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Article ; Online: Evolutionary mode and timing of dissemination of high-grade serous carcinomas.

Sveen, Anita / Johannessen, Bjarne / Klokkerud, Solveig Mk / Kraggerud, Sigrid M / Meza-Zepeda, Leonardo A / Bjørnslett, Merete / Bischof, Katharina / Myklebost, Ola / Taskén, Kjetil / Skotheim, Rolf I / Dørum, Anne / Davidson, Ben / Lothe, Ragnhild A

JCI insight

2024 Volume 9, Issue 3

Abstract: Dissemination within the peritoneal cavity is a main determinant of poor patient outcomes from high-grade serous carcinomas (HGSCs). The dissemination process is poorly understood from a cancer evolutionary perspective. We reconstructed the evolutionary ... ...

Abstract	Dissemination within the peritoneal cavity is a main determinant of poor patient outcomes from high-grade serous carcinomas (HGSCs). The dissemination process is poorly understood from a cancer evolutionary perspective. We reconstructed the evolutionary trajectories across a median of 5 tumor sites and regions from each of 23 patients based on deep whole-exome sequencing. Polyclonal cancer origin was detected in 1 patient. Ovarian tumors had more complex subclonal architectures than other intraperitoneal tumors in each patient, which indicated that tumors developed earlier in the ovaries. Three common modes of dissemination were identified, including monoclonal or polyclonal dissemination of monophyletic (linear) or polyphyletic (branched) subclones. Mutation profiles of initial or disseminated clones varied greatly among cancers, but recurrent mutations were found in 7 cancer-critical genes, including TP53, BRCA1, BRCA2, and DNMT3A, and in the PI3K/AKT1 pathway. Disseminated clones developed late in the evolutionary trajectory models of most cancers, in particular in cancers with DNA damage repair deficiency. Polyclonal dissemination was predicted to occur predominantly as a single and rapid wave, but chemotherapy exposure was associated with higher genomic diversity of disseminated clones. In conclusion, we described three common evolutionary dissemination modes across HGSCs and proposed factors associated with dissemination diversity.
MeSH term(s)	Female ; Humans ; Mutation ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Carcinoma
Language	English
Publishing date	2024-01-04
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.170423
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Article ; Online: Impact of the APOBEC3A/B deletion polymorphism on risk of ovarian cancer.

Gansmo, Liv B / Sofiyeva, Nigar / Bjørnslett, Merete / Romundstad, Pål / Hveem, Kristian / Vatten, Lars / Dørum, Anne / Lønning, Per E / Knappskog, Stian

Scientific reports

2021 Volume 11, Issue 1, Page(s) 23463

Abstract: A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in ... ...

Abstract	A germline 29.5-kb deletion variant removes the 3' end of the APOBEC3A gene and a large part of APOBEC3B, creating a hybrid gene that has been linked to increased APOBEC3 activity and DNA damage in human cancers. We genotyped the APOBEC3A/B deletion in hospital-based samples of 1398 Norwegian epithelial ovarian cancer patients without detected BRCA1/2 germline mutations and compared to 1,918 healthy female controls, to assess the potential cancer risk associated with the deletion. We observed an association between APOBEC3A/B status and reduced risk for ovarian cancer (OR = 0.75; CI = 0.61-0.91; p = 0.003) applying the dominant model. Similar results were found in other models. The association was observed both in non-serous and serous cases (dominant model: OR = 0.69; CI = 0.50-0.95; p = 0.018 and OR = 0.77; CI = 0.62-0.96; p = 0.019, respectively) as well as within high-grade serous cases (dominant model: OR = 0.79; CI = 0.59-1.05). For validation purposes, we mined an available large multinational GWAS-based data set of > 18,000 cases and > 26,000 controls for SNP rs12628403, known to be in linkage disequilibrium with the APOBEC3A/B deletion. We found a non-significant trend for SNP rs12628403 being linked to reduced risk of ovarian cancer in general and similar trends for all subtypes. For clear cell cancers, the risk reduction reached significance (OR = 0.85; CI = 0.69-1.00).
MeSH term(s)	Aged ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Cytidine Deaminase/genetics ; Female ; Gene Expression Regulation, Neoplastic/genetics ; Genetic Predisposition to Disease/genetics ; Genotype ; Germ-Line Mutation/genetics ; Humans ; Middle Aged ; Minor Histocompatibility Antigens/genetics ; Ovarian Neoplasms/genetics ; Polymorphism, Genetic/genetics ; Proteins/genetics ; Sequence Deletion/genetics
Chemical Substances	Biomarkers, Tumor ; Minor Histocompatibility Antigens ; Proteins ; APOBEC3A protein, human (EC 3.5.4.5) ; APOBEC3B protein, human (EC 3.5.4.5) ; Cytidine Deaminase (EC 3.5.4.5)
Language	English
Publishing date	2021-12-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-02820-z
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Article ; Online: Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers

Bjørnslett Merete / Knappskog Stian / Lønning Per / Dørum Anne

BMC Cancer, Vol 12, Iss 1, p

2012 Volume 454

Abstract: Abstract Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 ... ...

Abstract	Abstract Background While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods 221 BRCA related ovarian cancer cases ( BRCA1; n = 161 and BRCA2 n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls ( n = 2,465). Results The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT ( p = 0.068). No such associations were found in BRCA2 related ovarian cancer. Conclusions Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.
Keywords	Ovarian cancer ; BRCA ; MDM2 SNP285 ; MDM2 SNP309 ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2012-10-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genomic and prognostic heterogeneity among RAS/BRAF

Berg, Kaja C G / Brunsell, Tuva H / Sveen, Anita / Alagaratnam, Sharmini / Bjørnslett, Merete / Hektoen, Merete / Brudvik, Kristoffer W / Røsok, Bård I / Bjørnbeth, Bjørn Atle / Nesbakken, Arild / Lothe, Ragnhild A

Molecular oncology

2021 Volume 15, Issue 4, Page(s) 830–845

Abstract: Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co-mutations are associated with a poor prognosis after resection, but there is large variation in patient ... ...

Abstract	Hepatic resection is potentially curative for patients with colorectal liver metastases, but the treatment benefit varies. KRAS/NRAS (RAS)/TP53 co-mutations are associated with a poor prognosis after resection, but there is large variation in patient outcome within the mutation groups, and genetic testing is currently not used to evaluate benefit from surgery. We have investigated the potential for improved prognostic stratification by combined biomarker analysis with DNA copy number aberrations (CNAs), and taking tumor heterogeneity into account. We determined the mutation status of RAS, BRAF
MeSH term(s)	Biomarkers, Tumor/genetics ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; DNA Copy Number Variations ; GTP Phosphohydrolases/genetics ; Genes, ras ; Genomics ; Hepatectomy ; Humans ; Liver Neoplasms/genetics ; Liver Neoplasms/secondary ; Membrane Proteins/genetics ; Microsatellite Instability ; Mutation ; Norway ; Prognosis ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Biomarkers, Tumor ; KRAS protein, human ; Membrane Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2021-01-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.12885
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Article ; Online: E-cadherin is a robust prognostic biomarker in colorectal cancer and low expression is associated with sensitivity to inhibitors of topoisomerase, aurora, and HSP90 in preclinical models.

Bruun, Jarle / Eide, Peter W / Bergsland, Christian Holst / Bruck, Oscar / Svindland, Aud / Arjama, Mariliina / Välimäki, Katja / Bjørnslett, Merete / Guren, Marianne G / Kallioniemi, Olli / Nesbakken, Arild / Lothe, Ragnhild A / Pellinen, Teijo

Molecular oncology

2021 Volume 16, Issue 12, Page(s) 2312–2329

Abstract: Cell-cell and cell-matrix adhesion proteins that have been implicated in colorectal epithelial integrity and epithelial-to-mesenchymal transition could be robust prognostic and potential predictive biomarkers for standard and novel therapies. We analyzed ...

Abstract	Cell-cell and cell-matrix adhesion proteins that have been implicated in colorectal epithelial integrity and epithelial-to-mesenchymal transition could be robust prognostic and potential predictive biomarkers for standard and novel therapies. We analyzed in situ protein expression of E-cadherin (ECAD), integrin β4 (ITGB4), zonula occludens 1 (ZO-1), and cytokeratins in a single-hospital series of Norwegian patients with colorectal cancer (CRC) stages I-IV (n = 922) using multiplex fluorescence-based immunohistochemistry (mfIHC) on tissue microarrays. Pharmacoproteomic associations were explored in 35 CRC cell lines annotated with drug sensitivity data on > 400 approved and investigational drugs. ECAD, ITGB4, and ZO-1 were positively associated with survival, while cytokeratins were negatively associated with survival. Only ECAD showed independent prognostic value in multivariable Cox models. Clinical and molecular associations for ECAD were technically validated on a different mfIHC platform, and the prognostic value was validated in another Norwegian series (n = 798). In preclinical models, low and high ECAD expression differentially associated with sensitivity to topoisomerase, aurora, and HSP90 inhibitors, and EGFR inhibitors. E-cadherin protein expression is a robust prognostic biomarker with potential clinical utility in CRC.
MeSH term(s)	Antigens, CD ; Biomarkers, Tumor/metabolism ; Cadherins/metabolism ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Epithelial-Mesenchymal Transition ; Humans ; Immunohistochemistry ; Keratins ; Prognosis
Chemical Substances	Antigens, CD ; Biomarkers, Tumor ; CDH1 protein, human ; Cadherins ; Keratins (68238-35-7)
Language	English
Publishing date	2021-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13159
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Article ; Online: Psychological distress related to BRCA testing in ovarian cancer patients.

Bjørnslett, Merete / Dahl, Alv A / Sørebø, Øystein / Dørum, Anne

Familial cancer

2015 Volume 14, Issue 4, Page(s) 495–504

Abstract: An increasing demand for genetic testing has moved the procedure from highly selected at-risk individuals, now also including cancer patients for treatment associated testing. The heritable fraction of ovarian cancer is more than 10%, and our department ... ...

Abstract	An increasing demand for genetic testing has moved the procedure from highly selected at-risk individuals, now also including cancer patients for treatment associated testing. The heritable fraction of ovarian cancer is more than 10%, and our department has offered BRCA testing to such patients irrespective of family history since 2002. This study examined potential psychosocial distress associated with this procedure using The Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire and other patient-rated generic distress instruments. Patients were divided into four groups according to cancer risk: mutation carriers, own history of breast cancer and ovarian cancer, family history of breast cancer and/or ovarian cancer, and patients without family history. In a postal survey, 354 patients responded. Good acceptance of the MICRA was observed, and previously described good psychometric properties were confirmed. A significant association between MICRA total score and receiving a positive BRCA test result was found. No significant between-group differences were observed with generic distress instruments. Time since cancer diagnosis, test result, and survey showed no significant associations with MICRA scores. Internal consistencies of instruments were adequate. Exploratory and confirmatory factor analyses showed adequate fit indices for a three factor solution of the MICRA, but further refinement of the items should be considered. In conclusion, the specific types of worry and distress most relevant to receiving genetic testing irrespective of family history were not captured by the generic distress instruments. The MICRA was supported as a useful tool for detection of mental distress related to genetic testing and risk evaluation.
MeSH term(s)	Aged ; Anxiety/genetics ; BRCA1 Protein/genetics ; BRCA2 Protein/genetics ; Female ; Follow-Up Studies ; Genetic Counseling ; Genetic Predisposition to Disease ; Genetic Testing/methods ; Humans ; Middle Aged ; Mutation/genetics ; Neoplasm Staging ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/psychology ; Prognosis ; Risk Assessment ; Stress, Psychological/genetics
Chemical Substances	BRCA1 Protein ; BRCA1 protein, human ; BRCA2 Protein ; BRCA2 protein, human
Language	English
Publishing date	2015-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1502496-9
ISSN	1573-7292 ; 1389-9600
ISSN (online)	1573-7292
ISSN	1389-9600
DOI	10.1007/s10689-015-9811-2
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Zs.A 6099: Show issues

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Article ; Online: Impact of

Helwa, Reham / Gansmo, Liv B / Bjørnslett, Merete / Halle, Mari Kyllesø / Werner, Henrica M J / Romundstad, Pål / Hveem, Kristian / Vatten, Lars / Dørum, Anne / Lønning, Per E / Knappskog, Stian

Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals

2021 Volume 26, Issue 4, Page(s) 302–308

Abstract: Background: While large GWAS analyses have not found convincing associations between : Material and methods: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospital-based cohorts of patients with ovarian (n = 1,332) and endometrial ( ... ...

Abstract	Background: While large GWAS analyses have not found convincing associations between Material and methods: Using a custom LightSNiP assay, we genotyped SNP55 in two large hospital-based cohorts of patients with ovarian (n = 1,332) and endometrial (n = 1,363) cancer and compared genotypes to healthy female controls (n = 1,858). Results: Among individuals harbouring the SNP309TT genotype, the minor SNP55T-allele was associated with a reduced risk of endometrial (dominant model: OR = 0.63; CI = 0.45-0.88; Conclusions: MDM2
MeSH term(s)	Aged ; Alleles ; Case-Control Studies ; Cohort Studies ; Endometrial Neoplasms/diagnosis ; Endometrial Neoplasms/genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Genotype ; Humans ; Linkage Disequilibrium ; Middle Aged ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins c-mdm2/genetics
Chemical Substances	Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2021-02-28
Publishing country	England
Document type	Journal Article
ZDB-ID	1324372-x
ISSN	1366-5804 ; 1354-750X
ISSN (online)	1366-5804
ISSN	1354-750X
DOI	10.1080/1354750X.2021.1891291
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Article ; Online: A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis.

Lopes, Nair / Bergsland, Christian / Bruun, Jarle / Bjørnslett, Merete / Vieira, André Filipe / Mesquita, Patrícia / Pinto, Rita / Gomes, Rosa / Cavadas, Bruno / Bennett, Eric / Pereira, Luisa / Lothe, Ragnhild A / Almeida, Raquel / David, Leonor

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association

2020 Volume 23, Issue 5, Page(s) 811–823

Abstract: Background: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of ... ...

Abstract	Background: Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin). Methods: This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results. Results: Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level. Conclusions: Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.
MeSH term(s)	Aged ; Antigens, Differentiation/metabolism ; Biomarkers, Tumor/metabolism ; CDX2 Transcription Factor/metabolism ; Cadherins/metabolism ; Cell Differentiation ; Female ; Follow-Up Studies ; Humans ; Intestines/cytology ; Male ; Membrane Glycoproteins/metabolism ; Prognosis ; Retrospective Studies ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology ; Stomach Neoplasms/surgery ; Survival Rate
Chemical Substances	Antigens, Differentiation ; Biomarkers, Tumor ; CDH17 protein, human ; CDX2 Transcription Factor ; CDX2 protein, human ; Cadherins ; GPA33 protein, human ; Membrane Glycoproteins
Language	English
Publishing date	2020-03-25
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1463526-4
ISSN	1436-3305 ; 1436-3291
ISSN (online)	1436-3305
ISSN	1436-3291
DOI	10.1007/s10120-020-01064-6
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Article ; Online: Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers.

Bjørnslett, Merete / Knappskog, Stian / Lønning, Per Eystein / Dørum, Anne

BMC cancer

2012 Volume 12, Page(s) 454

Abstract: Background: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms ...

Abstract	Background: While BRCA mutation carriers possess a 20-40% lifetime risk of developing ovarian cancer, knowledge about genetic modifying factors influencing the phenotypic expression remains obscure. We explored the distribution of the MDM2 polymorphisms SNP309T>G and the recently discovered SNP285G>C in Norwegian patients with BRCA related ovarian cancer. Methods: 221 BRCA related ovarian cancer cases (BRCA1; n = 161 and BRCA2; n = 60) were tested for the MDM2 polymorphisms. Results were compared to healthy controls (n = 2,465). Results: The SNP309G allele was associated with elevated OR for ovarian cancer in BRCA1 mutation carriers (SNP309TG: OR 1.53; CI 1.07-2.19; p = 0.020; SNP309GG: OR 1.92; CI 1.19-3.10; p = 0.009; SNP309TG+GG combined: OR 1.61; CI 1.15-2.27; p = 0.005). In contrast, the SNP285C allele reduced risk of BRCA1 related ovarian cancer in carriers of the SNP309G allele (OR 0.50; CI 0.24-1.04; p = 0.057). Censoring individuals carrying the SNP285C/309G haplotype from the analysis elevated the OR related to the SNP309G allele (OR 1.73; CI 1.23-2.45; p = 0.002). The mean age at disease onset was 3.1 years earlier in carriers of SNP309TG+GG as compared to carriers of SNP309TT (p = 0.068). No such associations were found in BRCA2 related ovarian cancer. Conclusions: Our results indicate the SNP309G allele to increase and the SNP285C allele to reduce the risk of BRCA1 related ovarian cancer. If confirmed in independent studies, this finding may have implications to counseling and decision-making regarding risk reducing measures in BRCA1 mutation carriers.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Alleles ; BRCA1 Protein/genetics ; Female ; Gene Frequency ; Genetic Predisposition to Disease/genetics ; Genotype ; Heterozygote ; Humans ; Middle Aged ; Mutation ; Norway ; Ovarian Neoplasms/genetics ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins c-mdm2/genetics ; Risk Factors
Chemical Substances	BRCA1 Protein ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2012-10-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/1471-2407-12-454
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Article ; Online: Digital image analysis of multiplex fluorescence IHC in colorectal cancer recognizes the prognostic value of CDX2 and its negative correlation with SOX2.

Lopes, Nair / Bergsland, Christian Holst / Bjørnslett, Merete / Pellinen, Teijo / Svindland, Aud / Nesbakken, Arild / Almeida, Raquel / Lothe, Ragnhild A / David, Leonor / Bruun, Jarle

Laboratory investigation; a journal of technical methods and pathology

2019 Volume 100, Issue 1, Page(s) 120–134

Abstract: Flourescence-based multiplex immunohistochemistry (mIHC) combined with multispectral imaging and digital image analysis (DIA) is a quantitative high-resolution method for determination of protein expression in tissue. We applied this method for five ... ...

Abstract	Flourescence-based multiplex immunohistochemistry (mIHC) combined with multispectral imaging and digital image analysis (DIA) is a quantitative high-resolution method for determination of protein expression in tissue. We applied this method for five biomarkers (CDX2, SOX2, SOX9, E-cadherin, and β-catenin) using tissue microarrays of a Norwegian unselected series of primary colorectal cancer. The data were compared with previously obtained chromogenic IHC data of the same tissue cores, visually assessed by the Allred method. We found comparable results between the methods, although confirmed that DIA offered improved resolution to differentiate cases with high and low protein expression. However, we experienced inherent challenges with digital image analysis of membrane staining, which was better assessed visually. DIA and mIHC enabled quantitative analysis of biomarker coexpression on the same tissue section at the single-cell level, revealing a strong negative correlation between the differentiation markers CDX2 and SOX2. Both methods confirmed known prognostic associations for CDX2, but DIA improved data visualization and detection of clinicopathological and biological associations. In summary, mIHC combined with DIA is an efficient and reliable method to evaluate protein expression in tissue, here shown to recapitulate and improve detection of known clinicopathological and survival associations for the emerging biomarker CDX2, and is therefore a candidate approach to standardize CDX2 detection in pathology laboratories.
MeSH term(s)	Biomarkers, Tumor/analysis ; Biomarkers, Tumor/metabolism ; CDX2 Transcription Factor/metabolism ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/metabolism ; Fluorescent Antibody Technique ; Humans ; Image Interpretation, Computer-Assisted ; SOXB1 Transcription Factors/metabolism ; Tissue Array Analysis
Chemical Substances	Biomarkers, Tumor ; CDX2 Transcription Factor ; CDX2 protein, human ; SOX2 protein, human ; SOXB1 Transcription Factors
Language	English
Publishing date	2019-10-22
Publishing country	United States
Document type	Evaluation Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80178-1
ISSN	1530-0307 ; 0023-6837
ISSN (online)	1530-0307
ISSN	0023-6837
DOI	10.1038/s41374-019-0336-4
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