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- 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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| 2. |
- Siesing, Christina, et al.
(författare)
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High RBM3 expression is associated with an improved survival and oxaliplatin response in patients with metastatic colorectal cancer
- 2017
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 12:8
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Tidskriftsartikel (refereegranskat)abstract
- Background: High expression of the RNA-binding motif protein 3 (RBM3) has been shown to correlate, with prolonged survival in several malignant diseases and with the benefit of platinumbased chemotherapy in ovarian cancer. The aim of this study was to evaluate RBM3 in metastatic colorectal cancer (mCRC) as a prognostic factor for overall survival and in relation to benefit of first-line chemotherapy.Methods: Immunohistochemical staining was conducted and evaluated in tumours from 455 mCRC patients. Kaplan- Meier analysis and Cox regression proportional hazards models were used to access the impact of RBM3 expression on overall survival (OS) and progressionfree survival (PFS).Results: High RBM3 expression, both nuclear and cytoplasmic, was an independent prognostic factor for prolonged OS (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.50-0.90 and HR 0.66, 95% CI 0.48-0.91, respectively). PFS was significantly longer in patients with high RBM3 expression who had received first-line oxaliplatin based treatment, compared to those who had received irinotecan based treatment, both regarding nuclear and cytoplasmic expression (p-value 0.020 and 0.022 respectively).Conclusion: High RBM3 expression is an independent predictor of prolonged survival in mCRC patients, in particular in patients treated with first-line oxaliplatin based chemotherapy.
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| 3. |
- Siesing, Christina
(författare)
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Prognostic and predictive biomarkers in metastatic colorectal cancer constant and evolutionary perspectives
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) affects nearly 2 million people each year and accounts for 900 000 deaths worldwide. The main prognostic factor is disease stage at diagnosis and around 40% of the patients presents with or develop metastatic CRC (mCRC). Even if the disease has disseminated, cure is sometimes possible, but despite thorough selection of patients for metastasectomy, most patients will suffer relapse of the disease. Hence, there is a great need for new prognostic and predictive biomarkers in order to better select the appropriate treatment for each patient. The aim of this thesis was to study the prognostic and predictive impact of selected biomarkers, with particular focus on RNA-binding motif protein 3 (RBM3), in mCRC and to perform an extensive mapping of the spatial heterogeneity in mCRC with peritoneal carcinomatosis. In paper I, RBM3 expression was assessed by immunohistochemistry (IHC) in primary tumours from 455 patients with mCRC. High RBM3 expression was an independent predictor of prolonged survival, and in the group with high RBM3 expression, a longer progression-free survival was seen in patients treated with oxaliplatin compared to patients treated with irinotecan in first line. In paper II, RBM3 expression was assessed by IHC in 211 resected lung metastases and 164 paired primary tumours. High RBM3 expression in the lung metastases was an independent predictor of prolonged survival, in particular in patients treated with oxaliplatin at any time point. Other prognostic factors for prolonged survival were age ≤ 60 years, one metastasis, a lung metastasis <3 cm in size, disease free interval >24 months and adjuvant treatment. In paper III, the spatial molecular heterogeneity was delineated in seven curatively treated patients with mCRC disseminated to the peritoneum. Multiregional targeted sequencing and IHC analysis of RBM3, special AT-rich sequence-binding protein 2 (SATB2) and mismatch repair (MMR) proteins were performed. The expression of RBM3 and SATB2 was allover low. Mutations in key CRC driver genes, i.e KRAS, APC and TP53, were homogenous across samples from individual patients, whereas less common mutations were more heterogenous. In some cases, a higher similarity was seen between PC and lymph node metastases than between PC and the primary tumour. Paper IV is a study protocol for the planned On-treatment biomarkers in metastatic Colorectal Cancer for Life (On- CALL) study. The aim of this prospective, observational study is to follow up on relevant findings from the present thesis and to generate further knowledge on the spatial and temporal tumour heterogeneity and evolution of mCRC during curative treatment.
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| 5. |
- Vidarsdottir, Halla, et al.
(författare)
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Clinical significance of RBM3 expression in surgically treated colorectal lung metastases and paired primary tumours
- 2021
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Ingår i: Journal of Surgical Oncology. - : Wiley. - 0022-4790 .- 1096-9098. ; 123:4, s. 1144-1156
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Tidskriftsartikel (refereegranskat)abstract
- Background The lungs are the second most common site of metastases in colorectal cancer (CRC). The aim of this study was to investigate prognostic factors, including RNA‐binding motif protein 3 (RBM3) expression, in patients with CRC treated with pulmonary metastasectomy (PM). Methods The cohort included all patients treated with PM at Skåne University Hospital, Lund, Sweden, from 2000 to 2014. Clinicopathological, treatment, and survival data were collected. Immunohistochemical staining of RBM3 was evaluated on tissue microarrays with samples from all lung metastases and a subset of paired primary tumors. Kaplan–Meier analysis and Cox proportional hazards modeling were applied to examine the associations of investigative factors with overall survival (OS) and recurrence‐free survival. Results In total, 216 patients with a primary tumor in the rectum (57%), left colon (34%), or right colon (9%) underwent PM. The 5‐year OS rate was 56%. Age > 60 years, more than one metastasis, size of metastasis > 3 cm, disease‐free interval < 24 months, low RBM3 score in the lung metastasis, and no adjuvant chemotherapy following PM were prognostic factors for shorter OS. Conclusions Several prognostic factors, including RBM3 expression, may be of aid in selecting CRC patients with lung metastases for PM as well as adjuvant therapy.
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