Inherited breast cancer susceptibility: novel factors, cellular mechanisms and disease modelling

Breast cancer is the most common malignancy in women. It is strongly influenced by hereditary risk factors (e.g. BRCA1, BRCA2 and PALB2 gene mutations), a majority of which still remain unknown. Of the known predisposing gene mutations, many result in compromised capability to cope with cellular DNA damage. The aim of our project is to identify novel breast cancer predisposing gene defects, resolve the related disease pathomechanisms, and ultimately, to improve diagnostics and genetic counseling. Northern Finnish breast cancer cohorts are used for the identification of novel susceptibility genes and alleles. For the functional characterization we use several genomics and transcriptomics approaches and combine these with CRISPR/Cas9 gene editing, sophisticated biochemical assays and disease modelling. Elucidating genetic susceptibility for breast cancer refines clinical risk assessment, and facilitates personalized cancer screening, aiming for improvements in prevention and early diagnosis. Improved knowledge on cancer predisposition genes and characterization of the mutated alleles in both normal tissues and in progression towards malignancy, combined with the knowledge on additional genetic and epigenetic alterations that occur to promote tumorigenesis, is expected to provide better tools also for targeted therapies.

Selected publications:

Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, Mannermaa A, Kallioniemi A, Pylkäs K, Karppinen SM, Rapakko K, Miron A, Sheng Q, Li G, Mattila H, Bell DW, Haber DA, Grip M, Reiman M, Jukkola-Vuorinen A, Mustonen A, Kere J, Aaltonen LA, Kosma VM, Kataja V, Soini Y, Drapkin RI, Livingston DM, Winqvist R. A recurrent mutation in PALB2 in Finnish cancer families. Nature 446:316-319, 2007.

Nikkilä J, Parplys AC, Pylkäs K, Bose M, Huo Y, Borgmann K, Rapakko K, Nieminen P, Xia B, Pospiech H, Winqvist R. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nat Commun 4:2578, 2013.

Mantere T, Winqvist R, Kauppila S, Grip M, Jukkola-Vuorinen A, Tervasmäki A, Rapakko K, Pylkäs K. Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility. PLoS Genet 12:e1005816, 2016.

Tervasmäki A, Mantere T, Eshraghi L, Laurila N, Tuppurainen H, Ronkainen VP, Koivuluoma S, Devarajan R, Peltoketo H, Pylkäs K. Tumor suppressor MCPH1 regulates gene expression profiles related to malignant conversion and chromosomal assembly. Int J Cancer. 2019 145(8):2070-2081.

Yang X, Leslie G, Doroszuk A, Schneider S, et al. Pylkäs K et al. Southey M, Winqvist R, Easton DF, Foulkes WD, Antoniou AC, Tischkowitz M. Cancer Risks Associated With Germline PALB2 Pathogenic Variants: An International Study of 524 Families. J Clin Oncol. 2020 In press.