Mohn Cancer Research Laboratory

Breast cancer therapy has improved significantly over the last decades. However, more than 3.700 Norwegian women are diagnosed with breast cancer (BC) and approximately 600 die from the disease annually, demonstrating that BC is a major health problem.

Currently there are few predictive biomarkers for BC therapy. Thus, while patients may be selected for endocrine and HER2 targeted therapies based on hormone receptor status and HER2 expression, we still can not precisely predict who will respond to each individual type of therapy for the majority of patients. In our recently completed first PETREMAC trial (completed accrual in August 2018), we systematically explored the benefits of different therapeutic options, selected based on established parameters (receptor status and HER2), but in addition TP53 (“the guardian of the genome”) mutation status. Tumors classified as Luminal A-like tumors (accounting for ~40% of all BC), characterized by high levels of hormone receptors and TP53 wt status, were treated with endocrine therapy in concert with a novel targeting agent alone. We confirmed endocrine therapy to be as efficient as chemotherapy. However, while endocrine therapy provided a high clinical response rate, few patients in this group achieved a pathological complete response (pCR). pCR is considered a good surrogate marker for long-term outcome in triple-negative and HER2 amplified breast cancers where neoadjuvant treatment is usually very efficient. In contrast, the impact of pCR is less clear for conventional neoadjuvant chemotherapy in luminal A-like breast cancer, where cytotoxic drugs are generally less effective.

In our next trial of personalized breast cancer therapy in the PETREMAC program, we will take a novel approach by implementing new endocrine regimens proven effective in metastatic breast cancer, into early treatment of Luminal A-like tumors. If successful, this may substantially enhance the benefit of endocrine therapy, to facilitate higher pCR rates and hopefully improved survival. Moreover, we amend the chemotherapy program for the other tumor subtypes, applying new types of targeted therapy aiming at improving pCR, but at the same time limiting toxicity. Importantly, systematic exploration of molecular parameters will allow for improved identification of patients for whom different treatment options may be optimal. Each tumor will be analysed for additional potential predictive factors; for tumors treated with endocrine therapy our main goal is to identify parameters predicting benefit from endocrine therapy, for tumors undergoing chemotherapy we focus on DNA repair defects, but also potential defects in the p53 pathway and other cell cycle regulators. By doing so, we aim at identifying predictive factors allowing individual therapy selection for patients. In the long term perspective, this may also enable development of novel therapeutic strategies.

Breast cancer (like most solid tumours) are heterogeneous. This means that every tumour consists of several subclones which are genetically different due to alterations arising during the evolution of the disease.

In collaboration with the Sanger Institute, we have performed multiple studies mapping the heterogeneity in early-stage (primary) breast tumours and the evolution of subclones, over time, towards a more advanced stage of the disease where the cancer has spread to other organs.

Key publications: 

• Venizelos et al Genome Medicine, 2022
• Yates et al Cancer Cell, 2017
• Yates et al Nature Med., 2015

The expression of the oncogene MDM2 is elevated in many cancers, and high expression levels are considered to cause tumour growth. In the general population there are multiple genetic variants (polymorphisms) in the promoter of this gene, and these are presumed to influence the levels of MDM2 expression and thus potentially cancer risk.

We have analyzed several MDM2 polymorphisms in a large number of samples from the Norwegian population and found that they have an impact on cancer risk. In particular we have found a polymorphism (SNP285) that affects the binding of both Sp1 and the estrogen receptor to reduce the risk of frequent female cancers (breast- and ovarian cancer).

Key publications:

• Gansmo et al. International J. Cancer, 2016
• Helwa et al. Scientific Rep., 2016
• Knappskog et al. European J. Cancer, 2012
• Knappskog et al. Cancer Cell, 2011

Malignant melanoma (cancer in melanocytes/nevi) is a type of cancer with particularly poor effect from conventional chemotherapy. However, in recent years, new immunotherapies have shown promising results and have become established as standard treatment.

We have two ongoing projects focusing on this disease: In one of the projects, we study the clonal evolution of metastases in melanoma patients with advanced disease and we evaluate the heterogeneity between different metastases within the same patients. In another project we analyze the underlying genetic causes of disease in families affected by a high number of melanoma cases, indicating an inherited factor to cause the risk of disease.  

Key publications:    

• Birkeland et al. Nature Communications 2018

The potential role of epigenetic changes in healthy cells with respect to risk of cancer later in life is controversial.

We have recently made a major breakthrough in this field. By combining studies of patients with established tumours with population-based studies, we have shown that abnormal methylation of the BRCA1 gene in some of the cells in the body, give a significantly higher risk of developing breast- and ovarian cancer later in life.

We have also demonstrated that the methylation of BRCA1 occurs early in the embryonic stage of development and that it affects many different organs in the body. We are aiming to pinpoint the direct link between BRCA1 methylation in normal cells and the clonal expansion of such cells towards tumours in affected individuals.

Key publications:

• Lønning et al. JAMA Oncology, 2022
• Lønning et al. ASCO annual meeting (oral presentation), 2022
• Lønning et al. Cell Stress, 2019
• Lønning et al. Annals of Internal Medicine, 2018

Breast cancer patients with seemingly similar disease may have very different responses to chemotherapy. We are performing genetic analyses of tumours from patients that have been treated with single chemotherapeutic drugs before surgery, and link our findings to detailed clinical records of the patients’ response to a given drug. This enables identification of genetic alterations predicting sensitivity or resistance to the individual drugs.

The aim of this project is to identify biomarkers that can be applied in the clinic to guide treatment choice for the individual patient, thereby enabling early administration of an optimal treatment regimen and sparing patients from side effects of inefficient drugs.

This project has led to implementation of several clinical trials.

Key publications:

• Knappskog et al. Molecular Oncol., 2015
• Knappskog et al. Breast Cancer Res., 2012
• Chrisanthar et al. PLoS ONE, 2008
• Geisler et al. Cancer Res., 2001
• Aas et al. Nature Med., 1996

subgroup of patients with advanced colorectal cancer have their metastases confined to the liver. These patients can be cured by surgery, although some experience relapse after the surgery has been performed.

We perform genetic analyses in different liver metastases from the same patients to evaluate the heterogeneity between them and to identify genetic alterations that can predict the outcome for patients after surgical removal of metastases from the liver.

Key publications:

• Sveen et al. PLoS Genetics, 2016
• Løes et al. International J. Cancer, 2016

Modern cancer research, both within basic laboratory research and clinical research involving patients, is increasingly dependent on generating, handling and interpreting large amounts of data. Often, there is no available software or established strategies to analyze the large quantities of data that are required for a specific project.

Therefore, a dedicated focus area in our research team is to develop our own, good methods for bioinformatic analyses. All processing of large-scale genetic data is performed inside SAFE, which is UiB’s secure data domain for sensitive information. There we have, among other resources, installed the top modern Illumina DRAGEN (Dynamic Read Analysis for GENomics) Bio-IT Platform which is customized for ultra-efficient analysis of genetic data. In addition, we continuously use our self-developed solutions for analysis of genomic and epigenetic data. 

Public repositories:

• Code at GitHub
• Data at DataverseNO
• Data at NCBI GEO 
   

Key publications:

• Nikolaienko et al. Bioinformatics, 2022
• Poduval et al. Clinical Epigenetics, 2020

• Nikolaienko, O., Eikesdal, H.P., Ognedal, E., Gilje, B., Lundgren, S., Blix, E.S., Espelid, H., Geisler, J., Geisler, S., Janssen, E.A.M., Yndestad, S., Minsaas, L., Leirvaag, B., Lillestøl, R., Knappskog, S. and Lønning, P.E. (2023). Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development. Genome Medicine, 15:104. https://doi.org/10.1186/s13073-023-01262-8

• Lønning, P.E., Nikolaienko, O., Pan, K., Kurian, A.W., Eikesdal, H.P., Pettinger, M., Anderson, G.L., Prentice, R.L., Chlebowski, R.T. and Knappskog, S. (2022). Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer. JAMA Oncology, e223846. doi: 10.1001/jamaoncol.2022.3846.

• Venizelos, A., Engebrethsen, C., Deng, W., Geisler, J., Geisler, S., Iversen, G.T., Aas, T. Aase, H.S., Seyedzadeh, M., Steinskog, E.S., Myklebost, O., Nakken, S., Vodak, D., Hovig, E., Meza‑Zepeda, L.A., Lønning, P.E., Knappskog, S. and Eikesdal, H.P. (2022). Clonal evolution in primary breast cancers under sequential epirubicin and docetaxel monotherapy. Genome Medicine, 14:86. https://doi.org/10.1186/s13073-022-01090-2.

• Eikesdal, H.P., Yndestad, S., Elzawahry, A., Llop-Guevara, A., Gilje, B., Blix, E.S., Espelid, H., Lundgren, S., Geisler, J., Vagstad, G., Venizelos, A., Minsaas, L., Leirvaag, B., Gudlaugsson, E.G., Vintermyr, O.K., Aase, H.S., Aas, T., Balmaña, J., Serra, V., … Lønning, P. E. (2021). Olaparib monotherapy as primary treatment in unselected triple negative breast cancer. Annals of Oncology, 32(2), 240–249. https://doi.org/10.1016/j.annonc.2020.11.009

• Yates, L.R., Gerstung, M., Knappskog, S., Desmedt, C., Gundem, G., Van Loo, P., Aas, T., Alexandrov, L.B., Larsimont, D., Davies, H., Li, Y., Ju, Y.S., Ramakrishna, M., Haugland, H.K., Lilleng, P.K., Nik-Zainal, S., McLaren, S., Butler, A., Martin, S., Glodzik, D., Menzies, A., Raine, K., Hinton, J., Jones, D., Mudie, L.J., Jiang, B., Vincent, D., Greene-Colozzi, A., Adnet, P-Y., Fatima, A., Maetens, M., Ignatiadis, M.,  Stratton, M.R., Sotiriou, C., Richardson, A.L., Lønning, P.E., Wedge, D.C., and Campbell, P.J. (2015). Subclonal diversification of primary breast cancer revealed by multiregion sequencing. Nature Medicine. 21(7): 751-759. 

• Sveen, A., Løes, I.M., Alagaratnam, S., Nilsen, G., Høland, M., Lingjærde, O.C., Sørbye, H., Berg, K.C.G., Horn, A., Angelsen, J-H., Knappskog, S., Lønning, P.E. and Lothe, R. (2016) Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection. PLoS Genetics. e1006225. doi: 10.1371/journal.pgen.1006225.

• Yates, L.R.*, Knappskog, S.*, Wedge, D.C, Farmery, J.H.R., Gonzalez, S., Martincorena, I., Alexandrov, L.B., Van Loo, P., Haugland, H.K., Lilleng, P.K., Gundem, G., Gerstung, M., Pappaemmanuil, E., Gazinska, P., Bhosle, S.G., Jones, D., Raine, K., Mudie, L., Latimer, C., Sawyer, E., Desmedt, C., Sotiriou, C., Stratton, M.R., Sieuwerts, A., Lynch, A.G., Martens, J.W., Richardson, A.L., Tutt, A., Lønning, P.E. and Campbell, P.J. (2017). Genomic evolution of breast cancer metastasis and relapse. Cancer Cell. 32: 169-184.

• Lønning, P.E., Berge, E.O., Bjørnslett, M., Minsaas, L., Chrisanthar, R., Høberg-Vetti, H., Dulary, C., Busato, F., Bjørneklett, S., Eriksen, C., Kopperud, R., Axcrona, U., Davidson, B., Bjørge, L., Evans, D.G., Howell, A., Salvesen, H.B., Janszky, I., Hveem, K., Romundstad, P., Vatten, L., Tost, J., Dørum, A. Knappskog, S. (2018). White blood cell BRCA1 promoter methylation status and ovarian cancer risk. Annals of Internal Medicine. 168(5): 326-334.

• Birkeland, E., Zhang, S., Poduval, D., Geisler, J., Nakken, S., Vodak, D., Meza-Zepeda, L.A., Hovig, E., Myklebost, O., Knappskog, S., Lønning, P.E. (2018). Patterns of genomic evolution in advanced melanoma. Nature Communications. 1-12. DOI:10.1038/s41467-018-05063-1.

PubMed

For en samlet oversikt over alle publikasjoner fra gruppens medlemmer i PubMed, se lenke.

2011

Dipak Sapkota

«S100 Gene Family Members in Oral Squamous Cell Carcinomas (OSCCs): Functional Characterization of S100A14 in Proliferation and Invasion of OSCC Derived Cells».

er - Brystkreftgruppen

Brystkreft under kjemoterapi og nevroendokrine karsinomer

Andreas Venizelos disputerer 08.10.2021 for ph.d.-graden ved Universitetet i Bergen med avhandlingen "Mutational characterisation of cancers".

Genetics and epigenetics in melanoma and breast cancer

Deepak B Poduval disputerer 15.12.2020 for ph.d.-graden ved Universitetet i Bergen med avhandlingen "Studies on sequencing analyses of genetic and epigenetics features in melanoma and breast cancer".

Betydningen av PTEN og PI3K-Akt-signalering ved brystkreft

Synnøve Yndestad disputerer torsdag 19. april 2018 for ph.d.- graden ved Universitet i Bergen med avhandlingen: "The role of PTEN, PI3K-Akt-mTOR signaling and pseudogene PTENP1 in breast cancer"

Evolusjon og behandlingsresistens i melanom og brystkreft

Einar Elvbakken Birkeland disputerer torsdag 12. april 2018 for ph.d.-graden ved Universitet i Bergen med avhandlingen: "Genomic evolution and therapy resistance in melanoma and breast cancer"

Hvorfor responderer brystkreftceller ulikt på cellegift?

Johanna Huun disputerer 28.02.2017 for ph.d.-graden ved Universitetet i Bergen med avhandlingen:"Response to doxorubicin in breast cancer cells; The role of p53-, MDM2- and pRb-variants ".

Spreiing frå tjukktarmskreft - genetiske variasjonar

Inger Marie Løes disputerer 12.04.16 for ph.d.-graden ved Universitetet i Bergen med avhandlinga: "Genetic heterogeneity in liver metastases from colorectal cancer"

Gir genetiske variasjoner økt kreftrisiko?

Liv Gansmo disputerte 20. desember 2013 for ph.d.-graden ved Universitetet i Bergen med avhandlingen: «MDM2 polymorphisms: The impact of four promoter variants on cancer risk».

Hvilke faktorer avgjør østrogennivåer i kreft?

Anne Hege Straume disputerte 26.10.2012 for ph.d-graden ved Universitetet i Bergen med avhandlingen: “A genetic perspective on estrogen metabolism in cancer: The potential role of alterations affecting CYP19, 17β-HSD2 and 17β-HSD7.”

Genendringar og resistens mot cellegift i brystkreft

Elisabet Ognedal Berge disputerte fredag 19. november 2010 for ph.d.-graden ved Universitetet i Bergen med avhandlinga: ”Chemotherapy Resistance in Breast Cancer: The potential role of Chk2 splice variants and RB1 alterations”.

Genforandringer ved føflekkreft

Christian Busch disputerte 26. oktober 2010 for ph.d.-graden ved Universitetet i Bergen med avhandlingen: ”Genetic biomarkers as prognostic and predictive factors in metastatic malignant melanoma”.

Genforandringer som årsak til kjemoresistens ved brystkreftbehandling

Ranjan Chrisanthar disputerte fredag 13. mars 2009 for PhD-graden ved Universitetet i Bergen med avhandlingen: ”Resistance to Chemotherapy in Breast Cancer: Potential role of p21B, p27 and the p53 apoptotic pathway”.

Arvelige genendringar og risiko for kreft

Cand. Scient. Stian Knappskog disputerte fredag 30. mars 2007 for PhD graden ved Universitetet i Bergen med avhandlinga: ”Germline Genetic Alterations Affecting CDKN2A, MDM2 and CDKN1A in Melanoma and Breast Cancer Patients”.

Genetisk grunnlag for resistens mot cellegiftbehandling ved brystkreft

Vidar Staalesen disputerte fredag 16. februar 2007 for PhD-graden ved Universitetet i Bergen med avhandlingen: ”Chemoresistance in Breast Cancer: Alterations in the p53 Pathway and Integrity of the DNA Damage Response”

Hemming av østrogenproduksjon hos brystkreftpasienter etter menopause

Cand.med. Jürgen Geisler disputerte 24 mai 2002 for dr. philos. - graden med avhandlingen: Aromatase Inhibition in Postmenopausal Breast Cancer Patients.

Insulin-liknende vekstfaktor og brystkreft

Cand. Med. Svein Inge Helle disputerte 14 juni 2001 for dr. philos.-graden med avhandlingen: The Insulin-like Growth Factor System in Breast Cancer - Effects of Endocrine Treatment and Alterations in Tumor Burden.

22.11.2022

2022

Kjersti Elvestad Hestetun

«Predictive and prognostic markers in localized colon cancer».

2018

Havjin Jacob

«Prognostic biomarkers in stage II and III colorectal cancer: A study with focus on microRNAs and S100A4».

2016

Luka Stanisavljevic

«Molecular and clinicopathological factors with emphasis on prognostic and predictive factors for survival».

2012

Mette Pernille Myklebust

«Molecular markers of anal cancer and colorectal cancer.A study of microRNAs, desmosomal cadherins and cyclin D1 isoforms».

2023

Jana Vásquez Navarro

Expression changes in BRCA1a and BRCA1b transcripts in response to PARP inhibition

2017

Åsta Ottesen

BRCA1 promoter methylation: the influence on gene expression and the effect of long term drug treatment

2016

Mia Madeleine Ankerud

Functional studies of miR-155 in breast cancer cell lines

Linn Andersen Rosenberg

MDM4 splice variants: Impact on the p53 pathway in breast cancer cell lines

2010

Karen Marie Hagen 

Functional consequences of 11 TP53 deletion mutants present in metastatic breast cancer

2022

2022 SABCS

6.-10. desember 2022 - San Antonio, USA

"Homologous recombination deficiency across subtypes of primary breast cancer" (posterpresentasjon)

Engebrethsen, C.*, Yndestad, S.*, Herencia-Ropero, A., Nikolaienko, O., Vintermyr, O.K., Lillestøl, R.K.,  Minsaas, L., Leirvaag, B., Iversen, G.,2, Gilje, B., Blix, E.S., Espelid, H., Lundgren, S., Geisler, J., Vassbotn, L.J., Aase, H.S., Aas, T., Llop-Guevara, A., Serra, V., Lønning, P.E., Knappskog, S., Eikesdal, H.P.

Bioinformatics in Bergen                      

13.-14. juni 2022 - Solstrand, Bergen, Norway

"epialleleR: an R/BioC package for sensitive allele-specific methylation analysis in NGS data" (foredrag)

Nikolaienko, O., Lønning, P.E., Knappskog, S.

"Clonal evolution in primary breast cancers under sequential epirubicin and docetaxel monotherapy" (posterpresentasjon)

Venizelos, A., Engebrethsen, C., Deng, W., Geisler, J., Geisler, S., Aas, T., Aase, H., Seyedzadeh, M., Steinskog, E.S., Myklebost, O, Nakken, S., Vodak, D., Hovig, E., Meza-Zepeda, L.A., Lønning, P.E., Knappskog, S.*, Eikesdal, H.P.*

ASCO Annual Meeting

3.-7. juni 2022 - Chicago, USA

"Constitutional BRCA1 methylation and risk of incident triple-negative breast cancer and high-grade serous ovarian cancer" (foredrag)

Lønning, P.E., Nikolaienko, O., Pan, K., Kurian, A.W., Eikesdal, H.P., Pettinger, M., Anderson, G.L., Prentice, R.L.,  Chlebowski, R.T.,  Knappskog, S.

SGO Annual Meeting on Women's Cancer

18.-21. mars 2022 - Phoenix, Arizona, USA

"Is APOBEC3A/B Deletion polymorphism Associated with the Risk of Ovarian Cancer in the Norwegian Population? A Case-Control Study" (posterpresentasjon)

Gansmo, L.B., Sofiyeva, N., Bjørnslett, M.B., Lønning, P.E., Knappskog, S.

"Association of APOBEC3A/B deletion variant with endometrial cancer risk in the Norwegian population: A case-control study" (posterpresentasjon)

Sofiyeva, N., Krakstad, C., Gansmo, L., Lønning, P.E., Knappskog, S. 

2021

Onkologisk Forum 

18.-19. november 2021 - Oslo, Norway

"Clonal evolution of breast cancer during neoadjuvant chemotherapy" (foredrag)

Venizelos, A., Engebrethsen, C., Deng, W., Geisler, J., Geisler, S., Iversen, G.T., Aas, T., Aase, H.S., Seyedzadeh M., Steinskog E.S., Myklebost O., Nakken S., Vodak D., Hovig E., et al. 

2019

ESMO Congress 2019

27. september-1.oktober 2019 - Barcelona, Spania

"Neoadjuvant olaparib monotherapy in primary triple negative breast cancer" (posterpresentasjon)

Eikesdal, H.P., Yndestad, S., Blix, E.S., Lundgren, S., Vagstad, G., Espelid, H., Gilje, B., Janssen, E.A., Geisler, J., Aas, T., Aase, H., Knappskog, S., Lønning, P.E.

"Neoadjuvant endocrine therapy with palbociclib in patients with high-risk breast cancer" (posterpresentasjon)

Lønning, P.E., Clausen, C., Blix, E.S., Lundgren, S., Vagstad, G., Espelid, H., Gilje, B., Janssen, E.A., Geisler, J., Aas, T., Aase, H., Knappskog, S., Lønning, P.E.

AACR Annual Meeting

29. mars-3. april 2019 - Atlanta, USA

"Whole exome sequencing (WES) of locally advanced breast cancers treated with monotherapy" (posterpresentasjon)

Løes, I.M., Venizelos, A., Knappskog, S., Eikesdal, H.P., Lønning, P.E.

7th CCBIO Annual Symposium

13.-14. mai 2019 - Solstrand, Bergen, Norway

"Genetic alterations affecting treatment response in locally advanced breast cancers " (posterpresentasjon)

Venizelos, A.,Clausen, C., Knappskog, S., Eikesdal, HP. and Lønning PE.