Just now

A new Stanford Medicine study has my mind turned upside down. Could the gene sequences we inherit at conception be powerful predictors of the breast cancer type we might develop decades in life? And predict mortality?

I am a radiation oncologist, and I help hundreds of patients annually with breast cancer management.

This Science title recently caught my eye:

“Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity.”

Have I been thinking about breast cancer wrongly for over three decades?

Today, I will share with you how supposedly benign DNA variants (with little to no function) may — in aggregate — determine breast cancer subtype, disease aggression, and risk for breast cancer mortality.

We’ll also examine how the immune system may be playing a role in determining who gets breast cancer (and how aggressive it is).

Context – Genes & Breast Cancer

Cancer is more than just a mass of abnormal cells. Scientists have identified key characteristics, “hallmarks of cancer,” that allow these cells to grow and spread uncontrollably.

This complexity means that even tumors with similar symptoms can be quite different on a molecular level.

These differences are crucial for cancer doctors, as they can guide our management recommendations and predict how the disease might progress.

Genes

One layer of complexity comes from our genetic makeup.

We inherit DNA variations from our parents, influencing how a tumor develops.

For example, certain gene mutations are linked to specific types of breast cancer.

Scientists are still trying to understand how these inherited variations influence cancer.

Cancer Is Not a One-Size-Fits-All Disease

Here’s a key takeaway: Cancer is not a one-size-fits-all disease.

Tumors can vary greatly between individuals, and even within the same type of cancer, there can be significant molecular differences.

These differences are important because they can influence treatment options and disease progress.

Genes & Breast Cancer: Breast Cancer types

We are increasingly using genetic information to categorize breast cancers. Doing so allows for more individualized management.

Breast cancer groups include:

It is important to note that these are just general descriptions of the different types of breast cancer.

Each case is unique, and the best course of treatment will vary depending on the specific characteristics of the cancer.

The next section will explore how we think about breast cancer biology today.

Most Cancers Are The Result of Random Errors

The current dogma is that most malignancies occur due to random mutations.

We accumulate these mutations over our lifetimes.

Cancer is much more likely to develop if a random mutation affects a critical gene, such as breast cancer gene #1 or #2 (BRCA1; BRCA2).

But is that thinking too simple?

A Novel Take on Cancer’s Origin

Could the active involvement of gene sequences we inherit from our parents — our germline genome — be involved in determining whether cells bearing potential cancer-causing mutations are recognized (and eliminated) by our immune system?

Or could these inherited genes allow cells to stay below our immune system radar to become developing cancer cells?

Perhaps the path to cancer development is constrained by hereditary factors and immunity.

An Innovative Research Approach

In 2012, scientist Dr. Laura Curtis made a breakthrough by using machine learning to analyze thousands of breast cancer cases.

This analysis revealed 11 distinct subtypes of the disease, each with its prognosis and risk of recurrence.

Importantly, four of these subtypes had a significantly higher chance of returning even after 10 or 20 years.

This crucial information empowers us to make more informed treatment decisions and have clearer conversations with our patients about long-term outcomes.

Genes & Breast Cancer: Historical Research

Prior research already suggested a link between inherited gene mutations (like BRCA1 and BRCA2) and a specific subtype of breast cancer called triple-negative breast cancer.

This connection hinted at a hidden influence — our inherited DNA might somehow be shaping the type of breast cancer that develops in an individual.

Intrigued by this possibility, the researchers, including Dr. Melissa Houlahan, decided to look closer.

Next, the researchers investigated how a person’s inherited DNA might shape how their tumor evolves, with a particular focus on the immune system’s role in this intricate dance.

Understanding Cancer Beyond Categories

We often classify cancers based on their location and the specific proteins they produce.

These factors influence how the cancer behaves and which treatments work best.

But here’s the surprising part: not all cancers within the same category are created equal.

The Hidden Influence of Genes and Immunity

New research by Houlahan and colleagues sheds light on these unexpected differences.

The Stanford investigators found that a person’s inherited genes play a surprising role.

These genes can influence how a tumor interacts with the body’s immune system.

Think of It This Way

Imagine the immune system as the body’s army.

In some cases, a patient’s genes might act like a uniform, making the tumor cells easily recognizable to the immune system, which then destroys them.

In other cases, the genes might disguise the tumor cells, allowing them to evade the immune system’s attack.

It’s The Bling

Before getting into the Stanford group’s research approach, I must discuss some basic science.

Let’s look at epitopes.

• Epitopes as Recognition Sites: Epitopes are specific regions of antigens (molecules from pathogens or foreign substances) that the immune system recognizes.
• Binding Specificity: Epitopes with high specificity bind to antigen receptors (like those on B cells). The interaction is often described as “lock and key,” emphasizing the complementary shapes of the epitope and receptor.
• Triggering Immune Response: This binding event triggers a cascade of immune reactions, producing antibodies.
• Targeted Defense: The produced antibodies recognize and bind to the same epitope that triggered their production. This phenomenon allows for a targeted defense against the invading pathogen.

Why Bling Matters

The Stanford group wondered if highly recognizable epitopes would be more likely to attract the immune system’s T cells’ attention.

For example, a cell with a flashy version of an oncogene might be less able to create protein amplification without alerting the immune system.

The researchers examined nearly 6,000 breast tumors (of various stages) to see if the breast cancer subtype correlated with the patients’ germline oncogene sequences.

Individuals with a large germline (inherited) epitope burden—one that could escape the roving immune system—tended to be aggressive and had a poor prognosis.

A High Epitope Burden is Good (and Bad)

Why would cells with more bling be worse?

A high germline epitope burden is protective against cancer for early, pre-invasive stages.

However, after the cell battles the immune system, it creates effective countermeasures; the cells with a high germline epitope birden are more aggressive and more likely to spread.

In other words, the developing tumor may be more vulnerable to immune system detection and destruction in the pre-invasive setting.

You and I likely have many tumors eliminated in this fashion.

However, if the immune system does not win initially, the persisting abnormal cells develop ways to evade immune detection and destruction.

The Importance of This Discovery

By understanding how genes and the immune system work together, scientists can potentially predict which tumors are more likely to be eliminated by the body’s natural defenses.

This knowledge can lead to more personalized treatment approaches, helping doctors tailor therapies to each patient’s unique situation.

Key takeaway: Genes & Breast Cancer

While classifying cancers by type is helpful, new research reveals a hidden layer of complexity.

Inherited genes can influence how a tumor interacts with the immune system, potentially impacting its behavior and response to treatment.

Today, we use only a few high-profile cancer-associated gene mutations to predict cancer risk.

These mutations include BRCA1 and BRCA2, which occur in about one in every 500 women.

This study suggests that there are perhaps hundreds of additional gene variants — identifiable in healthy individuals — pulling the strings on which subtype of breast cancer an individual may develop.

My Take – Genes & Breast Cancer

Scientists just discovered a new layer of complexity in the battle against breast cancer.

This research unveils a whole new set of players in the game of cancer development.

These previously unknown gene variations could hold the key to predicting and even preventing breast cancer in the future.

I’ve been considering this new lens of heredity, acquired factors, and tumor-immune co-evolution all week.

I hope we someday have personalized cancer immunotherapies and a better way to predict a healthy person’s cancer risk from a simple blood sample.

Thank you for reading “Genes & Breast Cancer.” Unless otherwise indicated, illustrations are from Google’s Gemini.

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