The Sequence 2/13-2/19
Bruce Willis’s Family Opens Up About His Diagnosis of Frontotemporal Dementia, AI for Reading Genomes, Polygenic Risk Scores and Chemotherapy Response, Glioblastoma Associated with Epigenetic Changes
Bruce Willis’s family opens up about his diagnosis of frontotemporal dementia
Frontotemporal dementia (FTD) is understood to be the most common cause of dementia for people under 60. It is characterized by dementia, unusual behaviors, emotional problems, trouble communicating, difficulty with work, or difficulty with walking. Symptoms usually begin between ages 40 and 60.
Alarmingly, FTD is frequently misdiagnosed, and many individuals with FTD are never given an accurate diagnosis. This rings true for Mr. Willis and his family, who shared his diagnosis of aphasia last year, and who only recently received the more specific and accurate diagnosis of FTD. In a joint statement with The Association for Frontotemporal Degeneration, Mr. Willis’s family said that since announcing Bruce’s diagnosis of aphasia in spring 2022, his condition progressed, and they received the diagnosis of FTD. They note that while painful, it is a relief to finally have a clear diagnosis.
FTD is caused by degeneration of the frontal and/or temporal lobes of the brain. Image credit: AFTD
So how is it diagnosed?
Genetic testing, an assessment of clinical symptoms and imaging are all used to help determine if someone has FTD or another cause for their symptoms. FTD occurs when abnormal proteins accumulate and clump together in brain cells called neurons. Some of the most common proteins that are known to accumulate and lead to FTD are called tau, TDP-43, and FUS. In some cases, these accumulations result from a mutation, or a harmful change in the DNA. While more than a dozen genetic variants are known to cause FTD, the most common are C9orf72, GRN, and MAPT.
What’s the takeaway?
For the purposes of this newsletter, a major part of the takeaway is the genetic component of this disorder. As pointed out earlier, FTD is often misdiagnosed, but sometimes family history can be a clue for a genetic disorder running in a family. Since FTD has such varying symptoms, familial FTD can look not only like a family history of dementia, but also a family history of a major psychiatric condition, or progressive challenges in movement. It’s important to be aware that 40 percent or more of FTD are known as familial. Although genetic testing for neurological conditions may not be standard everywhere, it’s worth a discussion with a physician if you suspect FTD in your family.
Importantly, there is no treatment for FTD. This ongoing research is something we can all help support. To end with a direct quote from Bruce Willis’s family, “Bruce always believed in using his voice in the world to help others, and to raise awareness about important issues both publicly and privately. ...Ours is just one family with a loved one who suffers from FTD, and we encourage others facing it to seek out the wealth of information and support available through AFTD (@theaftd, theaftd.org)”.
AI for reading genomes
Dalla-Torre et al. created an AI tool called the Nucleotide Transformer in order to study the efficacy of its ability to predict observable traits based on genetic sequences.
Tell me more.
Most genetic studies can be boiled down to one thing scientists are hoping to understand: genotype-phenotype correlation. This means, how does the DNA sequence (i.e. genotype) cause differences in observable traits (i.e. phenotype). Well, scientists are taking a hint from the chatGPT phenomenon to see if AI can similarly predict phenotype from genotype.
How? Let’s break it down: AI generally re-produces language by solving billions of cloze tests, which are tests in which one is asked to supply words that have been removed from a passage in order to measure comprehension of the text. This means that the computer is given sentences with some blanked-out words, and then is rewarded by suggesting the correct word to fill the gap. Think about using this approach, but for letters in genetic sequences instead of letters in sentences.
Interesting? Did it work?
Yes! Results showed that Nucleotide Transformer matched or outperformed on 11 of 18 prediction tasks, and up to 15 after fine-tuning. Not only that, but Nucleotide Transformer learned to pay attention to key elements of the genome such as parts that regulate gene expression.
What’s the takeaway?
Tools like Nucleotide Transformer have the potential to improve the prioritization of functional genetic variants in both clinical and research settings. This means greater understanding of genotype-phenotype correlations for different conditions, and getting more value and understanding out of genetic testing.
The utility of polygenic risk scores in predicting response to chemotherapy in patients with leukemia
A study by Elsayed et al. examined data on 177 participants being treated for acute myelogenous leukemia (AML) to evaluate the accuracy of polygenic risk scores in predicting their responses to different treatments for AML.
What is a polygenic risk score?
A polygenic risk score (PRS) is a number, or a ‘score’ that estimates an individual’s risk for a certain condition, or in this case a certain health outcome. They are used to predict health outcomes that are caused by changes in many genes, often coupled with environmental factors.
How are they determined?
Let’s use response to cancer treatment as an example, because that is the health outcome studied in this article. Scientists created PRSs for response to treatment by comparing the DNA of patients with different responses to cancer treatment to determine a ‘collection of genes’ that differ in the individuals with more positive versus more negative responses to treatment. Then, they can say if you have these ‘X’ number of genes, your PRS for response to cancer treatment is high or low.
In this particular study, patients with low scores were not able to efficiently convert one of the compounds of the treatment, called cytarabine, into a compound that helps to kill cancer cells. Those with high scores, conversely, were efficient activators of the compound cytarabine and able to achieve an anti-leukemic effect.
What did they find?
When patients with low scores were given combination therapies comprised of both clofarabine and cytarabine (that compound they can’t convert very well), they did significantly better compared with the patients with low scores who received only cytarabine. In contrast, in the group of patients with high scores, those on cytarabine did better than those who received the augmented therapy. Makes sense.
Taken together, this means the group did in fact find that genetically predicted risk for response to chemotherapy (i.e. based on PRS) added clinical value to the prediction of response to chemotherapy.
What's the takeaway?
The implementation of PRSs to predict responses to chemotherapy may have significant impact on clinical management for patients with AML. Furthermore, it may have a significant impact on patients with African ancestry with AML. In the team's analysis, patients with African ancestry were much more likely to have low scores than patients with Caucasian ancestry. This PRS may even contribute toward understanding the observed racial disparities in outcomes of different clinical trials of chemotherapy in patients with AML.
Want to see more news on PRS? This article describes positive response to using PRS in embryos
Glioblastoma associated with reparable epigenetic changes
Sun et al. studied tumor genome sequence data (genetics of the actual tumors) for more than 450 cases of glioblastoma, a type of brain cancer, in order to understand whether epigenetic changes may explain brain cancer growth in these individuals.
Why? Well, in most brain cancers, you will find mutations in the TP53 gene. This makes sense, because TP53 is a tumor suppressor, meaning if it has a mutation and it no longer works properly, tumors grow. TP53 mutations are found in the majority of brain cancers, except in glioblastoma.
Epigenetic what?
Epigenetics is the study of how the environment can cause changes that affect the way genes work.
It goes like this: Our DNA is made up of genes, and those genes are made up of a string of letters that act as a code, or like an alphabet, that tells our bodies how to grow and develop. While usually in genetics we are talking about conditions being caused from changes in those letters, called pathogenic genetic variants or mutations, epigenetics is talking about conditions being caused from the genetic code being activated or silenced. Epigenetic changes affect gene expression to turn genes “on” and “off”. In this case, then, we’re looking at whether brain cancer can be caused by the expression or silencing of certain genes.
Cool. What did they find?
After comparing tumors with and without TP53 mutations, the team narrowed in on a different gene, called BRD8, a gene that has regulatory functions like TP53. Specifically, they noticed that increased BRD8 expression interferes with TP53's typical tumor suppressor role.
In this article, one of the paper authors explains "It's like BRD8 is saying 'NO ENTRY' to TP53's tumor-preventing power, but when we hit BRD8 in the right way — go in there almost like a scalpel, but molecularly — the tumor is annihilated".
Interesting. What’s the takeaway?
It is! This study is among many that are beginning to understand more complex systems of the genome involved in cancer tumor growth. This is very important, because the now easy-to-spot single gene mutations (See my post here explaining very-well-understood founder variants in BRCA1 and BRCA2) only scratch the surface of how tumors develop. Research like this allows us to be able to more accurately test for the causes of cancer and eventually treat it. In fact, researchers in this study speculate a certain type of treatment called a bromodomain inhibitor may remove the epigenetic block on TP53 activity in a future treatment.
Want to see more news on new findings in cancer genetics?
This study identified a mechanism of repeat expansion, also potentially treatable, for kidney cancer
Also, clinical genetics research hub Geisinger is Offering Prophylactic Thyroidectomy to Patients with Cancer-Linked RET Variants