Research
Multi-cancer studies
Cancer is a complex disease with both genetic and environmental risk factors. Cancer tends to cluster in families, and relatives to affected individuals are themselves at higher risk to develop the same cancer. In addition, some types of cancers (for example breast and ovarian cancer) tend to co-cluster in the same family. It is not known how much of this co-clustering is due to shared environment versus shared genetics. Most cancer epidemiological studies focus on individual cancer types, ignoring any shared heritability across cancers. In contrast, studies by our group and others show that common cancers share genetic origins. Thus, simultaneous study of multiple cancer types holds promise for further understanding the drivers of cancer development.
Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with cancer risk, but much of cancer heritability remains unexplained. Our group leverages cancer GWAS data with the aim of identifying additional cancer susceptibility loci and further understanding the biological pathways leading to cancer. Currently, we are using GWAS and sequence data or summary statistics in multiple cross-cancer studies using publicly available data (e.g., dbGaP and UK Biobank).
Relevant papers
Chen H, Majumdar A, Wang L, (other authors), Kraft P, Pasaniuc B, Lindström S. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals. HGG Adv. 2021 Jul 8;2(3):100041. PMCID: PMC8336922.
Jiang X, Finucane H, Schumacher F, (other authors), Amos CI, Kraft P, Lindström S. Shared heritability and functional enrichment across six solid cancers. Nature Comm. 2019 10: 431. Published Jan 25. PMCID: PMC6347624.
Gao C, Patel CJ, Michailidou K, (other authors), Pierce BL, Lindström S, Kraft P on behalf of GAME-ON. Mendelian randomization study of adiposity-related traits and risk of breast, ovarian, prostate, lung and colorectal cancer. Int J Epidemiol. 2016 Jul 17. PMCID: PMC6372135.
Chen H, Kichaev G, Bien SA, MacDonald JW, Wang L, Bammler TK, Auer P, Pasaniuc B, Lindström S. Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues. Hum Genet. 2019 Oct;138(10):1019-1104.
Breast cancer and mammographic density
Like many other cancer types, breast cancer has been linked to both genetic and non-genetic risk factors, and the genetic architecture is largely unknown. Our group aims to identify genetic variants associated with breast cancer, and to study gene-environment interactions for common and rare genetic variants. To do this, we are working with the Breast Cancer Association Consortium (BCAC), an international collaboration with GWAS data on > 120,000 breast cancer cases and 100,000 controls, and the CARRIERS consortium with exome sequencing data for cancer predisposition genes in > 30,000 breast cases and 30,000 controls.
To further understand the genetic architecture of breast cancer, we are conducting multiple studies of mammographic density, a measure of epithelial and stromal tissue in the breast, and one of the strongest risk factors for breast cancer. By studying mammographic density, we aim to increase our understanding of the biology underlying breast tissue composition and its role in breast cancer development. Our group has led multiple initiatives to map the genetic architecture of mammographic density, and our results strongly suggests that mammographic density and breast cancer share a genetic origin.
We are currently conducting Mendelian Randomization and gene-environment interaction studies of mammographic density leveraging data from the BCAC and Markers Of Density (MODE) consortium.
Relevant papers
Lindström S, Thompson DJ, Paterson AD, (other authors), Boyd NF, Vachon CM, Tamimi RM. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk. Nature Comm. 2014 Oct 24;5:5303. PMCID: PMC4320806.
Michailidou K*, Lindström S*, Dennis J*, (other authors), Simard J, Kraft P, Easton D. Association analysis identifies 65 new breast cancer loci. Nature. 2017 Nov 2;551(7678):92-94. *These authors contributed equally. PMCID: PMC5798588.
Kapoor PM, Lindström S, Behrens S, (other authors), Easton DF, Milne RL, Chang-Claude J; Breast Cancer Association Consortium. Assessment of interactions between 205 breast cancer susceptibility loci and 13 established risk factors in relation to breast cancer risk, in the Breast Cancer Association Consortium. Int J Epidemiol. 2019 Oct 12. PMCID: PMC7426027.
Chen H, Yaghjyan L, Li C, Peters U, Rosner B, Lindström S*, Tamimi R*. Interactions between mammographic density phenotypes and established risk factors on breast cancer risk by tumor subtype and menopausal status. Am J Epidemiol. 2021 Jan 4; 190(1):44-58. PMCID: PMC7946796.
Haas CB, Chen H, Harrison T, (other authors), Vachon C, Tamimi RM, Lindström S. Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian Randomization. Breast Cancer Res Treat. 2024 Apr 24. doi: 10.1007/s10549-024-07306-w. Online ahead of print. PMID: 38653906.
Venous thromboembolism
Venous thromboembolism (VTE) is a disorder that includes deep vein thrombosis (DVT) and pulmonary embolism (PE). A DVT occurs when a blood clot forms in a deep vein (usually in the lower leg, thigh or pelvis) and a PE occurs when a clot ends up in the lungs. VTE is a complex trait associated with both genetic and non-genetic factors. Our group is interested in understanding the role of genetics and lifestyle factors on the risk of VTE. In collaboration with the International Network Against Venous Thrombosis (INVENT) consortium, we have identified multiple genetic risk factors for VTE.
Relevant papers
Lindström S, Wang L, Smith EN, (other authors), Kabrhel C, Trégouët DA, Smith NL. Genomic and Transcriptomic Association Studies Identify 16 Novel Susceptibility Loci for Venous Thromboembolism. Blood. 2019 Nov 7;134(19):1645-1657. PMCID: PMC6871304.
Lindström S, Brody JA, Turman C, (other authors), Kraft P, Smith NL, Kabrhel C; INVENT Consortium. A large-scale exome array analysis of venous thromboembolism. Genet Epidemiol. 2019 Jun;43(4):449-457. PMCID: PMC6520188.
Kim J, Kraft P, Hagan KA, Harrington LB, Lindström S, Kabrhel C. Interaction of a genetic risk score with physical activity, physical inactivity, and body mass index in relation to venous thromboembolism risk. Genet Epidemiol. 2018 Jun;42(4):354-65.
Lindström S, Germain M, Crous-Bou M, (other authors), Tregouet D, Kabrhel; INVENT Consortium. Assessing the causal relationship between obesity and venous thromboembolism through a Mendelian Randomization study. Hum Genet. 2017 May 20. PMID: 28528403. PMCID: PMC5531049.
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