ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA
Abstract Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in s...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-04-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-023-01171-w |
| _version_ | 1797840906423894016 |
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| author | Ariana Huebner James R. M. Black Francesca Sarno Roberto Pazo Ignacio Juez Laura Medina Rocio Garcia-Carbonero Carmen Guillén Jaime Feliú Carolina Alonso Carlota Arenillas Ana Belén Moreno-Cárdenas Helena Verdaguer Teresa Macarulla Manuel Hidalgo Nicholas McGranahan Rodrigo A. Toledo |
| author_facet | Ariana Huebner James R. M. Black Francesca Sarno Roberto Pazo Ignacio Juez Laura Medina Rocio Garcia-Carbonero Carmen Guillén Jaime Feliú Carolina Alonso Carlota Arenillas Ana Belén Moreno-Cárdenas Helena Verdaguer Teresa Macarulla Manuel Hidalgo Nicholas McGranahan Rodrigo A. Toledo |
| author_sort | Ariana Huebner |
| collection | DOAJ |
| description | Abstract Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy. |
| first_indexed | 2024-04-09T16:21:14Z |
| format | Article |
| id | doaj.art-21716a2b02ec46eb8dbe1a817c4a0bab |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-09T16:21:14Z |
| publishDate | 2023-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-21716a2b02ec46eb8dbe1a817c4a0bab2023-04-23T11:24:29ZengBMCGenome Medicine1756-994X2023-04-0115111510.1186/s13073-023-01171-wACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNAAriana Huebner0James R. M. Black1Francesca Sarno2Roberto Pazo3Ignacio Juez4Laura Medina5Rocio Garcia-Carbonero6Carmen Guillén7Jaime Feliú8Carolina Alonso9Carlota Arenillas10Ana Belén Moreno-Cárdenas11Helena Verdaguer12Teresa Macarulla13Manuel Hidalgo14Nicholas McGranahan15Rodrigo A. Toledo16Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstituteCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstitutePeaches BiotechHospital Universitario Miguel ServetHospital Universitario de FuenlabradaIBIMAHospital Universitario 12 de OctubreHospital Universitario Ramón Y CajalHospital Universitario La PazPeaches BiotechVall d’Hebron Institute of Oncology (VHIO)Vall d’Hebron Institute of Oncology (VHIO)Vall d’Hebron Institute of Oncology (VHIO)Vall d’Hebron Institute of Oncology (VHIO)Weill Cornell MedicineCancer Research UK Lung Cancer Centre of Excellence, University College London Cancer InstituteVall d’Hebron Institute of Oncology (VHIO)Abstract Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.https://doi.org/10.1186/s13073-023-01171-wPancreatic cancerTumour evolutionIntra-tumour heterogeneityctDNACopy numbercfDNA |
| spellingShingle | Ariana Huebner James R. M. Black Francesca Sarno Roberto Pazo Ignacio Juez Laura Medina Rocio Garcia-Carbonero Carmen Guillén Jaime Feliú Carolina Alonso Carlota Arenillas Ana Belén Moreno-Cárdenas Helena Verdaguer Teresa Macarulla Manuel Hidalgo Nicholas McGranahan Rodrigo A. Toledo ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA Genome Medicine Pancreatic cancer Tumour evolution Intra-tumour heterogeneity ctDNA Copy number cfDNA |
| title | ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA |
| title_full | ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA |
| title_fullStr | ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA |
| title_full_unstemmed | ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA |
| title_short | ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA |
| title_sort | act discover identifying karyotype heterogeneity in pancreatic cancer evolution using ctdna |
| topic | Pancreatic cancer Tumour evolution Intra-tumour heterogeneity ctDNA Copy number cfDNA |
| url | https://doi.org/10.1186/s13073-023-01171-w |
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