Germline Genetics in Breast Cancer

The DNA sequences we inherit at conception are strong indicators of the sort of breast cancer we might get decades later and how fatal it might be, according to a Stanford Medicine study that examined hundreds of cases of breast cancer. The findings refute the conventional wisdom that the majority of malignancies originate from haphazard mutations that accumulate throughout a lifetime. Rather, it emphasizes the active role of the gene sequences inherited from our parents, or your germline genome, in determining whether cells with potentially cancer-causing mutations are detected and destroyed by the immune system or if they slip through the cracks and develop into early cancers.

“Apart from a few highly penetrant genes that confer significant cancer risk, the role of heredity factors remains poorly understood, and most malignancies are assumed to result from random errors during cell division or bad luck,” said Christina Curtis, Ph.D., the RZ Cao Professor of Medicine and a professor of genetics and biomedical data science.

“This would imply that tumor initiation is random, but that is not what we observe. Rather, we find that hereditary factors and immunity constrain the path to tumor development. This new result unearths a new class of biomarkers to forecast tumor progression and an entirely new way of understanding breast cancer origins.”

Senior author Curtis is listed as the author of the study in Science. The research’s principal author is Kathleen Houlahan, Ph.D., a postdoctoral scholar.

“Back in 2015, we had posited that some tumors are ‘born to be bad’—meaning that their malignant and even metastatic potential is determined early in the disease course,” Curtis said. “We and others have since corroborated this finding across multiple tumors, but these findings cast a whole new light on just how early this happens.”

Rethinking the cause of cancer

The work is expected to aid researchers and clinicians in better predicting and treating breast tumors since it provides a sophisticated and potent new knowledge of the interaction between freshly formed cancer cells and the immune system.

Only a few numbers of well-known gene mutations linked to cancer are currently routinely utilized to forecast malignancies. These include rarer mutations in the TP53 gene, which produces a condition known as Li Fraumeni syndrome, which predisposes to cancers that develop in childhood and adulthood, and BRCA1 and BRCA2, which affect roughly one in every 500 women and carry an elevated risk of breast or ovarian cancer. 

According to the research, there are dozens or perhaps hundreds of additional gene variants that can be found in healthy individuals that are responsible for some people’s lifetime immunity to cancer.

“Our findings not only explain which subtype of breast cancer an individual is likely to develop,” Houlahan said, “but they also hint at how aggressive and prone to metastasizing that subtype will be. Beyond that, we anticipate that these inherited variants may influence a person’s risk of developing breast cancer.”

Our germline genome is made up of the genes we inherited from our parents. They are genetic reflections of our parents, and they can differ somewhat from person to person, giving some of us brown hair, blue eyes, or type O blood. Certain hereditary genes, such as TP53, BRCA1, and BRCA2, have mutations that raise the risk of cancer from birth. However, it has proven challenging to find additional germline mutations that are substantially linked to cancers in the future.

On the other hand, the majority of genes linked to cancer are found in our somatic genome. Tens of millions of our cells divide and die during our lifetimes. Errors occur during DNA replication, leading to the potential accumulation of mutations. To determine which modifications most likely contributed to the cell’s transformation into a malignant form, the germline genomes of the tumor and the patient’s normal tissues or blood are frequently compared.

Sorting out Breast Tumors

With the aid of machine learning, Curtis started delving deeply into the many kinds of somatic mutations that are present in thousands of breast cancer cases in 2012. Eventually, she was able to divide the illness into 11 subtypes, each with a different prognosis and risk of recurrence. She discovered that four of the 11 groups had a significantly higher chance of recurrence even 10 or 20 years after diagnosis, which is important information for doctors to know when deciding on a course of treatment and talking to patients about their long-term prognoses.

Previous research has demonstrated that individuals with hereditary mutations in either BRCA1 or BRCA2 are more likely to develop triple-negative breast cancer, a subtype of breast cancer. This link suggests that the germline genome may engage in some manipulative behavior that influences the subtype of breast cancer that an individual may get.

“We wanted to understand how inherited DNA might sculpt how a tumor evolves,” Houlahan said. To do so, they took a close look at the immune system.

A peculiarity of life is that, even in healthy cells, bits of the proteins floating around in their cytoplasm are regularly used to adorn their outer membranes, an external manifestation of their internal fashion.

The HLA proteins, which are extremely varied across individuals, serve as the foundation for this display. Immune cells known as T cells patrol the body like fashion police, searching for any unusual or excessively gaudy jewelry (known as epitopes) that could indicate a problem within the cell. A virus-infected cell will show fragments of viral proteins; a diseased or malignant cell will cover itself in aberrant proteins. These blunders cause the T cells to attack and kill the perpetrators.

Houlahan and Curtis decided to concentrate on oncogenes, which are normally occurring genes that, when altered, can release a cell from regulatory mechanisms intended to keep it on course. These mutations frequently manifest as several copies of the normal gene, aligned along the DNA’s nose to tail. This is known as amplification, a type of genomic stutter. In Curtis’s initial research, alterations in particular oncogenes were utilized to distinguish between distinct breast cancer subtypes and to drive distinct cancer pathways.

The significance of bling

The question the researchers asked themselves was if T cells would be more drawn to highly identifiable epitopes than to alternative, less conspicuous presentations (e.g., golf-ball-sized, dangling turquoise earrings versus a plain silver stud). If that’s the case, a cell with a more subdued allele of an oncogene may have an easier time amplification without raising the immune system than a cell with a more conspicuous allele. (One excessively flashy set of turquoise earrings is acceptable, but five pairs might turn a patrolling fashionista T-cell from tutting to terminating.)

To determine whether the subtype of each tumor connected with the patients’ germline oncogene sequences, the researchers examined around 6,000 breast cancers that were at different stages of the disease. Researchers discovered that those who inherited an oncogene with a high germline epitope burden (i.e., lots of bling) and an HLA type that can prominently display that epitope had a much lower risk of developing breast cancer subtypes where that amplified oncogene is present.

But there was a twist to the story. Researchers discovered that early in their development, tumors with a high germline epitope burden that evade wandering immune cells are likely to be more aggressive and have a worse prognosis than their more modest counterparts.

“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. The emerging tumor may initially be more vulnerable to immune monitoring and eradication in the preinvasive setting. Indeed, a lot of cancers are probably removed in this way without being detected. Still, the immune system is not infallible.

“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 inform the optimal timing of therapeutic intervention, as well as how to make an immunologically cold tumor hot, rendering it more sensitive to therapy.”

In the future, the researchers see using the germline genome to better stratify the 11 breast cancer subtypes that Curtis uncovered to inform treatment choices, enhance prognoses, and enable recurrence surveillance.

The results of the study might also provide more hints in the search for customized cancer immunotherapies and might eventually allow medical professionals to estimate a healthy individual’s chance of developing cancer from a simple blood sample.

“We started with a bold hypothesis,” Curtis said. “The field had not thought about tumor origins and evolution in this way. We’re examining other cancers through this new lens of heredity and acquired factors and tumor-immune co-evolution.”

For more information: Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity, Science, DOI: 10.1126/science.adh8697