssey. The time from their first doctors visit as babies to getting a diagnosis can take more than 10 years.

It is important that these patients and their families discover the cause of their condition and if they can access a therapy based on their genetic diagnosis, that could be life changing.

Dr Lavigne said: Finding out the impact of the mutation on the function of MAX is the first step towards the development of a treatment for these children.

The researchers now plan to look for additional patients with mutations in MAX to better understand the disorder and investigate whether the potential treatment improves the symptoms caused by the mutation.

The research was carried out in collaboration with the Leeds Teaching Hospitals Trust, the NHS Wales All Wales Medical Genomics Service and Radboud University Medical Center, The Netherlands.

It used data from the Deciphering Developmental Disorders study, which was led by the Wellcome Sanger Institute.

Professor Firth said: The DDD study recruited across the UK from 2011-2015. Its exciting that in 2024, were still making new discoveries. This new finding is a diagnosis for our DDD patients. Furthermore, this publication will now enable other children worldwide to be diagnosed with this novel disorder.

Further information

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes is published in American Journal of Human Genetics.

Email University of Leeds press officer Lauren Ballinger on l.ballinger@leeds.ac.uk with media enquiries.

This work was funded by a UK Research & Innovation Future Leaders Fellowship to James Poulter and a Canadian Institutes of Health Research project grant (PL). The genetic sequencing was undertaken as part of the DDD (Deciphering Developmental Disorders) study which presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003]. This study makes use of DECIPHER , which is funded by the Wellcome Trust and hosted by EMBL-EBI [grant number WT223718/Z/21/Z].

University of Leeds

The University of Leeds is one of the largest higher education institutions in the UK, with more than 38,000 students from more than 150 different countries. We are renowned globally for the quality of our teaching and research.

We are a values-driven university, and we harness our expertise in research and education to help shape a better future for humanity, working through collaboration to tackle inequalities, achieve societal impact and drive change.

The University is a member of the Russell Group of research-intensive universities, and plays a significant role in the Turing, Rosalind Franklin and Royce Institutes. http://www.leeds.ac.uk

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American Journal of Human Genetics

A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

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Rare disorder causing extra fingers and toes identified - EurekAlert

Genetics

Researchers discover mechanism that protects tissue after faulty gene expression – News-Medical.Net

The genetic material, in the form of DNA, contains the information that is crucial for the correct functioning of every human and animal cell. From this information repository, RNA, an intermediate between DNA and protein, the functional unit of the cell, is generated. During this process, the genetic information must be tailored for specific cell functions. Information that is not needed (introns) is cut out of the RNA and the important components for proteins (exons) are preserved. A team of researchers led by Professor Dr Mirka Uhlirova at the University of Cologne's CECAD Cluster of Excellence in Aging Research has now discovered that if the processing of this information no longer works properly, a protein complex (C/EBP heterodimer) is activated and directs the cell towards a dormant state, known as cellular senescence. The results have appeared under the title 'Xrp1 governs the stress response program to spliceosome dysfunction' in Nucleic Acids Research.

All eukaryotes (i.e. organisms in which DNA is enclosed within the cell nucleus) have a spliceosome. This is a machine that performs 'splicing', the removal of introns and linking exons to form messenger RNA (mRNA). Malfunctions in the spliceosome lead to diseases known as spliceosomopathies, which may affect many different tissues, and manifest as retinal degeneration or myelodysplastic syndrome, a group of bone marrow diseases affecting the blood.

In the study, the Uhlirova lab used the model organism Drosophila melanogaster, a fruit fly, to investigate how cells within a developing organism respond to spliceosome malfunction. The scientists used a combination of genomics and functional genetics to determine the role of individual genes and interactions among them. The study showed that cells suffering from a defective spliceosomal U5 snRNP (U5 small nuclear ribonucleoprotein particle) activate a stress signaling response and cellular behaviors that are characteristic of cellular senescence. The senescence program changes crucial functions of the cells. It prevents cells from dividing while stimulating their secretion. Senescence is triggered to preserve cells that are damaged, as their immediate elimination would cause more harm than good. However, senescent cell accumulation can have a negative impact on a tissue as well as the whole organism. Therefore, these cells are ultimately eliminated.

Uhlirova's team identified the C/EBP-heterodimer protein complex, Xrp1/Irbp18, as the critical driver of the stress response program caused by faulty splicing. Upregulation of Xrp1/Irbp18 in damaged cells led to increased protein production and induced a senescence-like state. "Senescence is a double-edged sword," said Uhlirova. One advantage of senescent cells is that they are not all eliminated by cell death at the same time, thus maintaining the integrity of the tissue. After all, partially intact tissue is better than none at all. However, these cells create problems in the long term, as their accumulation promotes disease and aging.

"A functioning spliceosome is a basic prerequisite for healthy cells, tissue and the entire organism," she concluded. "Additional investigation of the stress signaling program we have identified will be important to further unpack the complex responses triggered by defects in the essential machines controlling gene expression - and how we can influence them." In future, the results could contribute to the development of therapeutic approaches to treat diseases that are caused by malfunctions of the spliceosome.

Source:

Journal reference:

Stankovi, D.,et al.(2024) Xrp1 governs the stress response program to spliceosome dysfunction. Nucleic Acids Research. doi.org/10.1093/nar/gkae055.

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Researchers discover mechanism that protects tissue after faulty gene expression - News-Medical.Net

Genetics

Retinal OCT and Genetics Identify Links Between Ocular and Systemic Health – Photonics.com

BOSTON, Feb. 1, 2024 A study conducted by Mass Eye and Ear, the Broad Institute at MIT, and Harvard Medical School has demonstrated links between the thinning of different retinal layers and an increased risk of disease. The work used OCT retinal images and genetic data from thousands of UK Biobank participants and could serve to advance the use of OCT to predict ocular disease and inspire further research on disease prediction beyond the eye.

The researchers analyzed data from more than 44,000 UK Biobank participants who underwent OCT retinal imaging and genotyping in 2010. The participants were subsequently followed for an average of 10 years.

The team performed a cross-phenotype analysis using OCT images from the UK Biobank and identified associations between retinal layer thickness and ocular, neuropsychiatric, and cardiometabolic diseases experienced by the participants during the 10-year follow-up period.

The researchers observed a consistency between epidemiologic and genetic associations that indicated links between a thinner retinal nerve fiber layer and glaucoma, and between a thinner photoreceptor segment and age-related macular degeneration. They also linked poor cardiometabolic and pulmonary function with a thinner photoreceptor segment.

Weve come to realize recently that there is a lot more information that we can get from our retina images than we thought was possible, Zebardast said.

Previous studies have revealed links between retinal health and aging, cardiometabolic diseases such as diabetes and hypertension, and neurological diseases such as dementia, stroke, and multiple sclerosis. Unlike earlier studies that focused on the genes associated with overall retinal health, the Mass Eye and Ear study addressed the role of the different cell layers that comprise the retina, in addition to investigating the genes that affect retinal health.

Although retinal OCT imaging is already a standard clinical procedure in ophthalmology, the researchers believe that it could be put to broader use. Further work to establish the connection between ocular and cardiometabolic health will provide more insight into the value of retinal OCT imaging as a clinical tool.

Patients come to us for their eye health, but what if we could tell them more than that, Zebardast said. What if we could use someones retinal images to tell them, You seem to have a high risk of having high blood pressure, maybe you should get screened, or maybe your primary care doctor should know about that.

The study is part of an ongoing effort at Mass Eye and Ear to identify genetic markers of glaucoma and other ocular diseases.

The research was published in Science Translational Medicine (www.doi.org/10.1126/scitranslmed.adg4517).

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Retinal OCT and Genetics Identify Links Between Ocular and Systemic Health - Photonics.com

Genetics

Why Some Folks Get COVID, and Others Never Do – HealthDay

FRIDAY, Feb. 2, 2024 (HealthDay News) -- Everyone knows someone who gets COVID-19 repeatedly, and they probably also have that annoying friend who's never had the illness. What gives?

According to new research, over the long-term it's probably genetics that drives an individual's level of susceptibility to SARS-Cov-2.

Our results suggest that initially, differences in shared home environment influenced who was infected with COVID-19 more than genetic differences, explained study lead author Katie LaRow Brown, a Ph.D. candidate at Columbia University in New York City.

Over time, however, the importance of these differences in shared home environment decreased -- and the importance of genetics increased -- eventually eclipsing shared home environment," she said. Brown spoke in a news release from Cedars-Sinai in Los Angeles, which was also involved in the research.

According to background info, since the pandemic began over 340 million Americans have been infected by the SARS-Cov-2 coronavirus.

However, the role that environment and genetics may play in who gets infected is still poorly understood.

In the new study, Brown and colleagues looked at data from the electronic health records of patients at New York-Presbyterian/Columbia University Irving Medical Center.

Almost 13,000 of the patients received conclusive results on COVID-19 PCR tests taken between late February 2021 and late October 2022.

Typically, patients came from families where an average 2.5 members had contracted COVID-19.

Parsing out genetics versus environmental factors, the researchers found that the relationship changed over time.

Earlier in the pandemic, a person's genetics accounted for about 33% of the variation in their susceptibility to COVID-19, but by the second half of the study, genetics' role in susceptibility rose to 70%.

Looking at the severity of COVID illness (based on days spent in the hospital), genetics again trumped home environments. The study found that genetics explained 41% of variations in case severity, while shared environment explained 33%.

We were especially surprised by the percentages of susceptibility, said senior study author Nicholas Tatonetti.

The findings were published recently in the journal Nature Communications.

Since this is an infectious disease, we assumed that home environment differences would explain most variation for the entirety of the study," said Tatonetti, vice chair of operations in the department of computational biomedicine and an associate director of computational oncology at Cedars-Sinai Cancer.

It's not yet clear which DNA is driving the gap between who gets COVID-19 and who doesn't. Finding out "is very important in terms of directing resources and defining future research goals," Tatonetti said.

More information

Find out more about shielding yourself from COVID at the U.S. Centers for Disease Control and Prevention.

SOURCE: Cedars-Sinai, news release, Jan. 31, 2024

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Why Some Folks Get COVID, and Others Never Do - HealthDay

Genetics

From plant genetics to fresh produce to be showcased in Berlin – FreshPlaza.com

BayWa Global Produce together with its international subsidiaries will be presenting its international activities from plant genetics to fresh produce in Berlin. By investing in the operational infrastructure of its entities over the past two years, the sector-specific portfolio manager has successfully increased its sorting, packing, storing, and ripening capacities and has improved process efficiency using state-of-the-art technologies for future-oriented growth.

Following a challenging year in 2023, Fruit Logistica is a great moment to look ahead and, together with our subsidiaries, pave the way for a successful year in 2024. Although the current political crises and economic environmental factors in various regions of the world continue to influence our business, we look positively into the future as challenges like these will both spur on change and offer new opportunities, says Benedikt Mangold, CEO at BayWa Global Produce.

Looking at the German apple business BayWa Obst, an improving market environment with promising consumption figures and a weaker market supply at stable prices provide a positive outlook for the rest of marketing season. In times of sharply rising production and wage costs, increased consumption at good price levels is an important development for both our farmers and for us, says Mangold.

After the severe weather event a year ago in New Zealand, we see good signs of recovery with a promising crop of Scifresh and Scilate apples, branded as JAZZTM and EnvyTM, growing on the trees. Our T&G team has done a remarkable job in cleaning-up and re-building our impacted orchards following Cyclone Gabrielle in Hawkes Bay, says Gareth Edgecombe, CEO of T&G Global. As a result of their hard work together with new plantings beginning to bear fruit and great weather over the summer, we look forward to increased export volumes this year - and this will continue to grow year-on-year into the future.

There are also positive developments in the exotics category. By investing in a new facility in Waddinxveen, TFC Holland has been able to further increase its attractiveness and efficiency, particularly by expanding its ripening capacities.

In late 2023, BayWa Global Produce also intensified its long-standing partnership with the Spanish fruit specialist Nufri. As part of a joint-venture based in Huelva, Spain, BayWa Global produce has taken the next big step towards verticalization and growth of its berry business. Pending approval by the European Commission, the partners will jointly be marketing the first blueberry volumes from their joint farm this spring while testing new varieties from T&G Globals VentureFruit business.

The company will have a joint stand in Hall 27 stand C-55.

For more information: BayWa Global Produce GmbH Tel.: +49 89 9222-0 Email: info@baywa-gp.com

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From plant genetics to fresh produce to be showcased in Berlin - FreshPlaza.com

Genetics

New genetic test in England aims to make blood transfusions safer – Sickle Cell Disease News

Englands National Health Service (NHS) is introducing a new genetic test that seeks to make it safer for people with sickle cell disease and other blood disorders to receive transfusions.

Thousands of people living with sickle cell disease and thalassaemia will be eligible for this new world-first blood test which is set to transform their care, Health Minister Andrea Leadsom said in a press release. This is a huge step forward in improving the quality of life for people who are living with these blood disorders.

The NHS said it is the first healthcare system in the world to offer this new test, and the agency is encouraging patients in England to get this test done alongside their routine blood tests.

The initiative will rely on patients attending hospital and having their blood sent to NHS Blood and Transplant for testing. We strongly encourage clinical and laboratory teams to work with patients to support this programme, said Sara Trompeter, MD, a consultant hematologist at NHS Blood and Transplant.

The NHS estimates there are about 17,000 people with sickle cell and 800 people with thalassemia living in England. Both disorders are caused by genetic mutations that cause abnormalities with hemoglobin the protein inside red blood cells that is responsible for oxygen transport.

People with these disorders frequently require blood transfusions, where healthy blood cells from a donor are infused into the body with the goal of easing anemia and other disease symptoms.

Transfusions continue to be crucial in the treatment of sickle cell disorder, said John James, chief executive of the Sickle Cell Society.

With the introduction of this innovative test, we take a remarkable stride towards achieving better blood matches for all those living with the condition, he said. We urge individuals with sickle cell disorder to have the blood test as it will not only support more accurate treatment but also hold the potential to save more lives in the future.

If Id had this test several years ago before my transfusion, I might not have antibodies now.

Although blood transfusions can be life-saving, finding a matching donor can be challenging. The problem is the bodys immune system is hardwired to assume anything that isnt part of the body is a hostile threat. If the immune system recognizes the donated blood cells as foreign, it will attack them, which can cause problematic side effects and reduce the efficacy of the transfusion.

Thats what happened to Ama Aryee, a 34-year-old science teacher living with sickle cell in Cheshunt in Hertfordshire. After receiving emergency blood transfusions for complications from pneumonia, Aryee developed antibodies against many common blood types. Now, if she needs a transfusion, there are only two to four units of blood in England that she can receive safely, according to the NHS.

The doctors and laboratory team find it very difficult to find matching blood for me, Aryee said. It is a worry to know that if there was an emergency and I needed blood it would not be straightforward to find enough. I try not to dwell on it but its there in my mind. Its a bit scary to think about future pregnancies or problems with sickle cell, I am well aware that theres almost no blood I can receive at the moment.

To prevent the immune system from attacking donated blood cells after a transfusion, transfused cells need to look similar enough to the patients own blood cells, so that the immune system wont recognize them as foreign. This has traditionally been done through a relatively crude analyses of large protein markers on the surface of blood cells (thats where the traditional blood-typing system of A, B, AB, and O comes from).

The new test is basically a more detailed version of this type of testing, using genetics to provide more precise matching of different blood cell markers that the immune system might recognize.

While blood matching for patients with inherited blood disorders, including sickle cell disease and transfusion-dependent thalassaemia is already done to a high standard, we can learn more and develop better blood matching further by using this exciting new world-leading test, said Ryan Mullally, MD, a consultant hematologist at Whittington Health NHS Trust. We are keen to raise awareness of it among patients and specialist medical and nursing teams involved in their care.

Aryee definitely supports people getting their blood groups tested.

If Id had this test several years ago before my transfusion, I might not have antibodies now, she said. And if this new testing could help people like me receive blood again that would be wonderful.

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New genetic test in England aims to make blood transfusions safer - Sickle Cell Disease News

Genetics

Significance of genetic mutations in toxic tort cases – Massachusetts Lawyers Weekly

The primary question in many toxic tort cases is what caused the disease? When defending these cases, one necessarily asks: (1) is the product/substance I am defending capable of causing the disease in question; and (2) was the plaintiff exposed to enough of it to have done so.

With cases involving cancer, particularly mesothelioma, genetic science is adding to the mix and providing information that, in the right case, changes the equation entirely.

Generally, cancer is a genetic disease caused by gene mutations that control how cells grow and multiply (NIH The Genetics of Cancer, 2022). While cells are the bodys building blocks, genes are sections of DNA in each cell that provide instructions to make required proteins and control cell growth. Hundreds of DNA and genetic changes (variants, mutations or alterations) have been discovered that help cancer form, grow and spread.

My experience with these issues arises from the defense of asbestos cases. The principles raised, however, may well apply to other toxic torts involving cancer.

It is now recognized that there are multiple causes for malignant mesothelioma, a number of which are unrelated to asbestos. Diffuse malignant mesotheliomas are variably associated with prior asbestos exposure, and the strength of the association varies with anatomical tumor site, gender and asbestos fiber type.

The relationship between asbestos and mesothelioma has also evolved and shows significant geographic variation. The epidemiological evidence correlating time trends, incidence by gender, and commercial asbestos use indicates that a majority of pleural mesotheliomas in women, and almost all peritoneal mesotheliomas in women and men, in the United States, appear unrelated to asbestos.

In July 2019, many of the worlds foremost experts on the subject detailed the current state-of-the-art knowledge on the development of mesothelioma. See Carbone, et al., Mesothelioma: Scientific Clues for Prevention, Diagnosis, and Therapy, CA Cancer J Clin., 69:402-429 (2019).

Among the co-authors of the publication were preeminent researchers and practitioners from the University of Hawaii Cancer Center, Memorial Sloan Kettering Cancer Center, Rutgers Robert Wood Johnson Medical School, Brigham and Womens Hospital, Mayo Clinic, Icahn School of Medicine at Mount Sinai, and MD Anderson Cancer Center. Under a section of the publication entitled The Role of Genetics, the authors state:

When examining a toxic tort/cancer case, it may not always be the environment or the toxin that is the culprit. If a plaintiff has an appropriate family history of cancer, genetic testing may provide a viable defense.

Cancer is caused by the accumulation of genetic damage. Genetic damage can be inherited, can develop spontaneously, can be caused by exposure to carcinogens and oncogenic infectious agents, or can be caused by the interplay of a combination of these factors. Currently, there is a very active debate about the relative contribution of these factors to human cancer . [A] growing percentage of cancers are attributed to inherited mutations of DNA repair genes and of other genes that, when mutated, accelerate the accumulation of DNA damage and/or the percentage of cells carrying DNA damage . These concepts apply to mesothelioma.

In broad strokes, there are two types of genetic cases: (1) cases involving somatic or random genetic mutations; and (2) cases involving a germline genetic mutation.

Somatic random mutations develop because of DNA changes that occur during stem cell divisions. These mutations arise naturally and accumulate as a person ages. Age is a significant risk factor for almost all forms of cancer, including spontaneous or naturally occurring mesothelioma.

The basis for age-induced tumorigenesis relates to the hosts generation of critical driver mutations within cells and the subsequent formation of clonally expanded proliferation of mutated cells to form tumors. Stem cell division occurs continuously and requires a faithful replication of the highly complex genetic information contained within the genome and cell nucleus.

Random mistakes or mutations (replication errors) occur continuously and with increasing frequency over time, with the capacity of the host to efficiently identify and correct such mutations diminishing with age.

Because mutation accumulation occurs spontaneously and continuously over time, the risk of spontaneous or naturally occurring mesothelioma, either pleural or peritoneal, increases continuously with age.

Random mutations account for two-thirds of the risk of getting many types of cancer. In such cases, no exposure to an exogenous agent (such as asbestos or therapeutic radiation) is required for tumor initiation. Replicative mutations can be responsible for either initiating the process or driving tumor progression.

The current best available scientific evidence is that some mesotheliomas are linked to inherited germline mutations. Overall, at least 12 percent of mesotheliomas occur in carriers of germline genetic mutations. These germline genetic-induced mesotheliomas typically occur in persons of younger age and are often peritoneal rather than pleural mesotheliomas.

As the cohorts of asbestos workers vanish due to old age, increasing percentages of mesotheliomas, especially peritoneal mesotheliomas, occur in individuals who are not occupationally exposed to asbestos. These mesotheliomas may be caused by environmental exposure, genetic predisposition or both.

Pathogenic germline mutations of BAP1 and, less frequently, of other tumor suppressor genes have also been detected in approximately 12 percent of patients. This subgroup of genetically linked mesotheliomas occurs in younger individuals who rarely report asbestos exposure, and with a M:F ratio of 1:1 and survival ranging from five to 10 or more years.

While heritable gene mutations can predispose an individual to cancer (i.e., lower the amount of exposure necessary to cause disease), they can also be sufficient to cause cancers, including mesothelioma, in and of themselves.

Put another way, the presence of a heritable germline mutation, absent or independent of extrinsic factors such as asbestos exposure, can be a cause of mesothelioma.

While the import of these findings may be largely self-evident, there are some takeaways worth considering. First, when examining a toxic tort/cancer case, it may not always be the environment or the toxin that is the culprit. If a plaintiff has an appropriate family history of cancer, genetic testing may provide a viable defense.

Second, genetic germline mutations do not automatically turn a plaintiff into an eggshell plaintiff. While that argument may work in some cases, given that the mutation can be independently causative, it should not apply in all of them.

Anthony J. Sbarra is a shareholder at Segal McCambridge in Boston and focuses his practice on product liability and toxic tort cases.

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Significance of genetic mutations in toxic tort cases - Massachusetts Lawyers Weekly