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Molecular Biology

Hereditary Cancer Syndromes

We’ve explored how we find genetic mistakes in the cancer cells themselves (somatic mutations) to guide treatment. Now, we’re going to take a step back and look at a different, but profoundly important, question: “Was this person born with a genetic mutation that put them at a much higher risk of developing cancer in the first place?”

This is the world of hereditary cancer syndromes. These are conditions caused by an inherited mutation in a single, critical gene that is present in every single cell of a person’s body. This mutation is called a germline mutation because it’s passed down through the germ cells (sperm or egg). A person who inherits one of these mutations doesn’t necessarily have cancer, but they are playing with a “loaded deck”—their lifetime risk of developing certain cancers is dramatically increased

Molecular testing for these syndromes has a huge impact not just on the patient, but on their entire family

The “Two-Hit” Hypothesis: Why It’s a Loaded Deck

To understand hereditary cancer, we need to remember the “Two-Hit Hypothesis,” proposed by Alfred Knudson

  • You Have Two Copies: For most genes, including the important tumor suppressor genes, you inherit two copies—one from your mother and one from your father. These genes are the cell’s “brakes”
  • Sporadic Cancer (The “Unlucky” Two Hits): In the general population, a person is born with two healthy, working copies of a tumor suppressor gene like BRCA1. For a cancer to develop, a cell must acquire two “hits”—two separate, random somatic mutations that knock out both copies of that gene in that single cell. This takes time and is a relatively rare event
  • Hereditary Cancer (Born with the First Hit): A person with a hereditary cancer syndrome is born with the “first hit” already present as a germline mutation in every cell of their body. They have one broken copy and one working copy. Now, for a cancer to develop, a cell only needs to acquire one additional random “hit” to knock out the remaining good copy. Because it only takes one hit instead of two, the chance of this happening is much, much higher, and it often happens at a younger age

The Role of Molecular Testing

Our job in the lab is to analyze a patient’s germline DNA (usually from a blood or saliva sample) to see if they are carrying one of these inherited “first hit” mutations. The technology of choice is almost always Next-Generation Sequencing (NGS), which allows us to analyze a large panel of genes associated with hereditary cancer all at once

The impact of finding a germline mutation is threefold

  1. For the Patient It explains why they may have developed cancer, especially at a young age. It also means they are at a higher risk for developing other cancers in the future. This guides intensive surveillance (e.g., more frequent mammograms and MRIs) and opens the door to risk-reducing strategies, such as prophylactic surgery (e.g., mastectomy or oophorectomy)
  2. For Treatment Some germline mutations, particularly in BRCA1 and BRCA2, create a specific weakness in the cancer cells’ DNA repair system. This makes the cancer highly susceptible to a class of targeted drugs called PARP inhibitors. So, a germline test can also act as a companion diagnostic
  3. For the Family (Cascade Testing) This is perhaps the most significant impact. If a person is found to have a germline mutation, it means their first-degree relatives (parents, siblings, children) each have a 50% chance of having inherited the same mutation. Cascade testing is the process of offering genetic testing to these at-risk family members. Unaffected family members who test positive can then take proactive steps to prevent cancer or catch it at its earliest, most treatable stage. Those who test negative are relieved of the burden of uncertainty and can often return to general population screening guidelines

The Major Syndromes We Test For

While there are many hereditary cancer syndromes, two major ones dominate the testing landscape

Hereditary Breast and Ovarian Cancer (HBOC) Syndrome

  • The Genes: Primarily caused by germline mutations in the BRCA1 and BRCA2 genes. These are critical tumor suppressor genes involved in repairing damaged DNA
  • The Risks
    • Breast Cancer: Women with a BRCA1 or BRCA2 mutation have up to a ~70% lifetime risk of developing breast cancer (compared to ~12% in the general population)
    • Ovarian Cancer: The lifetime risk is significantly elevated, up to ~44% for BRCA1 carriers (vs. ~1% in the general population)
    • Other Cancers: Increased risk of male breast cancer, prostate cancer, and pancreatic cancer
  • Modern Testing: While BRCA1/2 are the most famous, we now know that mutations in many other genes (PALB2, CHEK2, ATM, etc.) also increase breast cancer risk. That’s why testing is now done using multi-gene panels

Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer)

  • The Genes: Caused by germline mutations in one of the DNA Mismatch Repair (MMR) genes: MLH1, MSH2, MSH6, and PMS2. Their job is to fix small errors that occur during DNA replication
  • The Risks
    • Colorectal Cancer: Extremely high lifetime risk (up to 70-80%), with cancers often developing at a much younger age (average age ~45)
    • Endometrial Cancer: This is the second most common cancer in Lynch syndrome, with a lifetime risk up to 70% in women
    • Other Cancers: Increased risk of ovarian, stomach, small bowel, and urinary tract cancers
  • How it’s Detected: Often, the first clue is found by testing the tumor tissue itself. A tumor from a Lynch syndrome patient will show signs of a broken MMR system—either by lacking one of the MMR proteins (tested by IHC) or by exhibiting Microsatellite Instability (MSI). A positive tumor screening result then prompts germline testing to find the inherited “first hit”

Key Terms

  • Germline Mutation: A heritable gene change that is present in the egg or sperm and is therefore present in every cell of an individual’s body from birth. It can be passed down to offspring
  • Somatic Mutation: A gene change that is acquired by a single cell after conception. It is present only in the tumor and its descendants and is not inherited or passed on to children
  • Hereditary Cancer Syndrome: A condition characterized by a significantly increased risk for developing certain types of cancer, caused by an inherited germline mutation in a single critical gene
  • BRCA1 & BRCA2: Tumor suppressor genes that are central to the Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Germline mutations in these genes dramatically increase the risk of breast, ovarian, and other cancers
  • Lynch Syndrome: The most common hereditary colorectal cancer syndrome, caused by germline mutations in DNA Mismatch Repair genes (e.g., MLH1, MSH2). It confers a high risk for colon, endometrial, and other cancers
  • Cascade Testing: The process of extending genetic testing to the at-risk, first-degree relatives of an individual who has been identified with a pathogenic germline mutation
  • PARP Inhibitors: A class of targeted therapy drugs that are particularly effective against tumors with mutations in BRCA1 or BRCA2, as they exploit the specific DNA repair deficiency caused by these mutations