Stanford Medicine has analysed thousands of breast cancer tumours and discovered that DNA patterns seen in the womb can predict the type and seriousness of Breast cancer many years later.
These results challenge the belief that most cancers start from random genetic mistakes over time. Instead, the DNA inherited from parents may decide if the immune system spots and destroys cancer-causing mutations or allows them to grow.
Christina Curtis, PhD, explained that people still know little about the inherited factors behind cancer and health, and most believe random errors or chance play the biggest role. Not every cancer appears by chance alone. Genes and the immune system both help defend the body against cancer.
This research offers a new theory about how breast cancer begins and develops, giving doctors new clues for tumour assessment. Curtis, the study’s senior author, led the project with postdoctoral scholar Kathleen Houlahan.
The idea that some tumours are aggressive and able to spread from the start was first put forward in 2015. Other studies have supported this, but these new findings show how early such changes take place. Research into what causes breast cancer continues to shift.
By uncovering how the immune system and cancer cells interact, the study may help improve how breast cancer is predicted and treated.
Predicting breast cancer risk
Currently, doctors use a few gene mutations to predict breast cancer risk. For example, BRCA1 and BRCA2 mutations can lead to breast and ovarian cancer in about one in 500 women. Li-Fraumeni syndrome raises the risk of cancers in both children and adults.
Experts now think that many healthy gene variants may offer long-lasting protection against cancer. This knowledge may lead to better predictions about cancer subtypes, spread, and aggressiveness.
Inherited traits such as blood type, hair colour, and eye colour all come from parents. Mutations in genes like BRCA1, BRCA2, and TP53 can increase a newborn’s cancer risk. However, finding other inherited changes that link to future cancer has proved tough.
Most cancer-related gene mutations occur in the body’s cells after birth. Each day, millions of cells divide and die, and mistakes can happen as DNA copies itself. Scientists spot cancer-causing mutations by comparing tumour DNA with normal DNA from blood or tissue.
Back in 2012, Curtis used machine learning to study somatic mutations in hundreds of breast cancers. She discovered 11 subtypes, each with different recovery chances and risks of returning. Four of these subtypes were more likely to come back after 10 or 20 years, which helps doctors plan treatments and discuss what patients may expect in the long term.
Proteins on cell surfaces
BRCA1 and BRCA2 mutations are linked to triple-negative breast cancer. The inherited genome may also affect which breast cancer subtype a person gets. Curtis explained that their team wanted to see how inherited DNA shapes tumour growth, so they tested the role of immunity.
Proteins on cell surfaces can reveal if breast cells are healthy or cancerous.
In this study, researchers looked at HLA mutants. T cells in the immune system check for abnormal protein markers, a bit like fashion inspectors. Cancer cells produce unusual proteins, while infected cells show viral proteins. These signs trigger T cells to attack.
Houlahan and Curtis examined oncogenes, which are normal genes that can fuel cancer if they malfunction. Sometimes, DNA copying errors make these genes behave differently. Curtis had already used these gene changes to identify breast cancer subgroups.
Some T cells may respond more strongly to clear signals of trouble. Oncogenes that stand out can trigger a bigger immune response. Multiple strong signals can drive T cells to act.
Researchers looked at tumours at different stages to see how inherited oncogene patterns affected subtype. They found that people with a high genetic load of clear immune signals, plus an HLA type that shows these signals, often had fewer tumours with certain aggressive gene amplifications. This was unexpected.
Pre-invasive cancers
Wandering immune cells can also encourage tumours that are harder to treat and come with a poorer outlook. Curtis said that, at an early stage, a heavy inherited load of these immune signals seems to protect against cancer. In cases where the immune system struggles, tumours with this high load may spread more quickly, but they may also shrink.
There is a constant struggle between tumours and the immune system. Some pre-invasive cancers may be caught and treated more easily, and many could disappear before anyone knows they exist. Sometimes, though, the immune response weakens.
Cancers can learn to dodge the immune system. This study clarifies how that happens and may help doctors find the best times and ways to treat cancers that avoid detection.
Researchers now plan to use the inherited genome to sort the 11 breast cancer subtypes Curtis described, helping personalise treatment, track recovery, and watch for recurrence.
Doctors already use this information to guide cancer immunotherapy and estimate cancer risk in healthy people from blood tests.
Curtis said their research started with a bold idea. Until now, experts hadn’t thought much about tumour origins and how they change over time. Looking at cancer through inherited DNA, genetic changes, and immune responses together helps explain the differences seen in cancer.
