Group Leader @emblebi | Former postdoc in @getz_lab @broadinstitute | Former PhD student @sangerinstitute | Lineage tracing, cancer genomics, human development
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Very happy and excited to announce that I'll be starting my own research group at @emblebi! The group will focus on lineage tracing, somatic evolution and the origins of cancer. Interested in doing a postdoc in the group or know someone who is? Please reach out!
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Very proud and excited that our work on placental genomics has now been published by @nature! The placenta is an absolutely fascinating organ in terms of the genomic stories told through its mutations.
A little thread below, if you missed the pre-print.
nature.com/articles/s41586-0…
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Very excited to see our study on a case of ALL to AML switch after CAR-T treatment out in @NatureCancer! Using deep genome sequencing, we show the cancer switched cell types to escape therapy.
@broadinstitute @sangerinstitute @getz_lab
Thread below 🧵
nature.com/articles/s43018-0…
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How does a single cell generate different organs and tissues of the human body? Do early cells contribute equally? Do embryonic patterns differ between people? Sequencing normal cells reveals the developmental stories hidden in their DNA @NaturePortfolio nature.com/articles/s41586-0…
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Very excited to share our latest preprint on somatic mutations in the normal stomach. We found many surprises, incl. hypermutant glands, recurrent somatic trisomies and a unique landscape of driver mutations. Thread below! biorxiv.org/content/10.1101/…
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Delighted to share our first preprint of the year: sequencing somatic mutations in human placentas, where we find early lineage segregation, highly clonal development and extensive mutagenesis in this unique organ. Bear with me, it's a wild ride [1/16]
biorxiv.org/content/10.1101/…
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Very excited to release Sequoia, our pipeline for phylogenetic tree reconstruction from mutations in normal cells. A detailed description is now published in @NatureProtocols! nature.com/articles/s41596-0…
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Our latest paper is out today in NEJM! Together with Sam Behjati, I explored the origins of bilateral neuroblastoma from somatic mutations. [1/6]
nejm.org/doi/full/10.1056/NE…
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Very excited to share our latest preprint! By sequencing many different microbiopsies of many different organs from a few individuals, we built large phylogenetic trees of human development [1/12]
biorxiv.org/content/10.1101/…
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Very happy and excited to have been awarded an @EMBO Postdoctoral Fellowship! Will continue working in the @getz_lab at the @broadinstitute on cancer genomics and using mutations for lineage tracing. 🥳🍾
Time to celebrate! 🥳
We are announcing 134 @EMBO Postdoctoral Fellowships of the Spring 2022 round. Congratulations!
Awardees are listed here: embo.org/funding/fellowships…
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Our paper on the origins of malignant rhabdoid tumours is out now in @NatureComms! A very nice collaboration between @prinsesmaximac and @sangerinstitute. Some findings, explanations and musings below.
nature.com/articles/s41467-0…
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Very excited to share our latest preprint! Read all about the effect of germline DNA polymerase mutations on somatic mutations in normal tissues. Great work with Phil Robinson, @clpalles, @imartincorena, Ian Tomlinson, Mike Stratton & many many more [1/6]
biorxiv.org/content/10.1101/…
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Really happy to see our review article on somatic and germline variation out in @NatureRevGenet! Great effort with amazing team of superstars @ZhiYu_ACGT, @M_Mesbah_Uddin, Kristin Ardlie, @nialljlennon and @pnatarajanmd.
Our review article is out!🎉
Grateful for the chance @NatureRevGenet @pnatarajanmd to delve into the similarities, differences, and interplay between somatic and germline mutations🧬with super talented @TimCoorens!
Also, thank @haertl17 for the dedication in handling the review!
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After an amazing few years doing my PhD at the @sangerinstitute, I've now moved across an ocean to start my postdoc at the @broadinstitute in the @getz_lab. Very excited for this next adventure in a new Cambridge, but want to take this opportunity to thank a few people.
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Our new perspective article describing the human and non-human primate developmental GTEx projects is now out in @Nature! We outline the scope, vision, opportunities and challenges of these projects here:
nature.com/articles/s41586-0…
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1/Chemotherapy-related blood cancers are a major challenge in treating childhood cancers, affecting 7 to 11% of children treated for high-risk neuroblastoma. In our new case report in @BloodJournal, we trace the origins of therapy-related myeloid neoplasms
ashpublications.org/blood/ar…
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Very excited that our paper on the embryonic origins of childhood kidney cancer is out! Read all about it here:
science.sciencemag.org/conte…
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Spread the word! Registration for the "Mutations in Time and Space" conference is open. The meeting is all about the origins, patterns, and consequences of mutations across cells, individuals, populations, species. Abstract submission deadline: Jan 17th broadinstitute.swoogo.com/mi…...
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Also very thoughtful of @nature to make the publication coincide with my birthday. It'll make the celebratory drink taste even better.
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The abstract deadline for "Mutations in Time and Space 2025" is in a week! Please register here: broadinstitute.swoogo.com/mi…
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Our latest work on elevated mutation loads in normal tissues of patients with germline polymerase mutations is now out in @NatureGenet! See this amazing thread by @drphilrobinson for more information.
Delighted to share our paper
➡️Increased somatic mutation burdens in normal human cells due to defective DNA polymerases
go.nature.com/3kUQVJy
Implications for our understanding of cancer risk and the somatic mutation theory of #ageing
🧵⬇️
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Why is the placenta interesting? 1) It's derived from cells that don't form the embryo, so we can look at early lineages 2) It often has confined placental mosaicism, aneuploidies absent from the fetus 3) It's a temporary organ, maybe no pressure to keep mutation rate low
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If you're at #AACR22 and want to chat about how normal stomach cells mutate and becomes cancer (or just want to hang out), head to poster 5 in section 11 this afternoon!
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These last few years have been so much fun, thanks to so many great colleagues and friends. A recent group photo @imartincorena @ATJCagan @_Luke_MRH_ @andrewrjlawson @PrzybillaMoritz @RuxandraTesloi1 @sciencejannat @EllieDunstone @AbascalFed, with @nbrzozowska961 taking the photo
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A very special thanks to @sciencejannat, who stood by my side through all this and has just handed in her own thesis! Very proud and immensely grateful to have such an amazing friend
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Another beautiful study on tracing early human development from somatic mutations, with stunning insights. Huge congrats @doctor_msc! Very happy to have been able to contribute a little to this.
1/ How do our bodies – with their incredible complexity - come from a single fertilised egg? How is it co-ordinated? What tissues come from what? Why (and how) might it go wrong? These are the questions we asked in our study out in @nature this week.
doi.org/10.1038/s41586-021-0…
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Taken together, because of its early segregation, highly clonal evolution and extensive mutagenesis, the placenta naturally exhibits a very high degree of confined mosaicism. Maybe because it's a temporary organ, it tolerates one of the highest mutation rates seen so far.
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Lastly, I just want to thank everyone involved that has made this part of my PhD so enjoyable and interesting, especially Mike Stratton, @luiza_moore, @imartincorena, @R_Rahbari, @ATJCagan, @drphilrobinson, @PrzybillaMoritz, @andrewrjlawson, @RasheshSanghvi and so many others.
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Fantastic to see this study out and very happy I could be a part of it! We have gained new insights on symmetry breaking during early human embryonic development. Congrats to @matteo_mole @Marta_Shahbazi @A_Weberling @BailWeatherbee @roserventotormo
Our study on human embryos identifying the symmetry breaking event to specify anterior is out! Thanks to my wonderful lab,superb collaborators,parents who donated embryos @MZG_Lab @roserventotormo @TimCoorens@Cambridge_Uni nature.com/articles/s41467-0…
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Check out this absolutely amazing work by @ATJCagan @imartincorena and many others on the somatic mutation rate across many different species. Already a classic. Many congrats!
Incredibly excited to share our paper ‘Somatic mutation rates scale with lifespan across mammals’ now published @nature.
nature.com/articles/s41586-0…
An illustrated & updated tweetorial… [1/24]
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Another fun example of inferring human development from somatic mutations! And completely impossible without Thomas Oliver, Steve Charnock-Jones, Gordon Smith and Sam Behjati. With help from many people including @RasheshSanghvi, @roserventotormo, @Muzz_Haniffa, @R_Rahbari
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There are so many more colleagues/friends to thank for collaborations, support, crosswords and great times @redtbutler @heatherEmachado @R_Rahbari @drphilrobinson @luiza_moore @RasheshSanghvi @doctor_msc @Emily_LMitchell @nathanielDA_PhD @constantAmateur @GerdaKild
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This enhances our picture of asymmetric lineage contribution in early embryogenesis and provides another common way for embryo and placenta to completely segregate as early as the first cell division. This of course echoes the beautiful work done by Magda
@ZernickaGoetz
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Thanks, Pradeep! And many thanks to the other speakers @SChoudhury_Phd @KathleenHBurns @ChrisAWalsh1 for an amazing session
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Another study on clonal dynamics in embryogenesis from somatic mutations completes the triad this week. Many congrats to @GenomeDoctor, @psy700 and colleagues! It’s been a privilege seeing these projects develop side by side
nature.com/articles/s41586-0…
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Our first surprise: even a bulk biopsy of placenta is (mono)clonal! We find 145 SNVs with a median VAF of 0.24 per bulk sample. Completely different from other bulk tissues so far, which are far too polyclonal to call SNVs. Also minimal sharing between placental biopsies.
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We were lucky to directly observe the consequences of this with another surprising finding: a mosaic trisomic rescue of chr10! The child inherited two maternal copies, but lost the paternal one completely in umbilical cord (and embryo). The trisomy is abundant in placenta.
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This can also explain the phenomenon of confined placental mosaicism: it is a consequence of the natural development and mutagenesis of the placenta.
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I want to thank my de facto triumvirate of supervisors: Mike Stratton, @imartincorena and Sam Behjati. Incredibly grateful for all the opportunities, guidance and lessons (from colour schemes to beta-binomial distributions) and making the PhD so productive, varied and interesting
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This means there was an early reversal of the trisomy through loss of an extra copy of 10. The trisomic cells are purged (selection?) from the embryonic lineage (the child is completely fine), but are tolerated in the placenta, resulting in confined placental mosaicism.
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Because we used the LCM approach, we can map these driver clones to their location in tissues, which reveals expansions of mutant clones and local selective pressures. We find three CTNNB1 mutant clones right next to one another, rather than evenly distributed.
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We even found an early case of segregation of DNA damage in vivo! Echoing the work by @S_J_Aitken et al. Sister lineages with different mutations at the same site, one a C>A and one a C>T, indicating unrepaired damage passed on during cell division
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Just want to thank everyone involved that has made this part of my PhD so enjoyable and interesting, especially Mike Stratton, @luiza_moore, @imartincorena, @R_Rahbari, @ATJCagan and many many others [12/12]
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Intriguingly, these trisomies happen multiple times in the same donor, with different alleles amplified. In one case, we found trisomies in 9 of 12 glands sampled. Timing analysis shows these all happened around the same time, suggesting a sudden burst or selective advantage.
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This day is extra special because of the twin publication on the landscape of somatic mutations, also out in @NaturePortfolio! It dives into mutational processes and burdens in adult life, and the remarkable differences between soma and germline.
nature.com/articles/s41586-0…
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Together, this paints a picture of the placenta seeded by single cells very early in embryogenesis which grow out to be a mosaic of huge clonal patches. A bit like a balloon blowing up. Any SNVs (or aneuploidies) acquired along the way, will be present in a large patch.
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All in all, this shows that some childhood cancers have their origins very early in development, just about when the embryo starts forming.
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Our data consists of placentas from 42 pregnancies, for each we sampled multiple quadrants, either for bulk WGS or laser capture microdissection. We also had umbilical cord (a proxy for the inner cell mass/embryonic lineage) and maternal DNA.
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Lastly, the stomach also shows a rich landscape of driver mutations, most notably in epigenetic modifiers (ARID1A, ARID1B, KDM6A) and surprisingly inactivating mutations in CTNNB1 (unlike the activating ones observed in cancer).
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This comes amidst a huge boom of activity in mutation-based lineage tracing, with beautiful studies by @ChrisAWalsh1 , @doctor_msc, Flora Vaccarino and others. It’s amazing that, with different approaches and backgrounds, we converge on very similar results.
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The left and right tumour arise independently, but they undergo remarkably parallel convergent events, mostly shaped by germline predisposition. For example, a second hit in a tumour suppressor by independent LOH events (Chr19), as well as a recurrent trisomy (Chr7). [4/6]
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All cells accumulate mutations, starting when you're just a fertilised egg cell. This leaves a natural marker for all the descendants of cells. We might have inherited a single genome from our parents, but we instantly become a mosaic of genetic diversity.
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While this work explores early mutations and embryonic development, another preprint dives into adult tissue maintenance, mutational processes and burdens throughout adult life, and the remarkable differences between somatic and germline cells. [11/12] biorxiv.org/content/10.1101/…
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Neuroblastoma is a common childhood cancer that can manifest as multiple tumours in both adrenal glands. Whether these come from the same ancestral clone, represent metastases or arise completely independently was unknown. [2/6]
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Another fun example of inferring human development from somatic mutations! And completely impossible without Thomas Oliver, Steve Charnock-Jones, Gordon Smith and Sam Behjati. With help from many people including @RasheshSanghvi, @roserventotormo, @Muzz_Haniffa, @R_Rahbari
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All in all, this shows the embryonic patterns we can deduce from somatic mutations and highlights the variability across individuals. This variation could be due to strong genetic bottlenecks early in development. So much left to learn.
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We were lucky to directly observe the consequences of this with another surprising finding: a mosaic trisomic rescue of chr10! The child inherited two maternal copies, but lost the paternal one completely in umbilical cord (and embryo). The trisomy is abundant in placenta [12/16]
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The most surprising finding, however, comes from the CNVs in the stomach. We find extraordinarily high rates of somatic trisomies in the stomach, mostly of chrs 20 and 13, highly concentrated in a few patients.
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The AML lineage split off very early from the ALL relapse lineages. Chemotherapy-induced mutations show this split happened during initial treatment, nearly five years before CAR-T treatment and AML diagnosis! This hints at a reservoir of long-lived, persistent cancer clones
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Together, this paints a picture of the placenta seeded by single cells very early in embryogenesis which grow out to be a mosaic of huge clonal patches. A bit like a balloon blowing up. Any SNVs (or aneuploidies) acquired along the way, will be present in a large patch. [7/16]
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By looking at the somatic mutations from both left and right tumour in bulk blood of the same patient, we saw that each tumour shared mutations with blood not found in the other. This means that the tumours diverged very early in embryogenesis, before gastrulation. [3/6]
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We used targeted re-sequencing to look more into the development of the brain and found that there's a strong spatial spatial effect in the development of the cerebrum, hinting at how this organ developed just from the patterns of early mutations [7/12].
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The burden and VAFs weren't different between our normal placenta and those with some abnormalities (i.e. preeclampsia or low birthweight). We did find a huge contribution of signature 18, probably due to the heavy oxidative stress in the placenta.
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Congratulations and very interesting, @ZernickaGoetz and team! Very much looking forward to reading the paper in detail.
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Many thanks to all who have actively helped develop this pipeline over the years, including Nick Williams, @imartincorena, @jyoti_nangalia, Mike Stratton, Peter Campbell and especially @doctor_msc!
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The MRCA for most tissues is the zygote. We also found that different embryonic progenitor cells contribute in very different amounts to the adult body. These asymmetries differ drastically between individuals and sometimes even between tissues from the same individual. [4/12]
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The mutational signatures are mostly SBS1, SBS5 and SBS18, like other epithelial tissues. Hypermutant glands have much more SBS1 and SBS18, linked to inflammation, proliferation and oxidative stress, and many more indels linked to polymerase slippage/high rates of cell division.
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The distinction between a set of independent tumours and aggressive, spreading tumours is clinically very important. Without mets, less intensive treatment can be considered, with fewer side effects. Genomics can clarify the origins of these cancers and how to tackle them [5/6]
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I encourage you to read the paper! Many details and analyses in there, such as RAG-mediated deletions causing therapy resistance, an explosion of aneuploidy after late TP53 loss and convergent evolution in different clones.
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This mutational diversity can be used to retrace development. Cells sharing mutations share part of their development. Together, this becomes a large family tree of cell showing human development in action (root=zygote, internal node=ancestral cell, splits=cell divisions)
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Thanks to all the donors and their families for making this study possible. And many thanks to Grace Collord, @KSaebParsy, Peter Campbell, @imartincorena, SY Leung, Mike Stratton and all other co-authors.
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These patterns are even similar halfway across the world. Check out this very relevant and great preprint by @GenomeDoctor and colleagues delving into embryonic dynamics using somatic mutations [10/12]
biorxiv.org/content/10.1101/…
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This enhances our picture of asymmetric lineage contribution in early embryogenesis and provides another common way for embryo and placenta to completely segregate as early as the first cell division. This of course echoes the beautiful work done by Magda @ZernickaGoetz [11/16]
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These individuals don't show a premature ageing phenotype, besides early onset colorectal and endometrial cancer. These normal cells tolerate extremely high mutation rates. Hence, genome-wide mutation accumulation alone might not directly explain ageing. [6/6]
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We found lineages of primordial germ cells without sharing any mutations with any other tissues. This point towards somatic tissues experiencing a bottleneck that is not felt by the PGCs. Consistent with a contribution to PGCs from the amnion lineage?
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Congrats @landau_lab! Amazing to see this out and very much looking forward to reading in detail
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Sequoia addresses this through joint germline filtering and robust removal of overdispersed variants, tree building and mutation mapping to branches; enabling downstream analyses of signatures, human development and somatic evolution. Code available at github.com/TimCoorens/Sequoi…
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This case study shows how much we can learn from sequencing a cancer and its relapses in depth, especially now that genomic surveillance of childhood cancers enters the clinic. If we can predict therapy resistance, we can better treat patients and drastically improve outcomes.
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From genome sequencing paired with laser capture microdissection, we can build these large phylogenies of normal cells. There is a wealth of information encoded in these trees. I’ll outline a few observations of mosaic developmental patterns on the body-, organ- and tissue-level.
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Different embryonic cells contribute unequally to the adult body. These asymmetries differ drastically between individuals and even between tissues from the same individual, such as brain, colon, and testis from one patient -> different embryonic bottlenecks shape these lineages
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We used targeted re-sequencing to look more into the development of the brain and found that there's a strong spatial effect in the development of the cerebrum, hinting at how this organ developed just from the patterns of early mutations.
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All cells accumulate mutations over time, starting when you're just a fertilised egg. Mutations shared between different cells imply shared development. With enough mutations and enough samples from the same person, you can build a large family tree of cells [2/12].
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Since DNA is stable during our lives, we don’t need fetal or embryonic material. You can see what happens in the first divisions of life from adult samples. From the DNA of our 79yo patient, we can reconstruct what happened nearly eight decades ago in the womb.
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An advantage of the LCM approach is retaining spatial information. Using physical distances and genetic sharedness of colonic crypts from the same microbiopsy, we can deduce that a single embryonic progenitor cell seeds contiguous patches of ~ 300 colonic crypts
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And if anyone is at the @GeneticsSociety Meeting and wants to meet up and chat, feel free to reach out!
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The patient, a 3yo girl, developed B cell-ALL and was in remission for three years after initial chemotherapy. She then relapsed twice with ALL over the next years, was treated with anti-CD19 CAR-T cells and blinatumomab, only to relapse with a very aggressive AML.
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Yes! We think the ALL->AML switch happened before therapy, and treatment selected for AML by targeting the ALL. Nevertheless, the AML originates from the ALL and isn't an independent, second cancer
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Using the mutations in the primary ALL, relapsed ALL and AML samples, we saw that the AML was a direct descendant of the ALL, even retaining VDJ recombinations. The cancer had changed its cell type from lymphoid to myeloid and so escaped anti-CD19 therapy.
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To assess the early lineage allocation between trophectoderm (placenta) and inner cell mass (embryo), we used the umbilical cord (UC) DNA and looked for early mutations. In 19/42 pregnancies, UC and placenta share a MRCA, the zygote, with an asymmetric contribution in UC.
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From the LCM data it's clear that the trophoblasts cause the clonality we see in bulk: their median VAF is 0.39 and within each biopsy, they share ~53% of SNVs with other trophoblast clusters, far more than mesenchymal cores or normal tissues such as colon or endometrium
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We have been using the Sequoia framework to perform lineage tracing in normal tissues for many years now in many different projects. These range from inferring human development from mutations in adult tissues (nature.com/articles/s41586-0…) ...
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We are heavily indebted to the patient and her family.
Thanks to all co-authors for bringing this story together, especially Sam Behjati and @gaddyg
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Taken together, because of its early segregation, highly clonal evolution and extensive mutagenesis, the placenta naturally exhibits a very high degree of confined mosaicism. Maybe because it's a temporary organ, it tolerates one of the highest mutation rates seen so far. [15/16]
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Over recent years, we have studied mutations in normal tissues from clonal samples, through in vitro expansions and laser capture microdissection. However, early shared mutations often get confused for germline variant or recurrent artefacts, hampering phylogenetic inference.
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The lining of the stomach produces acid, and is the origin of stomach cancer, with many risk factors (diet, smoking, H. pylori infection). We used LCM to isolate and sequence normal stomach glands, from gastric cancer patients and non-cancer donors, from Hong Kong, the US and UK.
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