Li-Fraumeni Syndrome

In a finding that vastly expands the understanding of tumor evolution, researchers discover genetic biomarkers that can predict the breast cancer subtype a patient is likely to develop. A Stanford Medicine study of thousands of breast cancers has found that the gene sequences we inherit at conception are powerful predictors of the breast cancer type we might develop decades later and how deadly it might be. The study challenges the dogma that most cancers arise as the result of random mutations that accumulate during our lifetimes. Instead, it points to the active involvement of gene sequences we inherit from our parents -- what's known as your germline genome -- in determining whether cells bearing potential cancer-causing mutations are recognized and eliminated by the immune system or skitter under the radar to become nascent cancers. "Apart from a few highly penetrant genes that confer significant cancer risk, the role of heredity factors remains poorly understood, and most malignancies are assumed to result from random errors during cell division or bad luck," said Christina Curtis, PhD, the RZ Cao Professor of Medicine and a professor of genetics and of biomedical data science. "This would imply that tumor initiation is random, but that is not what we observe. Rather, we find that the path to tumor development is constrained by hereditary factors and immunity. This new result unearths a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins." Curtis is the senior author of the study, which will be published May 31 in Science. Postdoctoral scholar Kathleen Houlahan, PhD, is the lead author of the research. "Back in 2015, we had posited that some tumors are 'born to be bad' -- meaning that their malignant and even metastatic potential is determined early in the disease course," Curtis said. "We and others have since corroborated this finding across multiple tumors, but these findings cast a whole new light on just how early this happens." A new take on cancer's origin The study, which gives a nuanced and powerful new understanding of the interplay between newly arisen cancer cells and the immune system, is likely to help researchers and clinicians better predict and combat breast tumors. Currently, only a few high-pro mutations in genes are regularly used to predict cancers. Those include BRCA1 and BRCA2, which occur in about one of every 500 women and confer an increased risk of breast or ovarian cancer, and rarer mutations in a gene called TP53 that causes a disease called Li Fraumeni syndrome, which predisposes to childhood and adult-onset tumors. The findings indicate there are tens or hundreds of additional gene variants -- identifiable in healthy people -- pulling the strings that determine why some people remain cancer-free throughout their lives. "Our findings not only explain which subtype of breast cancer an individual is likely to develop," Houlahan said, "but they also hint at how aggressive and prone to metastasizing that subtype will be. Beyond that, we anticipate that these inherited variants may influence a person's risk of developing breast cancer." The genes we inherit from our parents are known as our germline genome. They're mirrors of our parents' genetic makeup, and they can vary among people in small ways that give some of us blue eyes, brown hair or type O blood. Some inherited genes include mutations that confer increased cancer risk from the get-go, such as BRCA1, BRCA2 and TP53. But identifying other germline mutations strongly associated with future cancers has proven difficult. In contrast, most cancer-associated genes are part of what's known as our somatic genome. As we live our lives, our cells divide and die in the tens of millions. Each time the DNA in a cell is copied, mistakes happen and mutations can accumulate. DNA in tumors is often compared with the germline genomes in blood or normal tissues in an individual to pinpoint which changes likely led to the cell's cancerous transformation. Classifying breast cancers In 2012, Curtis began a deep dive -- assisted by machine learning -- into the types of somatic mutations that occur in thousands of breast cancers. She was eventually able to categorize the disease into 11 subtypes with varying prognoses and risk of recurrence, finding that four of the 11 groups were significantly more likely to recur even 10 or 20 years after diagnosis -- critical information for clinicians making treatment decisions and discussing long-term prognoses with their patients. Prior studies had shown that people with inherited BRCA1 or BRCA2 mutations tend to develop a subtype of breast cancer known as triple negative breast cancer. This correlation implies some behind-the-scenes shenanigans by the germline genome that affects what subtype of breast cancer someone might develop. "We wanted to understand how inherited DNA might sculpt how a tumor evolves," Houlahan said. To do so, they took a close look at the immune system. It's a quirk of biology that even healthy cells routinely decorate their outer membranes with small chunks of the proteins they have bobbing in their cytoplasm -- an outward display that reflects their inner style. The foundations for this display are what's known as HLA proteins, and they are highly variable among individuals. Like fashion police, immune cells called T cells prowl the body looking for any suspicious or overly flashy bling (called epitopes) that might signal something is amiss inside the cell. A cell infected with a virus will display bits of viral proteins; a sick or cancerous cell will adorn itself with abnormal proteins. These faux pas trigger the T cells to destroy the offenders. Houlahan and Curtis decided to focus on oncogenes, normal genes that, when mutated, can free a cell from regulatory pathways meant to keep it on the straight and narrow. Often, these mutations take the form of multiple copies of the normal gene, arranged nose to tail along the DNA -- the result of a kind of genomic stutter called amplification. Amplifications in specific oncogenes drive different cancer pathways and were used to differentiate one breast cancer subtype from another in Curtis' original studies. The importance of bling The researchers wondered whether highly recognizable epitopes would be more likely to attract T cells' attention than other, more modest displays (think golf-ball-sized, dangly turquoise earrings versus a simple silver stud). If so, a cell that had inherited a flashy version of an oncogene might be less able to pull off its amplification without alerting the immune system than a cell with a more modest version of the same gene. (One pair of overly gaudy turquoise earrings can be excused; five pairs might cause a patrolling fashionista T cell to switch from tutting to terminating.) The researchers studied nearly 6,000 breast tumors spanning various stages of disease to learn whether the subtype of each tumor correlated with the patients' germline oncogene sequences. They found that people who had inherited an oncogene with a high germline epitope burden (read: lots of bling) -- and an HLA type that can display that epitope prominently -- were significantly less likely to develop breast cancer subtypes in which that oncogene is amplified. There was a surprise, though. The researchers found that cancers with a large germline epitope burden that manage to escape the roving immune cells early in their development tended to be more aggressive and have a poorer prognosis than their more subdued peers. "At the early, pre-invasive stage, a high germline epitope burden is protective against cancer," Houlahan said. "But once it's been forced to wrestle with the immune system and come up with mechanisms to overcome it, tumors with high germline epitope burden are more aggressive and prone to metastasis. The pattern flips during tumor progression." "Basically, there is a tug of war between tumor and immune cells," Curtis said. "In the preinvasive setting, the nascent tumor may initially be more susceptible to immune surveillance and destruction. Indeed, many tumors are likely eliminated in this manner and go unnoticed. However, the immune system does not always win. Some tumor cells may not be eliminated and those that persist develop ways to evade immune recognition and destruction. Our findings shed light on this opaque process and may inform the optimal timing of therapeutic intervention, as well as how to make an immunologically cold tumor become hot, rendering it more sensitive to therapy." The researchers envision a future when the germline genome is used to further stratify the 11 breast cancer subtypes identified by Curtis to guide treatment decisions and improve prognoses and monitoring for recurrence. The study's findings may also give additional clues in the hunt for personalized cancer immunotherapies and may enable clinicians to one day predict a healthy person's risk of cancer from a simple blood sample. "We started with a bold hypothesis," Curtis said. "The field had not thought about tumor origins and evolution in this way. We're examining other cancers through this new lens of heredity and acquired factors and tumor-immune co-evolution." The study was funded by the National Institutes of Health (grants DP1-CA238296 and U54CA261719), the Canadian Institutes of Health Research and the Chan Zuckerberg Biohub.

The Y220C target mutation is a common oncogenic missense mutation, with a slightly lower mutation frequency compared to R249S and G245S located on the DNA binding surface (it accounts for only 1.4% of p53 missense mutations).  According to World Health Organization statistics, approximately 75,000 cancer cases every year are related to the Y220C mutation. Tyr-220 is located on the surface of the β-sandwich structure, connecting β-strands S7 and S8. Its aromatic ring portion is a component of the hydrophobic core of the β-sandwich structure, but its hydroxyl group can interact with water molecules in the solution. The Y220C mutation leads to a reduction in the thermal stability of the p53 core domain by 4Kcal/mol and results in the mutation of Tyr-220 to Cys-220 between the S3/S4 loop and the S7/S8 loop, forming a hydrophobic cavity on the p53 surface, thereby triggering p53's denaturation and aggregation precipitation.  Strategies for the development of p53-related targeted drugsMoreover, the hydrophobic cavity formed by the Y220C mutation is far from the DNA binding functional domain, thus making this hydrophobic pocket an ideal site for stabilizer design. Stabilizer design based on this hydrophobic cavity does not affect the binding of p53 to DNA or its ability to inhibit cancer. According to data from the Synapse database, there are currently six drugs in the research and development stage targeting p53 Y220C. These drugs cover three different indications, with five organizations developing these drugs. One of these drugs have achieved positive results in clinical trials, providing a solid basis for further development.  In addition, there are already 31 patents and 43 articles related to research on p53 Y220C target drugs, reflecting the scientific activity and knowledge accumulation in this field. With continuous progress in research, we believe that p53 Y220C target drugs will bring new breakthroughs for the treatment of related diseases. Competitive LandscapeAccessing the Synapse database, you can find 6 drug entries by searching for p53 Y220C drug target. Among them, PC-14586 is in Phase 1/2 clinical trials; MB-710 and MB-725 from MRC Laboratory, JAB-30300 from Jacobio Pharmaceuticals, PK-083 from Cambridge University, and PK-9318 from Cambridge BioMedical are all in preclinical stages. Key Drug: PC14586PMVPharma has reported on the small molecule activator PC14586, the structure of which has yet to be disclosed, but which can bind specifically to the Y220C pocket, making it the first Y220C reactivator to enter clinical trials. Preclinical data show that PC14586 can induce tumor regression in xenograft models of Y220C p53 mutant tumors, with an IC50 of ~192-722nM in cell lines derived from Y220C mutant lymphomas and sarcoma tumors. Moreover, PC14586 showed synergistic antitumor activity when combined with anti-PD-1 therapy, as evidenced by the results from the Phase I clinical trial of PC14586.  In terms of safety, the most common treatment-induced adverse events (>15%) include nausea, vomiting, increased AST, increased ALT, anemia, increased creatinine, and fatigue. The maximum tolerable dosage (MTD) is set to be 1500 mg, taken twice daily. In terms of effectiveness, researchers evaluated according to RECIST v1.1, the ORR of patients with an initial daily dose of 1150 mg or more is 32% (8/25). Among the 8 patients who responded, 6 have confirmed partial response, and 2 have unconfirmed partial response and are awaiting confirmation. The ORR of all dose groups is 24% (8/33). Responses were observed in six different types of tumors, including breast cancer, endometrial cancer, prostate cancer, pancreatic cancer, ovarian cancer, and small cell lung cancer. When the dose is ≥1150mg, the best response of disease stability or partial relief was observed in 19/25 patients (76%). PMV Pharma has applied for 11 patents around this target, covering compound patents, use patents, P53 mutation detection method patents, co-crystal patents of small molecules and P53 proteins, and more. The earliest patent originated from WO2017143291, which disclosed a class of indole compounds with an acetylene substitution. The latest patent, US2023024905, disclosed the co-crystal of this type of indole compound with an acetylene substitution and P53 protein. The agonists targeting the mutated p53 Y220C as a novel treatment strategy is expected to treat more than 125,000 cancer patients carrying the p53 Y220C mutation each year, and as a preventative treatment to reduce the cancer risk of Li-Fraumeni syndrome.

Combining expertise to advance precision medicine, while enabling efficient and timely insights into the diagnosis of rare diseases and hereditary cancer around the world SOUTH SAN FRANCISCO, Calif. & CAMBRIDGE, Mass. & ROSTOCK, Germany & BERLIN--(BUSINESS WIRE)-- Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, and Centogene N.V. (Nasdaq: CNTG), the essential life science partner for data-driven answers in rare and neurodegenerative diseases, today announced the launch of three next-generation sequencing (NGS) target enrichment panels to support rare disease and hereditary cancer research and support diagnostics. This press release features multimedia. View the full release here: Target enrichment panels enable more in-depth sequencing on target genes, reducing the need for comprehensive sequencing. This allows for more sensitive detection of target genetic sequences and provides higher confidence that variants will be detected, further driving the understanding of diseases and supporting healthcare professionals in providing precision medicine. Labs and research institutions can purchase these ready-made panels to help accelerate their research, and also have the option of using CENTOGENE’s CentoCloud® for the identification, prioritization, and classification of human genetic variants to expedite diagnostic analysis. “There are over 7,000 rare diseases impacting over 350 million patients, many of whom are not diagnosed until the late stages of the disease. Our mission is to provide data-driven, life-changing answers as early as possible to ultimately accelerate the development of treatments,” said Kim Stratton, Chief Executive Officer at CENTOGENE. “By partnering with Twist to develop these custom panels, we are enabling access to diagnostics and generating novel insights for the medical community, fueled by multidimensional data from the CENTOGENE Biodatabank.” All three new Alliance Panels are highly curated using the CENTOGENE Biodatabank, with nearly 700,000 patients represented from over 120 highly diverse countries, over 70% of whom are of non-European descent. Identified sequences are then synthesized by Twist as biotinylated capture probes which are compatible with Twist’s library preparation solution and target enrichment workflows. The panels offered through Twist will include: The Twist Alliance CNTG Exome Panel, which enables whole exome analysis of genetic markers relevant to rare diseases. The Twist Alliance CNTG Rare Disease Panel, which offers analysis of focused rare-disease-related sequences. The Twist Alliance CNTG Hereditary Oncology Panel, which enables the detection of biomarkers that indicate a high risk of developing cancer. “Twist Alliance panels enable research by providing access to expert-developed panels tailored to specific research areas. CENTOGENE brings highly curated expertise and data in rare diseases, an important complement to our existing Alliance panels,” said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. “As we expand our offering of Alliance panels, we believe it is critical to offer expert-developed content in an off-the-shelf format, compatible with Twist’s extended custom panel offering, enabling a wider user base for these important tools.” For inquiries about the Twist Alliance CNTG panels please visit: . About Twist Alliance CNTG Exome Twist Alliance CNTG Exome is designed using Twist’s core exome and reference sequencing, a full mitochondrial genome and exclusive content for enhanced coverage of relevant genes and variants related to rare diseases. About Twist Alliance CNTG Rare Disease Panel The Twist Alliance CNTG Rare Disease Panel includes more than 2,500 relevant rare disease-associated genes and covers ≥99.5% of targeted regions, offering researchers a more lightweight tool for capturing the crucial rare disease coverage in the CNTG Exome without the full footprint. This panel can be used to detect genes associated with but not limited to rare treatable diseases, early onset childhood disorders, cardiac disorders, neurodegenerative diseases, skeletal abnormalities and metabolic disorders. About Twist Alliance CNTG Hereditary Oncology Panel The Twist Alliance CNTG Hereditary Oncology Panel includes 72 selected cancer-associated genes and covers ≥99.5% of targeted regions. The panel can be used to identify genetic predisposition to hereditary tumors including breast cancer, gastrointestinal tumors, Li-Fraumeni syndrome, MEN1, MEN2, paragangliomas and others. About Twist Alliance Panels In partnership with leading research institutions from around the world, Twist has curated a collection of high-quality target enrichment panels for applications ranging from carrier screening to cancer diagnostics and whole exome sequencing. The Twist Alliance Panels combine the strengths of precise, highly uniform oligonucleotide synthesis with the specialty expertise of leading scientific research partners. Well-designed, custom target enrichment panels enable increased sequencing depth on target genes while reducing overall sequencing. This allows for more sensitive detection of target sequences and higher confidence variant detection. About CentoCloud CentoCloud is a cloud-based Software as a Service (SaaS) platform specifically designed for the rapid bioinformatic analysis and interpretation of next-generation sequencing (NGS) data based on the proprietary CENTOGENE Biodatabank and external reference databases. It allows for the identification, prioritization, and classification of human genetic variants associated with genetic/inherited diseases. The fully automated bioinformatics pipeline analyzes NGS data based on CENTOGENE's validated testing products provided by Twist Bioscience. Powered by an end-to-end workflow with best-in-class bioinformatics as well as CENTOGENE's medical reporting service, CentoCloud encompasses the latest diagnostic insights – allowing physicians around the world to provide state-of-the-art individualized patient care, no matter where they are located. About Twist Bioscience Corporation Twist Bioscience is a leading and rapidly growing synthetic biology and genomics company that has developed a disruptive DNA synthesis platform to industrialize the engineering of biology. The core of the platform is a proprietary technology that pioneers a new method of manufacturing synthetic DNA by “writing” DNA on a silicon chip. Twist is leveraging its unique technology to manufacture a broad range of synthetic DNA-based products, including synthetic genes, tools for next-generation sequencing (NGS) preparation, and antibody libraries for drug discovery and development. Twist is also pursuing longer-term opportunities in digital data storage in DNA and biologics drug discovery. Twist makes products for use across many industries including healthcare, industrial chemicals, agriculture and academic research. Follow us on Twitter | Facebook | LinkedIn | YouTube About CENTOGENE CENTOGENE’s mission is to provide data-driven, life-changing answers to patients, physicians, and pharma companies for rare and neurodegenerative diseases. We integrate multiomic technologies with the CENTOGENE Biodatabank – providing dimensional analysis to guide the next generation of precision medicine. Our unique approach enables rapid and reliable diagnosis for patients, supports a more precise physician understanding of disease states, and accelerates and de-risks targeted pharma drug discovery, development, and commercialization. Since our founding in 2006, CENTOGENE has been offering rapid and reliable diagnosis – building a network of approximately 30,000 active physicians. Our ISO, CAP, and CLIA certified multiomic reference laboratories in Germany utilize Phenomic, Genomic, Transcriptomic, Epigenomic, Proteomic, and Metabolomic datasets. This data is captured in our CENTOGENE Biodatabank, with nearly 700,000 patients represented from over 120 highly diverse countries, over 70% of whom are of non-European descent. To date, the CENTOGENE Biodatabank has contributed to generating novel insights for more than 260 peer-reviewed publications. By translating our data and expertise into tangible insights, we have supported over 50 collaborations with pharma partners. Together, we accelerate and de-risk drug discovery, development, and commercialization in target & drug screening, clinical development, market access and expansion, as well as offering CENTOGENE Biodatabank Licenses and Insight Reports to enable a world healed of all rare and neurodegenerative diseases. To discover more about our products, pipeline, and patient-driven purpose, visit and follow us on LinkedIn. Twist Bioscience Legal Notice Regarding Forward-Looking Statements This press release contains forward-looking statements. All statements other than statements of historical facts contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the ability of the Twist Alliance CNTG Exome Panel to enable whole exome analysis of genetic markers relevant to rare diseases; the ability of the Twist Alliance CNTG Rare Disease Panel to offer analysis of focused rare-disease-related sequences; and the ability of the Twist Alliance CNTG Hereditary Oncology Panel to enable the detection of biomarkers that indicate a high risk of developing cancer. 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