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Branching copy number evolution and parallel immune profiles across the regional tumor space of resected pancreatic cancer

Petersson, Alexandra LU ; Andersson, Natalie LU orcid ; Olsson Hau, Sofie LU ; Eberhard, Jakob LU ; Karlsson, Jenny LU ; Chattopadhyay, Subhayan LU orcid ; Valind, Anders LU orcid ; Elebro, Jacob LU ; Nodin, Björn LU and Leandersson, Karin LU orcid , et al. (2022) In Molecular Cancer Research 20(5). p.749-761
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution... (More)
Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double immunohistochemical staining. Copy number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, a FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated PDAC patients. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected.Implications: Evolutionary copy number patterns may be associated with survival in patients with resected PDAC. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
20
issue
5
pages
749 - 761
publisher
American Association for Cancer Research
external identifiers
  • pmid:35149544
  • scopus:85129996680
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-21-0986
language
English
LU publication?
yes
id
0b4b3a4c-3a0b-4b9d-bbe2-25b308f7b428
date added to LUP
2022-02-15 20:08:51
date last changed
2024-01-29 02:52:08
@article{0b4b3a4c-3a0b-4b9d-bbe2-25b308f7b428,
  abstract     = {{Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. The only option for curative treatment is resection of the tumor followed by standard adjuvant chemotherapy. Yet, early relapse due to chemoresistance is almost inevitable. Herein, we delineated the genetic intratumor heterogeneity in resected PDAC, with the aim to identify evolutionary patterns that may be associated with overall survival (OS) following treatment with curative intent. Potential relationships with the adjacent immune microenvironment were also examined. The genetic and immune landscapes of the regional tumor space were analyzed in nine patients with resected PDAC. Targeted deep sequencing and genome wide SNP array were followed by clonal deconvolution and phylogenetic analysis. A mathematical complexity score was developed to calculate the network extent of each phylogeny. Spatial variation in abundancy and tumor nest infiltration of immune cells was analyzed by double immunohistochemical staining. Copy number heterogeneity was denoted as the major contributing factor to the branching architectures of the produced phylogenetic trees. Increased tree complexity was significantly inversely associated with OS, and larger regional maximum aberrations (higher treetops) were associated with increased PD-L1 expression on tumor cells. Contrastingly, a FREM1 gene amplification, found in one patient, coincided with a particularly vigorous immune response. Findings from this limited case series suggest that complex evolutionary patterns may be associated with a shorter survival in surgically treated PDAC patients. Some hypothesis-generating associations with the surrounding immune microenvironment were also detected.Implications: Evolutionary copy number patterns may be associated with survival in patients with resected PDAC.}},
  author       = {{Petersson, Alexandra and Andersson, Natalie and Olsson Hau, Sofie and Eberhard, Jakob and Karlsson, Jenny and Chattopadhyay, Subhayan and Valind, Anders and Elebro, Jacob and Nodin, Björn and Leandersson, Karin and Gisselsson Nord, David and Jirström, Karin}},
  issn         = {{1557-3125}},
  language     = {{eng}},
  month        = {{05}},
  number       = {{5}},
  pages        = {{749--761}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Research}},
  title        = {{Branching copy number evolution and parallel immune profiles across the regional tumor space of resected pancreatic cancer}},
  url          = {{http://dx.doi.org/10.1158/1541-7786.MCR-21-0986}},
  doi          = {{10.1158/1541-7786.MCR-21-0986}},
  volume       = {{20}},
  year         = {{2022}},
}