Genetic variation is a known contributor to cancer risk. The proportion of risk due to genetic factors varies by cancer type but has been estimated to account for 30% or more of the risk for some types. The identification of additional genetic variants that influence risk for specific types of cancer is a major research focus in the field. However, investigations into whether various cancers share genetic risk factors have been more limited. The knowledge of whether there are genetic components in common among different types could advance our understanding of mechanistic drivers of cancer development. Researchers from the Public Health Sciences Division recently published results from a study that assessed genetic correlations among six solid cancers in the journal Nature Communications.
The authors used data from six cancer-specific genome-wide association studies (GWAS) comprising in total nearly 600,000 individuals (approximately half of the study participants were non-cancer controls and half were cancer cases). The large population is a major strength of the study, as it is the largest such investigation to assess genetic correlations among cancer types conducted to date. The study was possible through the OncoArray Network (see Amos et al., 2016), an international collaboration formed to study the genetics of multiple types of cancer. Dr. Sara Lindstroem, assistant member at Fred Hutch and one of the senior authors of the study elaborated on the Network, “a group of scientists in specific cancers (e.g. breast, prostate, ovarian) came together to design a genotyping array that assessed genetic variation linked to the different cancers. The collaboration made it possible for us to genotype a large number of individuals, which drove down the per-sample cost.”
Leveraging from an analytical method known as linkage disequilibrium score regression (LDSC), the researchers used GWAS summary statistics to estimate genetic correlations between six cancers: breast, prostate, colorectal, ovarian, head/neck, and lung. Significant correlations were found between several pairs of cancer (see figure). “This paper quantifies for the first time the shared heritability between some common cancers. We show a shared heritability between lung and head/neck cancer, colorectal and lung cancer, breast and ovarian cancer, breast and lung cancer, and breast and colorectal cancer. In contrast, some cancer pairs showed minimal shared heritability including ovarian and prostate, lung and prostate and breast and head/neck,” said Dr. Lindstroem.
The authors then assessed genetic correlations between the six types of cancer and 38 non-cancer traits/other diseases. Several significant correlations were identified in this analysis. For example, correlations between smoking and lung cancer and head/neck cancer were significant. In addition, waist to hip ratio and lung cancer, body mass index and colorectal cancer, and high-density lipoprotein and lung cancer correlations were all statistically significant. However, most of the correlations between non-cancer traits and cancer were not significant. “We found no evidence that cancer shares a genetic component with previously suggested risk factors such as cardiovascular traits (coronary artery disease, hypertension, and blood pressure) or sleep characteristics (chronotype, duration, and insomnia),” Dr. Lindstroem explained.
This study provides strong evidence that some cancer types have genetic overlap and lays the foundation for additional studies to assess multiple cancers at the same time. Dr. Lindstroem described plans for follow-up work, “We are in the process of conducting a cross-cancer genome-wide association study, where we are looking to find genetic variants that are linked to cancer overall, or at least to a subset of cancers. As part of this work we have expanded the number of cancers we study from six (as in the Nature Communications paper) to twelve.”
Fred Hutch/UW Cancer Consortium members Sara Lindstroem, Chu Chen, Christopher Li, Polly Newcomb, Amanda Phipps, Mary Anne Rossing, Janet Stanford, Catherine Tangen, Emily White, and Ulrike Peters contributed to this research.
This research was supported by the National Cancer Institute.
Jiang X, Finucane HK, Schumacher FR, et al. 2019. Shared heritability and functional enrichment across six solid cancers. Nature Communication. doi: 10.1038/s41467-018-08054-4.
Amos CI, Dennis J, Wang Z, et al. 2016. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers. Cancer Epidemiology, Biomarkers and Prevention. doi: 10.1158/1055-9965.EPI-16-0106.