Genetic mechanisms causing resistance to chemotherapy in cancer patients.
Chemotherapy is one of the backbones of cancer treatment, but many patients experience poor effects of chemotherapeutic drugs. Our research focuses on the genetic and molecular mechanisms causing tumours to not respond to chemotherapy. The overall aim is to identify genetic alterations that can be used as predictive biomarkers, i.e. markers that can predict what kind of chemotherapy would be most beneficial for each individual patient. So, far we have identified inactivation of the p53- and pRB functional pathways as predictors of poor response to anthracycline treatment in breast cancer.
Knappskog et al. Breast Cancer Research, 2012
Knappskog et al Molecular Oncology, 2015.
Genetic variants modulating cancer risk
In addition to variants within the protein coding regions of DNA, cancer risk may be influenced by variations in the non-coding DNA. We are assessing common polymorphisms in promoter regions of genes involved in cancer. We are currently focusing on polymorphisms in the promoter of the MDM2 gene, where we have found one particular variant (SNP285) to reduce the risk of breast cancer with 37% and the risk of ovarian cancer with 39% in some subgroups of Caucasian women.
Knappskog et al. Cancer Cell, 2011
Knappskog et al. European Journal of Cancer 2012.
Many tumours are heterogenous and consist of genetically different subclones. Our research assesses the interplay of different sublcones with respect to tumour progression and metastasis as well as response to treatment.
Yates et al Nature Medicine, 2015
Løes et al International Journal of Cancer, 2016
Sveen et al PLoS Genetics, 2016
Yates et al Cancer Cell, 2017
Newspaper stories about major publication (2018.01.16)
Newspaper stories about major publication (2017.08.14)
Newspaper story about National Young Scientist award (2016.11.18)
TV case about the novel clinical trial PETREMAC (2016.07.03)
TV case about the novel clinical trial PETREMAC (2016.07.05)
Newspaper story about research funded by the Pink ribbon campaign (2015.10.29)
TV interview about Mohn donation to research (2014.12.23)
Film for the Norwegian Cancer Society’s Pink Ribbon Campaign (2013.09.20)
Newspaper story about the discovery of cancer risk reducing polymorphism (2011.02.15)
Publications registered in PubMed:
Publications registered in CRIStin:
- 2018. Patterns of genomic evolution in advanced melanoma. Nature Communications. 9:2665: 1-12. Published 2018-04-30. doi: 10.1038/s41467-018-05063-1
- 2018. High expression of the p53 isoform ? is associated with reduced progression-free survival in uterine serous carcinoma. BMC Cancer. 18:684: 1-10. doi: 10.1186/s12885-018-4591-3
- 2018. Introducing nano-scale quantitative polymerase chain reaction. Biochemical and Biophysical Research Communications - BBRC. 506: 923-926. doi: 10.1016/j.bbrc.2018.10.111
- 2018. Association of rs2279744 and rs117039649 promoter polymorphism with the risk of gynaecological cancer: A meta-analysis of case-control studies. Medicine.
- 2018. White blood cell BRCA1 promoter methylation status and ovarian cancer risk. Annals of Internal Medicine. 168: 326-334. doi: 10.7326/M17-0101
- 2018. BRCA1 methylation in newborns: Genetic disposition, maternal transfer, environmental influence, or by chance only? Clinical Epigenetics. 10. doi: 10.1186/s13148-018-0566-0
- 2017. MDM2 promoter polymorphism del1518 (rs3730485) and its impact on endometrial and ovarian cancer risk. BMC Cancer. 17:97: 1-6. doi: 10.1186/s12885-017-3094-y
- 2017. APOBEC3A/B deletion polymorphism and cancer risk. Carcinogenesis. 39: 118-124. doi: 10.1093/carcin/bgx131
- 2017. Tumor cells interact with red blood cells via galectin-4 - a short report. Cellular Oncology. Published ahead of print: 1-9. doi: 10.1007/s13402-017-0317-9
- 2017. The Functional roles of the MDM2 splice variants P2-MDM2-10 and MDM2-∆5 in breast cancer cells. Translational Oncology. 10: 806-817. doi: 10.1016/j.tranon.2017.07.006
- 2017. Impact of the MDM2 splice-variants MDM2-A, MDM2-B and MDM2-C on cytotoxic stress response in breast cancer cells. BMC Cell Biology. 18:17: 1-9. doi: 10.1186/s12860-017-0134-z
- 2017. Effects of concomitant inactivation of p53 and pRb on response to doxorubicin treatment in breast cancer cell lines. Cell death discovery. 3. doi: 10.1038/cddiscovery.2017.26
- 2017. Somatic mutations reveal asymmetric cellular dynamics in the early human embryo. Nature. 543: 714-718. doi: 10.1038/nature21703
- 2017. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell. 32: 169-184.e7. doi: 10.1016/j.ccell.2017.07.005
- 2017. High PTEN gene expression is a negative prognostic marker in human primary breast cancers with preserved p53 function. Breast Cancer Research and Treatment. 163: 177-190. doi: 10.1007/s10549-017-4160-5
- 2017. Activation of Akt characterizes estrogen receptor positive human breast cancers which respond to anthracyclines. OncoTarget. 8: 41227-41241. doi: 10.18632/oncotarget.17167
- 2016. EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. Neuro-Oncology. 18: 1644-1655. doi: 10.1093/neuonc/now113
- 2016. Treatment with aromatase inhibitors stimulates the expression of epidermal growth factor receptor-1 and neuregulin 1 in ER positive/HER-2/neu non-amplified primary breast cancers. Journal of Steroid Biochemistry and Molecular Biology. 165: 228-235. Published 2016-06-22. doi: 10.1016/j.jsbmb.2016.06.011
- 2016. The MDM4 SNP34091 (rs4245739) C-allele is associated with increased risk of ovarian—but not endometrial cancer. Tumour Biology. 37: 10697-10702. doi: 10.1007/s13277-016-4940-2
- 2016. Associations between the MDM2 promoter P1 polymorphism del1518 (rs3730485) and incidence of cancer of the breast, lung, colon and prostate. OncoTarget. 7: 28637-28646. doi: 10.18632/oncotarget.8705
- 2016. MDM2 promoter SNP55 (rs2870820) affects risk of colon cancer but not breast-, lung-, or prostate cancer. Scientific Reports. 6. 8 pages. doi: 10.1038/srep33153
- 2016. Promoter SNPs rs116896264 and rs73933062 form a distinct haplotype and are associated with galectin-4 overexpression in colorectal cancer. Mutagenesis. 31: 401-408. doi: 10.1093/mutage/gev086
- 2016. Prevalence of the CHEK2 R95* germline mutation. Hereditary Cancer in Clinical Practice. 14. 4 pages. doi: 10.1186/s13053-016-0059-0
- 2016. Impact of KRAS, BRAF, PIK3CA, TP53 status and intraindividual mutation heterogeneity on outcome after liver resection for colorectal cancer metastases. International Journal of Cancer. 139: 647-656. doi: 10.1002/ijc.30089
- 2016. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 534: 47-54. doi: 10.1038/nature17676
- 2016. Breast cancer genome and transcriptome integration implicates specific mutational signatures with immune cell infiltration. Nature Communications. 7. doi: 10.1038/ncomms12910
- 2016. Intra-patient inter-metastatic genetic heterogeneity in colorectal cancer as a key determinant of survival after curative liver resection. PLoS Genetics. 12:e1006225. 22 pages. doi: 10.1371/journal.pgen.1006225
- 2015. Estrogens correlate with PELP1 expression in ER positive breast cancer. PLoS ONE. 10:e0134351. 12 pages. doi: 10.1371/journal.pone.0134351
- 2015. Influence of MDM2 SNP309 and SNP285 status on the risk of cancer in the breast, prostate, lung and colon. International Journal of Cancer. 137: 96-103. doi: 10.1002/ijc.29358
- 2015. MDM4 SNP34091 (rs4245739) and its effect on breast-, colon-, lung-, and prostate cancer risk. Cancer Medicine. 4: 1901-1907. doi: 10.1002/cam4.555
- 2015. Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. Genome Research. 25: 814-824. doi: 10.1101/gr.190470.115
- 2015. Concomitant inactivation of the p53- and pRB- functional pathways predicts resistance to DNA damaging drugs in breast cancer in vivo. Molecular Oncology. 9: 1553-1564. doi: 10.1016/j.molonc.2015.04.008
- 2015. Performance comparison of three BRAF V600E detection methods in malignant melanoma and colorectal cancer specimen. Tumour Biology. 36: 1003-1013. doi: 10.1007/s13277-014-2711-5
- 2015. Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nature Medicine. 21: 751-759. doi: 10.1038/nm.3886
- 2014. TP53 status predicts long-term survival in locally advanced breast cancer after primary chemotherapy. Acta Oncologica. 53: 1347-1355. doi: 10.3109/0284186X.2014.922215
- 2014. Population distribution and ancestry of the cancer protective MDM2 SNP285 (rs117039649). OncoTarget. 5: 8223-8234.
- 2014. MDM2 SNP309 and risk of endometrial cancer. Tumour Biology. doi: 10.1007/s13277-014-2244-y
- 2014. MDM2 SNP309 and risk of cervical cancer. Tumour Biology. 35: 6185-6186. doi: 10.1007/s13277-014-1910-4
- 2014. MDM2 SNP309 and risk of cervical cancer. Tumour Biology. doi: 10.1007/s13277-014-1910-4
- 2014. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nature Genetics. 46: 487-491. doi: 10.1038/ng.2955
- 2014. Effects of SNP variants in the 17β-HSD2 and 17β-HSD7 genes and 17β-HSD7 copy number on gene transcript and estradiol levels in breast cancer tissue. Journal of Steroid Biochemistry and Molecular Biology. 143: 192-198. doi: 10.1016/j.jsbmb.2014.02.003
- 2014. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science. 345. doi: 10.1126/science.1251343
- 2013. Signatures of mutational processes in human cancer. Nature. 500: 415-421. doi: 10.1038/nature12477
- 2013. Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway. Langenbeck's archives of surgery (Print). 398: 869-874. doi: 10.1007/s00423-013-1093-2
- 2013. CXXC5 (retinoid-inducible nuclear factor, RINF) is a potential therapeutic target in high-risk human acute myeloid leukemia. OncoTarget. 4: 1438-1448.
- 2013. Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. Biochimica et Biophysica Acta - General Subjects. 1830: 2790-2797. doi: 10.1016/j.bbagen.2012.12.004
- 2013. Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma. Clinical and Experimental Metastasis. 30: 867-876. doi: 10.1007/s10585-013-9587-4
- 2013. Inverse regulation of EGFR/HER1 and HER2-4 in normal and malignant human breast tissue. PLoS ONE. 8. 12 pages. doi: 10.1371/journal.pone.0074618
- 2013. MDM2 SNP309 and risk of endometrial cancer. Polish Journal of Pathology. 64: 69-70. doi: 10.5114/PJP.2013.34607
- 2013. Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers. Oncogene. 32: 5315-5330. doi: 10.1038/onc.2013.48
- 2012. Effect of the MDM2 promoter polymorphisms SNP309T>G and SNP285G>C on the risk of ovarian cancer in BRCA1 mutation carriers. BMC Cancer. 12. 6 pages. doi: 10.1186/1471-2407-12-454
- 2012. Re: Murine double minute 2 promoter SNP309 polymorphism and prostate cancer risk: a meta-analysis. International journal of urology. 19: 966-966. doi: 10.1111/j.1442-2042.2012.03108.x
- 2012. Low expression levels of ATM may substitute for CHEK2/TP53 mutations predicting resistance towards anthracycline and mitomycin chemotherapy in breast cancer. Breast Cancer Research. 14. 12 pages. doi: 10.1186/bcr3147
- 2012. MDM2 Promoter SNP344T>A (rs1196333) Status Does Not Affect Cancer Risk. PLoS ONE. 7. 6 pages. doi: 10.1371/journal.pone.0036263
- 2012. P53 and its molecular basis to chemoresistance in breast cancer. Expert opinion on therapeutic targets. 16: S23-S30. doi: 10.1517/14728222.2011.640322
- 2012. SNP285C modulates oestrogen receptor/Sp1 binding to the MDM2 promoter and reduces the risk of endometrial but not prostatic cancer. European Journal of Cancer. 48: 1988-1996. doi: 10.1016/j.ejca.2011.10.024
- 2012. Chemosensitivity and p53; new tricks by an old dog. Breast Cancer Research. 14: 325. Published 2012-11-06. doi: 10.1186/bcr3326
- 2012. Synergistic induction of p53 mediated apoptosis by valproic acid and nutlin-3 in acute myeloid leukemia. Leukemia. 26: 910-917. doi: 10.1038/leu.2011.315
- 2012. Effect of CYP19 rs6493497 and rs7176005 haplotype status on in vivo aromatase transcription, plasma and tissue estrogen levels in postmenopausal women. Journal of Steroid Biochemistry and Molecular Biology. 128: 69-75. doi: 10.1016/j.jsbmb.2011.08.015
- 2012. Elevated levels of the steroidogenic factor 1 are associated with over-expression of CYP19 in an oestrogen-producing testicular Leydig cell tumour. European Journal of Endocrinology. 166: 941-949. doi: 10.1530/EJE-11-0849
- 2012. Correlation analysis of p53 protein isoforms with NPM1/FLT3 mutations and therapy response in acute myeloid leukemia. Oncogene. 31: 1533-1545. doi: 10.1038/onc.2011.348
- 2011. Alterations of the retinoblastoma gene in metastatic breast cancer. Clinical and Experimental Metastasis. 28: 319-326. doi: 10.1007/s10585-011-9375-y
- 2011. Predictive and Prognostic Impact of TP53 Mutations and MDM2 Promoter Genotype in Primary Breast Cancer Patients Treated with Epirubicin or Paclitaxel. PLoS ONE. 6. 10 pages. doi: 10.1371/journal.pone.0019249
- 2011. The MDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians. Cancer Cell. 19: 273-282. doi: 10.1016/j.ccr.2010.12.019
- 2011. Effects of the MDM2 promoter SNP285 and SNP309 on Sp1 transcription factor binding and cancer risk. Transcription. doi: 10.4161/trns.2.5.16813
- 2011. MDM2 promoter SNP285 and SNP309; phylogeny and impact on cancer risk. OncoTarget. 2: 251-258.
- 2011. RINF (CXXC5) is overexpressed in solid tumors and is an unfavorable prognostic factor in breast cancer(dagger). Annals of Oncology. 22: 2208-2215. doi: 10.1093/annonc/mdq737
- 2011. Exploring breast cancer estrogen disposition: The basis for endocrine manipulation. Clinical Cancer Research. 17: 4948-4958. doi: 10.1158/1078-0432.CCR-11-0043
- 2011. Recent data on intratumor estrogens in breast cancer. Steroids. 76: 786-791. doi: 10.1016/j.steroids.2011.02.040
- 2011. Clinical effect of Temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer. 117: 4617-4622. doi: 10.1002/cncr.26124
- 2010. Identification and characterization of retinoblastoma gene mutations disturbing apoptosis in human breast cancers. Molecular Cancer. 9. 13 pages. doi: 10.1186/1476-4598-9-173
- 2010. Alterations in the p53 Pathway and p16INK4a Expression Predict Overall Survival in Metastatic Melanoma Patients Treated with Dacarbazine. Journal of Investigative Dermatology. 130: 2514-2516. doi: 10.1038/jid.2010.138
- 2010. Gene Expression Profiling-Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome. Clinical Cancer Research. 16: 3356-3367. doi: 10.1158/1078-0432.CCR-09-2509
- 2010. Spontaneous Malignant Transformation of Human Mesenchymal Stem Cells Reflects Cross-Contamination: Putting the Research Field on Track - Letter. Cancer Research. 70: 6393-6396. doi: 10.1158/0008-5472.CAN-10-1305
- 2008. CHEK2 mutations affecting kinase activity together with mutations in TP53 indicate a functional pathway associated with resistance to epirubicin in primary breast cancer. PLoS ONE. 3:e0003062. 15 pages. doi: 10.1371/journal.pone.0003062
- 2007. P21/waf1 mutation and drug resistance to paclitaxel in locally advanced breast cancer. International Journal of Cancer. 120: 2749-2749. doi: 10.1002/ijc.22595
- 2007. Germline Genetic Alterations Affecting CDKN2A, MDM2 and CDKN1A in Melanoma and Breast Cancer Patients. 110 pages.
- 2007. Mutations and polymorphisms of the p21B transcript in breast cancer. International Journal of Cancer. 121: 908-910. doi: 10.1002/ijc.22777
- 2007. The level of synthesis and secretion of Gaussia princeps luciferase in transfected CHO cells is heavily dependent on the choice of signal peptide. Journal of Biotechnology. 128: 705-715. doi: 10.1016/j.jbiotec.2006.11.026
- 2007. Adjuvant treatment: the contribution of expression microarrays. Breast Cancer Research. 9. doi: 10.1186/bcr1812
- 2007. Breast cancer prognostication and prediction in the postgenomic era. Annals of Oncology. 18: 1293-1306. doi: 10.1093/annonc/mdm013
- 2007. UTRech tm: Exploiting mRNA Targeting To Increase Protein Secetion From Mammalian Cells. 261-268, pages 261-268. In:
- 2007. Cell Technology for Cell Products. Springer. 824 pages. ISBN: 978-1-4020-5475-4.
- 2006. A novel type of deletion in the CDKN2A gene identified in a melanoma-prone family. Genes, Chromosomes and Cancer. 45: 1155-1163. Published 2006-09-25. doi: 10.1002
- 2006. The novel p21 polymorphism p21(G251A) is associated with locally advanced breast cancer. Clinical Cancer Research. 12: 6000-6004.
- 2005. The SNP309HDM2 polymorphism is associated with chemoresistance and poor survival in breast cancers harboring mutations in the TP53 gene. Breast Cancer Research and Treatment. 94: S160-S160.