| 2. |
- Petersson, Alexandra, et al.
(författare)
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Branching copy number evolution and parallel immune profiles across the regional tumor space of resected pancreatic cancer
- 2022
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 20:5, s. 749-761
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Siesing, Christina, et al.
(författare)
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Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 35:7, s. 979-988
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Tidskriftsartikel (refereegranskat)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.
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