Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies

Simone Weiss; Philippe Lamy; Maria Rusan; Maibritt Nørgaard; Benedicte Parm Ulhøi; Michael Knudsen; Christine Gaasdal Kassentoft; Leila Farajzadeh; Jørgen Bjerggaard Jensen; Jakob Skou Pedersen; Michael Borre; Karina Dalsgaard Sørensen

doi:10.1002/ijc.34949

Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies

Simone Weiss, Philippe Lamy, Maria Rusan, Maibritt Nørgaard, Benedicte Parm Ulhøi, Michael Knudsen, Christine Gaasdal Kassentoft, Leila Farajzadeh, Jørgen Bjerggaard Jensen, Jakob Skou Pedersen, Michael Borre, Karina Dalsgaard Sørensen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

1 Citation (Scopus)

Abstract

Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-naïve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

Original language	English
Journal	International Journal of Cancer
Volume	155
Issue	2
Pages (from-to)	298-313
Number of pages	16
ISSN	0020-7136
DOIs	https://doi.org/10.1002/ijc.34949
Publication status	Published - Jul 2024

Keywords

ctDNA
genomics
liquid biopsies
prostate cancer
whole-genome sequencing
Prostatic Neoplasms/genetics
Circulating Tumor DNA/genetics
Humans
Middle Aged
Male
Genomics/methods
Biomarkers, Tumor/genetics
DNA Copy Number Variations
Liquid Biopsy/methods
Aged, 80 and over
Aged
Whole Genome Sequencing/methods
Mutation

Access to Document

10.1002/ijc.34949Licence: CC BY-NC-ND

Cite this

Weiss, S., Lamy, P., Rusan, M., Nørgaard, M., Ulhøi, B. P., Knudsen, M., Kassentoft, C. G., Farajzadeh, L., Jensen, J. B., Pedersen, J. S., Borre, M., & Sørensen, K. D. (2024). Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies. International Journal of Cancer, 155(2), 298-313. https://doi.org/10.1002/ijc.34949

@article{2a3f9d468e044ea0b6ff779246c4eeec,

title = "Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies",

abstract = "Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-na{\"i}ve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.",

keywords = "ctDNA, genomics, liquid biopsies, prostate cancer, whole-genome sequencing, Prostatic Neoplasms/genetics, Circulating Tumor DNA/genetics, Humans, Middle Aged, Male, Genomics/methods, Biomarkers, Tumor/genetics, DNA Copy Number Variations, Liquid Biopsy/methods, Aged, 80 and over, Aged, Whole Genome Sequencing/methods, Mutation",

author = "Simone Weiss and Philippe Lamy and Maria Rusan and Maibritt N{\o}rgaard and Ulh{\o}i, {Benedicte Parm} and Michael Knudsen and Kassentoft, {Christine Gaasdal} and Leila Farajzadeh and Jensen, {J{\o}rgen Bjerggaard} and Pedersen, {Jakob Skou} and Michael Borre and S{\o}rensen, {Karina Dalsgaard}",

year = "2024",

month = jul,

doi = "10.1002/ijc.34949",

language = "English",

volume = "155",

pages = "298--313",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "John Wiley & Sons Inc.",

number = "2",

}

Weiss, S, Lamy, P , Rusan, M, Nørgaard, M, Ulhøi, BP, Knudsen, M , Kassentoft, CG, Farajzadeh, L, Jensen, JB , Pedersen, JS , Borre, M & Sørensen, KD 2024, 'Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies', International Journal of Cancer, vol. 155, no. 2, pp. 298-313. https://doi.org/10.1002/ijc.34949

Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies. / Weiss, Simone; Lamy, Philippe ; Rusan, Maria et al.
In: International Journal of Cancer, Vol. 155, No. 2, 07.2024, p. 298-313.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies

AU - Weiss, Simone

AU - Lamy, Philippe

AU - Rusan, Maria

AU - Nørgaard, Maibritt

AU - Ulhøi, Benedicte Parm

AU - Knudsen, Michael

AU - Kassentoft, Christine Gaasdal

AU - Farajzadeh, Leila

AU - Jensen, Jørgen Bjerggaard

AU - Pedersen, Jakob Skou

AU - Borre, Michael

AU - Sørensen, Karina Dalsgaard

PY - 2024/7

Y1 - 2024/7

N2 - Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-naïve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

AB - Treatment resistance remains a major issue in aggressive prostate cancer (PC), and novel genomic biomarkers may guide better treatment selection. Circulating tumor DNA (ctDNA) can provide minimally invasive information about tumor genomes, but the genomic landscape of aggressive PC based on whole-genome sequencing (WGS) of ctDNA remains incompletely characterized. Thus, we here performed WGS of tumor tissue (n = 31) or plasma ctDNA (n = 10) from a total of 41 aggressive PC patients, including 11 hormone-naïve, 15 hormone-sensitive, and 15 castration-resistant patients. Across all variant types, we found progressively more altered tumor genomic profiles in later stages of aggressive PC. The potential driver genes most frequently affected by single-nucleotide variants or insertions/deletions included the known PC-related genes TP53, CDK12, and PTEN and the novel genes COL13A1, KCNH3, and SENP3. Etiologically, aggressive PC was associated with age-related and DNA repair-related mutational signatures. Copy number variants most frequently affected 14q11.2 and 8p21.2, where no well-recognized PC-related genes are located, and also frequently affected regions near the known PC-related genes MYC, AR, TP53, PTEN, and BRCA1. Structural variants most frequently involved not only the known PC-related genes TMPRSS2 and ERG but also the less extensively studied gene in this context, PTPRD. Finally, clinically actionable variants were detected throughout all stages of aggressive PC and in both plasma and tissue samples, emphasizing the potential clinical applicability of WGS of minimally invasive plasma samples. Overall, our study highlights the feasibility of using liquid biopsies for comprehensive genomic characterization as an alternative to tissue biopsies in advanced/aggressive PC.

KW - ctDNA

KW - genomics

KW - liquid biopsies

KW - prostate cancer

KW - whole-genome sequencing

KW - Prostatic Neoplasms/genetics

KW - Circulating Tumor DNA/genetics

KW - Humans

KW - Middle Aged

KW - Male

KW - Genomics/methods

KW - Biomarkers, Tumor/genetics

KW - DNA Copy Number Variations

KW - Liquid Biopsy/methods

KW - Aged, 80 and over

KW - Aged

KW - Whole Genome Sequencing/methods

KW - Mutation

UR - http://www.scopus.com/inward/record.url?scp=85190432859&partnerID=8YFLogxK

U2 - 10.1002/ijc.34949

DO - 10.1002/ijc.34949

M3 - Journal article

C2 - 38602058

SN - 0020-7136

VL - 155

SP - 298

EP - 313

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 2

ER -

Exploring the tumor genomic landscape of aggressive prostate cancer by whole-genome sequencing of tissue or liquid biopsies

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this