A study from the Stanford University School of Medicine (USA), which analyzed thousands of cases of breast cancer, challenges the belief that most cancers occur as a result of random mutations that accumulate throughout our lives and points out, however, that the genetic sequences inherited from our parents – known as the germline genome – can determine whether cells with possible cancer-causing mutations are recognized and eliminated by the immune system or, on the contrary, go unnoticed to become incipient cancers. Therefore, these genetic variants that we inherit at birth are significant predictors of type of breast cancer that we could develop decades later and its lethality.
“Apart from a few highly penetrant genes that confer significant cancer risk, the role of hereditary factors remains poorly understood, and most malignancies are assumed to be due to random errors during cell division or bad luck.” , he explained Christina Curtis, professor of Medicine and Genetics and of Biomedical Data Science at Stanford. “This would imply that tumor initiation is random, but that is not what we observed. Instead, we find that the path to Tumor development is conditioned by hereditary factors and immunity. “This new result uncovers a new class of biomarkers to predict tumor progression and a completely new way to understand the origins of breast cancer.”
“In 2015, we hypothesized that some tumors are ‘destined to be malignant’; That is, its malignant and even metastatic potential is determined early in the course of the disease,” explained Curtis, who is the lead author of the study. “We have since corroborated this finding in multiple tumors, but these results shed new light on how early this occurs.”
The results of this research have been published in Science and offer a nuanced and powerful understanding of the interaction between newly emerging cancer cells and the immune system, which will likely help researchers and doctors predict and better fight breast tumors.
“The hypothesis they have demonstrated breaks a paradigm: that in non-hereditary cancers that appear sporadically (not related to the inheritance of a pathological mutation in germ cells), the appearance of sporadic somatic mutations and their subsequent contribution to the creation of a cancer was completely independent of inherited non-pathological functional genetic variants. The authors have destroyed this principle,” he told Science Media Center Spain. Ramon Salazarhead of Medical Oncology and general director of the Catalan Institute of Oncology (ICO), who did not participate in the study.
“For the first time, it has been discovered that inherited genetic makeup has an influence on immunosurveillance and on the types of somatic or sporadic (non-inherited) mutations that can contribute to the appearance of cancer.” “At the moment they have only validated it for breast cancer and with a type of mutations based on increasing the number of copies of some oncogenes, such as HER2 or MYC, associating the changes with the different molecular subtypes of breast cancer, but they are trying to reproduce it in other tumors and with other mutations,” adds this expert.
New approach that destroys the paradigm on the origin of cancer
Currently, only a few high-profile cancer-associated mutations in genes are regularly used to predict cancers, but these represent a small minority of cases. These include BRCA1 and BRCA2, which appear in approximately one in 500 women and confer a increased risk of breast or ovarian cancerand rarer mutations in a gene called TP53 that cause a disease called Li Fraumeni syndrome, which predisposes to tumors in childhood and adulthood.
The findings suggest that there are dozens or hundreds of additional genetic variants – identifiable in healthy people – that, through interactions with the immune system, determine why some people remain cancer-free throughout their lives. “Our findings not only explain which subtype of breast cancer a person is likely to develop,” said Kathleen Houlahan, another of the lead authors, “but they also suggest how aggressive and likely to metastasize that subtype will be. Furthermore, we speculate that these inherited variants may influence a person’s risk of developing breast cancer. However, future studies will be needed to examine this.”
“Our findings not only explain which subtype of breast cancer a person is likely to develop, but they also suggest how aggressive and likely to metastasize that subtype will be.”
The genes we inherit from our parents are known as our germline genome. They reflect the genetic makeup of our parents and can vary between people so that some have blue eyes, brown hair or blood type O. Some inherited genes include mutations that increase cancer risk from the start, such as BRCA1, BRCA2 and TP53.
In contrast, most cancer-associated genes are part of what is known as our somatic genome. Throughout our lives, our cells divide and die in the tens of millions. Every time DNA is copied in a cell, errors occur and mutations can accumulate. The DNA in tumors is often compared to germline genomes in blood or normal tissues in an individual to identify what changes likely led to the cell’s cancerous transformation.
Classification of breast cancers
In 2012, Curtis began deep research—assisted by machine learning—into the types of somatic mutations that occur in thousands of breast cancers. Eventually, he was able to categorize the disease into 11 subtypes with different prognoses and risk of recurrence, finding that four of the 11 groups were significantly more likely to recur even 10 or 20 years after diagnosis, critical information for clinicians making treatment decisions. and discuss long-term prognoses with their patients.
Previous studies have shown that people with inherited mutations in BRCA1 tend to develop a subtype of breast cancer known as triple negative breast cancer. This correlation implies some behind-the-scenes influence of the germline genome that affects which subtype of breast cancer someone may develop. “We wanted to understand how inherited DNA could sculpt the evolution of a tumor,” Houlahan said. To do so, they looked closely at the immune system.
It is a quirk of biology that even healthy cells routinely decorate their outer membranes with small fragments of the proteins they have in their cytoplasm, an external display that reflects their internal style; These are what are known as HLA proteins and are highly variable between individuals.
As the fashion police the immune cells called T cells They patrol the body looking for any suspicious or overly conspicuous ornaments (called epitopes) that might indicate that something is wrong inside the cell. A cell infected with a virus will show fragments of viral proteins; A diseased or cancerous cell will be decorated with abnormal proteins. These errors trigger T cells to destroy the offenders.
Houlahan and Curtis decided to focus on oncogenes, normal genes that, when mutated, can free a cell from regulatory pathways meant to keep it on the straight and narrow. Often, these mutations take the form of multiple copies of the normal gene, arranged one after another along the DNA, the result of a kind of genomic stuttering called amplification. Amplifications in specific oncogenes drive different cancer pathways and were used to differentiate one breast cancer subtype from another in Curtis’s original studies.
Improve treatment based on breast cancer subtype
The researchers wondered whether highly recognizable epitopes would be more likely to attract the attention of T cells than other, more modest displays (think golf ball-sized turquoise dangle earrings versus a simple silver nail). If so, a cell that had inherited a striking version of an oncogene might be less able to carry out its amplification without alerting the immune system than a cell with a more modest version of the same gene. (One pair of overly flashy turquoise earrings may be excused; five pairs could take a patrol T-cell from mumbling to termination.)
The researchers studied nearly 6,000 breast tumors at various stages of the disease to learn whether the subtype of each tumor correlated with the patients’ germline oncogene sequences. They found that people who had inherited an oncogene with a high germline epitope load (read: lots of frills) and an HLA type that can display that epitope prominently were significantly less likely to develop breast cancer subtypes in which that oncogene is amplified.
However, there was a surprise. The researchers found that cancers with a high germline epitope load that managed to escape errant immune cells in their early stages of development tended to be more aggressive and have a worse prognosis than their more modest peers.
“In the early, pre-invasive stage, a high germline epitope load is protective against cancer,” Houlahan said. “But once it is forced to fight with the immune system and finds mechanisms to overcome it, tumors with high germline epitope load are more aggressive and prone to metastasis. The pattern changes during tumor progression.”
“Basically, there is a power struggle between the tumor and the immune cells,” Curtis said. “In the pre-invasive setting, the nascent tumor may initially be more susceptible to immune surveillance and destruction. In fact, many tumors are probably removed this way and go unnoticed. However, the immune system does not always win. Some tumor cells may not be eliminated and those that persist develop ways to evade immune recognition and destruction. “Our findings shed light on this opaque process and may indicate the optimal timing of therapeutic intervention and how to make an immunologically cold tumor hot, making it more sensitive to therapy.”
The researchers envision a future in which the germline genome is used to further stratify the 11 subtypes of breast cancer identified by Curtis to guide treatment decisions and improve prognoses and recurrence monitoring. The study’s findings may also provide additional clues in the search for personalized cancer immunotherapies and may allow doctors to predict a healthy person’s risk of developing invasive breast cancer from a simple blood sample.
“We started with a bold hypothesis,” Curtis said. “In this area, the origins and evolution of the tumor had not been thought about in this way. “We are examining other cancers through this new lens of hereditary and acquired factors and tumor-immunity coevolution,” concludes the researcher.