Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features

Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome...

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Hauptverfasser: Srinivasa Rao Rao, Verrill, Clare, Cerundolo, Lucia, Nasullah Khalid Alham, Kaya, Zeynep, O'hanlon, Miriam, Hayes, Alicia, Lambert, Adam, James, Martha, Tullis, Iain D C, Niederer, Jane, Lovell, Shelagh, Altan Omer, Lopez, Francisco, Leslie, Tom, Buffa, Francesca M, Bryant, Richard John, Lamb, Alastair D, Vojnovic, Boris, Wedge, David C, Mills, Ian G, Woodcock, Dan J, Tomlinson, Ian Pm, Hamdy, Freddie C
Format: Paper
Sprache:Englisch
Veröffentlicht: Cold Spring Harbor Cold Spring Harbor Laboratory Press 27.02.2023
Cold Spring Harbor Laboratory
Ausgabe:1.2
Schlagworte:
Adenocarcinoma
Cancer Biology
Copy number
Evolution
Genetic transformation
Genomes
Lymph nodes
Lymphatic system
Metastases
Metastasis
Morphology
Prostate cancer
Prostatectomy
Seminal vesicle
Tumors
Vesicles
Whole genome sequencing
ISSN:2692-8205, 2692-8205
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Abstract Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes. Based on these data, we delineated the route of tumour progression and metastasis following the transformation of adenocarcinoma to amphicrine morphology, the molecular events leading to whole genome duplication associated with a single clonal expansion and identified putative driver events associated with local invasion and lymph node metastasis. We also correlated genomic changes associated with differences in morphology and identified putative driver events associated with spread to seminal vesicle invasion and lymph node metastasis. Taken together, these findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes associated with morphological transformation. Our results demonstrate the value of integrating multi-region sequencing with histopathological data to study tumour evolution and identify mechanisms of prostate cancer spread.Competing Interest StatementThe authors have declared no competing interest.
AbstractList Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes. Based on these data, we delineated the route of tumour progression and metastasis following the transformation of adenocarcinoma to amphicrine morphology, the molecular events leading to whole genome duplication associated with a single clonal expansion and identified putative driver events associated with local invasion and lymph node metastasis. We also correlated genomic changes associated with differences in morphology and identified putative driver events associated with spread to seminal vesicle invasion and lymph node metastasis. Taken together, these findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes associated with morphological transformation. Our results demonstrate the value of integrating multi-region sequencing with histopathological data to study tumour evolution and identify mechanisms of prostate cancer spread.
Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The emergence and evolution of cancer clones at this early stage of expansion and spread has not been studied in detail. We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes. Based on these data, we delineated the route of tumour progression and metastasis following the transformation of adenocarcinoma to amphicrine morphology, the molecular events leading to whole genome duplication associated with a single clonal expansion and identified putative driver events associated with local invasion and lymph node metastasis. We also correlated genomic changes associated with differences in morphology and identified putative driver events associated with spread to seminal vesicle invasion and lymph node metastasis. Taken together, these findings have implications for diagnosis and risk stratification, in addition to providing a rationale for further studies to characterise the genetic changes associated with morphological transformation. Our results demonstrate the value of integrating multi-region sequencing with histopathological data to study tumour evolution and identify mechanisms of prostate cancer spread.Competing Interest StatementThe authors have declared no competing interest.
Author Woodcock, Dan J
Lambert, Adam
Srinivasa Rao Rao
Lovell, Shelagh
Lopez, Francisco
Bryant, Richard John
Verrill, Clare
Leslie, Tom
Mills, Ian G
Tomlinson, Ian Pm
Lamb, Alastair D
Kaya, Zeynep
Altan Omer
James, Martha
Wedge, David C
Nasullah Khalid Alham
Hamdy, Freddie C
O'hanlon, Miriam
Tullis, Iain D C
Cerundolo, Lucia
Hayes, Alicia
Niederer, Jane
Buffa, Francesca M
Vojnovic, Boris
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Cites_doi 10.1038/s41568-020-0290-x
10.1002/pros.24497
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2023, Posted by Cold Spring Harbor Laboratory
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Snippet Extension of prostate cancer beyond the primary site into the surrounding organs by local invasion or nodal metastasis is associated with poor prognosis. The...
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SubjectTerms Adenocarcinoma
Cancer Biology
Copy number
Evolution
Genetic transformation
Genomes
Lymph nodes
Lymphatic system
Metastases
Metastasis
Morphology
Prostate cancer
Prostatectomy
Seminal vesicle
Tumors
Vesicles
Whole genome sequencing
Title Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features
URI https://www.proquest.com/docview/2780240303
https://www.biorxiv.org/content/10.1101/2023.02.27.530113
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