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Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis

Siesing, Christina LU ; Petersson, Alexandra LU ; Ulfarsdottir, Thora ; Chattopadhyay, Subhayan LU orcid ; Nodin, Björn LU ; Eberhard, Jakob LU ; Brändstedt, Jenny LU ; Syk, Ingvar LU ; Gisselsson Nord, David LU and Jirström, Karin LU orcid (2022) In Modern Pathology 35(7). p.979-988
Abstract
In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who... (More)
In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients. (Less)
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author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Modern Pathology
volume
35
issue
7
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85124753727
  • pmid:35169225
ISSN
1530-0285
DOI
10.1038/s41379-022-01012-y
language
English
LU publication?
yes
id
226cc6f1-4db2-4699-8803-09bc16e66394
date added to LUP
2022-03-28 10:33:49
date last changed
2024-01-29 02:52:40
@article{226cc6f1-4db2-4699-8803-09bc16e66394,
  abstract     = {{In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients.}},
  author       = {{Siesing, Christina and Petersson, Alexandra and Ulfarsdottir, Thora and Chattopadhyay, Subhayan and Nodin, Björn and Eberhard, Jakob and Brändstedt, Jenny and Syk, Ingvar and Gisselsson Nord, David and Jirström, Karin}},
  issn         = {{1530-0285}},
  language     = {{eng}},
  number       = {{7}},
  pages        = {{979--988}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Modern Pathology}},
  title        = {{Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis}},
  url          = {{http://dx.doi.org/10.1038/s41379-022-01012-y}},
  doi          = {{10.1038/s41379-022-01012-y}},
  volume       = {{35}},
  year         = {{2022}},
}