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Exploring the link between MORF4L1 and risk of breast cancer
University of Texas Health Science Centre San Antonio.
Chemoresistance and Predictive Factors of Tumor Response and Stromal Microenvironment, IDIBELL, Spain.
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2011 (English)In: Breast Cancer Research, ISSN 1465-542X, Vol. 13, no 2Article in journal (Refereed) Published
Abstract [en]

Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P(trend) = 0.45 and 0.05, P(2df) = 0.51 and 0.14, respectively; and rs10519219, P(trend) = 0.92 and 0.72, P(2df) = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.

Place, publisher, year, edition, pages
Current Science Ltd / BioMed Central , 2011. Vol. 13, no 2
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-69933DOI: 10.1186/bcr2862ISI: 000292694600029OAI: diva2:433157
Available from: 2011-08-09 Created: 2011-08-08 Last updated: 2013-03-28

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Stenmark Askmalm, Marie
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OncologyFaculty of Health SciencesDepartment of Clinical Pathology and Clinical Genetics
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