In a significant discovery that greatly enhances our knowledge of tumor evolution, researchers have identified genetic biomarkers that can forecast the type of breast cancer a patient may develop.
A comprehensive study conducted by Stanford Medicine on numerous cases of breast cancer has revealed that the gene sequences inherited at birth can accurately predict the type of breast cancer an individual may develop many years later, as well as its potential fatality.
This study challenges the conventional belief that the majority of cancers emerge due to random mutations that accumulate over time. Instead, it indicates the active participation of genetic factors in determining the type and severity of breast cancer.
The genetic sequences we receive from our parents, known as our germline genome, play a crucial role in determining whether cells with potential cancer-causing mutations are detected and eliminated by the immune system or go undetected and develop into early-stage cancers. According to Christina Curtis, PhD, the RZ Cao Professor of Medicine and a professor of genetics and biomedical data science, aside from a small number of highly influential genes that increase the risk of cancer, the impact of hereditary factors is not well understood, and most cancers are believed to be the result of random errors during cell division or simply bad luck.The process of tumor formation is not random, but rather influenced by genetic factors and immunity. This discovery introduces a new set of biomarkers for predicting tumor progression and offers a fresh perspective on the origins of breast cancer. The study, led by senior author Curtis and lead author Houlahan, will be published in Science on May 31, 2022. In 2015, the researchers suggested that certain tumors are inherently aggressive, with their malignant and metastatic capabilities determined at an early stage.The disease progression,” Curtis mentioned. “We and others have since validated this discovery across various tumors, but these results shed a whole new perspective on just how early this occurs.”
An innovative perspective on cancer’s inception
The research offers a nuanced and powerful new comprehension of the interaction between newly developed cancer cells and the immune system, which is likely to assist researchers and health professionals in better anticipating and combating breast tumors.
Currently, only a few well-known cancer-related mutations in genes are consistently used to forecast cancers. These include BRCA1 and BRCA2 mutations, found in approximately 1 in 500 women, increase the risk of breast or ovarian cancer. Less common mutations in the TP53 gene cause Li Fraumeni syndrome, which makes individuals more susceptible to tumors in childhood and adulthood. The study suggests that there are possibly dozens or even hundreds of other gene variations present in healthy individuals that play a role in preventing cancer. This discovery not only helps predict the type of breast cancer a person may develop, but also provides insight into its aggressiveness and likelihood of spreading.
It is expected that identifying the subtype that these inherited variants belong to will be. Besides that, we predict that these inherited variations could impact an individual’s likelihood of developing breast cancer.”
Our germline genome refers to the genes we receive from our parents. These genes reflect the genetic characteristics of our parents and can differ slightly among individuals, resulting in different physical traits such as eye color, hair color, or blood type. Some of these inherited genes may have mutations that increase the risk of cancer, such as BRCA1, BRCA2, and TP53. However, identifying other germline mutations that are strongly linked to future cancers has been challenging.
In comparison, most genes associated with cancer are.The somatic genome, or the part of our genetic material that is not passed down through generations, is constantly changing as our cells divide and die. Each time our DNA is copied, mistakes can occur and mutations can build up. Researchers often compare the DNA in tumors with the germline genomes in blood or normal tissues to identify the specific changes that may have led to the development of cancer in a cell.
Identifying different types of breast cancers
In 2012, Curtis used machine learning to analyze the various somatic mutations present in thousands of breast cancers. This allowed her to classify the disease into 11 subtypes.Of the 11 different types of breast cancer, four were found to have a higher likelihood of recurring even 10 or 20 years after diagnosis. This information is crucial for doctors when making decisions about treatment and discussing long-term outlook with their patients.
Previous research has indicated that individuals with inherited BRCA1 or BRCA2 mutations are more likely to develop triple negative breast cancer. This suggests that genetic factors may influence the specific subtype of breast cancer that a person may develop.
“Our goal is to understand the different subtypes of breast cancer and their outcomes, allowing us to provide better care for our patients,” said the lead researcher.Houlahan said it is important to understand how genetic DNA could shape the development of a tumor. They examined the immune system closely for this purpose.
In the world of biology, it is a peculiar fact that even healthy cells regularly adorn their outer membranes with small portions of the proteins they contain. This outward display reflects their internal characteristics.
The basis for this display consists of HLA proteins, which vary greatly among individuals. Similar to fashion police, T cells, a type of immune cell, roam the body searching for any suspicious or overly flashy displays (known as epitopes) that may indicate something is amiss.Houlahan and Curtis chose to concentrate on oncogenes, which are regular genes that, when altered, can release a cell from regulatory pathways intended to keep it in line. Usually, these alterations come in the form of numerous copies of the regular gene, lined up end to end along the DNA – the outcome of a type of genomic stutter known as amplification. Amplifications in certain oncogenes drive various cancer pathways and were utilized to identify cancer cells inside the cell. A cell infected with a virus will display bits of viral proteins; a sick or cancerous cell will adorn itself with abnormal proteins. These missteps prompt the T cells to annihilate the wrongdoers.to distinguish one subtype of breast cancer from another in Curtis’ original research.
The importance of showiness
The scientists were curious if highly recognizable markers would be more likely to catch the attention of T cells compared to other, more subtle displays (like dangling, golf ball-sized turquoise earrings versus a simple silver stud). If this were the case, a cell that had inherited a flashy version of an oncogene might have a harder time amplifying it without alerting the immune system, unlike a cell with a more modest version of the same gene. (One pair of overly showy turquoise earrings can be forgiven; but five pairs might be a bit much).
The researchers examined almost 6,000 breast tumors at different stages of the disease to determine if the subtype of each tumor was linked to the patients’ inherited oncogene sequences. They discovered that individuals who had inherited an oncogene with a high germline epitope burden (or lots of bling) and an HLA type that could prominently display that epitope were much less likely to develop breast cancer subtypes in which that oncogene is amplified. However, there was a surprise. They also found that cancers with a large germline epitope burden caused a patrolling fashionista T cell to switch from tutting to terminating.The burden of genetic epitopes that evade the roaming immune cells during their early development has been found to result in more aggressive tumors with a poorer prognosis compared to those that are less resistant. “At the early, pre-invasive stage, a high germline epitope burden is protective against cancer,” Houlahan said. “But once it’s been forced to wrestle with the immune system and come up with mechanisms to overcome it, tumors with high germline epitope burden are more aggressive and prone to metastasis. The pattern flips during tumor progression.” “Basically, there is a tug of war between tumor and immune cells,” Curtis said. “In the preinvasive setting, the nasccancer subtypes, enabling a more targeted approach to treatment. This could lead to more personalized and effective therapies for patients, with the potential to improve outcomes and reduce side effects. The team also hopes that their findings will contribute to a better understanding of breast cancer biology and help to identify new therapeutic targets. Overall, the study represents an important step towards realizing the full potential of precision medicine in the treatment of breast cancer.The identification of cancer subtypes by Curtis can help with making treatment decisions and improving prognoses and monitoring for recurrence. The findings from the study may also provide additional information for personalized cancer immunotherapies and could potentially allow clinicians to predict an individual’s risk of cancer from a simple blood sample in the future.
Curtis stated, “We had a bold hypothesis to begin with. The field had not previously considered tumor origins and evolution in this manner. We are now looking at other cancers through the perspective of heredity, acquired factors, and tumor-immune co-evolution.”
This study was supported by a grant from the National Institutes of Health.DP1-CA238296 and U54CA261719, the Canadian Institutes of Health Research, and the Chan Zuckerberg Biohub funded the research.
