Scientists have carried out one of the largest experimental studies of breast cancer variants to date, helping pinpoint genetic changes that are most likely to contribute to the development of the disease.
The study, led by a team at The Institute of Cancer Research, London, analysed over 5,000 genetic variants linked to breast cancer risk, identifying over 700 across 140 risk regions appearing to alter gene activity. One gene emerged as a likely target of a particular risk variant, with its activity linked to a breast cancer subtype.
The findings, published in the journal Human Genetics and Genomics Advances, provide a prioritised list of variants for future investigation and offer new insights into the genetic changes that contribute to inherited breast cancer risk. The charity Breast Cancer Now provided the majority of the funding, with additional support from Cancer Research UK.
Breast cancer has a strong heritable basis, meaning some of a person’s risk of developing the disease can be inherited through their genes. Researchers have already identified 196 regions of DNA associated with breast cancer but determining exactly which genetic variants within those regions are responsible, and how they influence disease risk, remains a major challenge. Many of these variants are found in non-coding regions of DNA, meaning that instead of directly altering proteins, they can influence how genes are regulated and expressed.
To investigate the variants most likely to have a biological effect, the research team used a high-throughput technique, known as a ‘massively parallel reporter assay’, to simultaneously test 5,116 candidate variants that had previously been identified through large collaborative breast cancer risk genetic studies. This allowed them to assess whether different versions of each variant affected nearby DNA sequences that regulate gene activity
Of those screened, 709 showed significant differences in regulatory activity in T-47D breast cancer cells, suggesting they may play a functional role in influencing cancer risk.
Through laboratory follow-up analysis, the team identified CCDC88C as a likely target of a risk variant called rs7153397. The variant appeared to affect the regulation of CCDC88C, a gene previously linked to breast cancer progression and metastasis, suggesting a potential mechanism through which the variant could influence breast cancer risk.
The team also analysed tumour data from thousands of patients and found that CCDC88C activity was higher in oestrogen receptor-positive (ER+) breast cancers than in the oestrogen receptor-negative (ER-) tumours. Among patients with ER+ breast cancer, higher levels of CCDC88C were also associated with improved survival.
By providing a refined list of risk variants, breast cancer researchers can now prioritise which of those should be studied in greater detail.
First author Kate Mackie, a PhD student in the in the Division of Breast Cancer Research at The Institute of Cancer Research (ICR) at the time of the study, said: “It’s rewarding to see our approach pinpoint promising variants with demonstrable regulatory effects for future investigation. Next steps would include investigating the additional variants highlighted by the study, exploring how their effects differ across breast cancer subtypes and cell types, and studying the biological role of CCDD88C in greater detail.”
Senior author Dr Syed Haider, Leader of the Breast Cancer Data Science Group in the Division of Breast Cancer Research, said: “While our work alone cannot identify casual variants and gene targets for the reported 196 breast cancer risk regions, our intricate research provides a clearer understanding of the biological pathways involved in breast cancer susceptibility. Particularly CCDC88C’s role in the biology of ER+ breast cancer – contributing to improved risk prediction and potentially unravelling new therapeutic opportunities for patients.”
- Mackie K, Kemp H, Gunnell A, et al. Massively parallel functional profiling prioritizes breast cancer risk variants and implicates CCDC88C in ER-positive breast cancer. HGG Adv. 2026;7(4):100674. doi:10.1016/j.xhgg.2026.100674