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New View of the Brink of Cancer May Validate Preventive Mastectomy

Women who have prophylactic mastectomies to stay ahead of a BRCA2 mutation may have made a wise choice, according to findings of a study just published in Science Advances. I’m amazed at the bravery of these women who go the Angelina Jolie route.

Inheriting a BRCA2 mutation brings a 50 to 80 percent lifetime risk of developing breast cancer. But how does that population statistic shake out at a personal level? Is an individual among the 20 to 50 percent who won’t develop the cancer? If not, how long can she safely delay surgery until just before the first inklings of cancer arise?

There’s no crystal ball that can predict when cancer will begin, but Leif W. Ellisen and colleagues at the Massachusetts General Hospital Cancer Center are coming close. Their clever study detects genetic changes that happen before the effects of the underlying BRCA2 mutation kick in.

(NHGRI)

The BRCA2 risk mutation is stitched into every cell from conception. But it takes further mutations, occurring decades later in the breast cells themselves, to jumpstart and then drive the cancer. A BRCA2 mutation is “germline,” meaning it’s in every cell from conception, whereas the other mutations are “somatic,” starting in body (not sperm or egg) cells.

Women can elect surgery if they have a germline mutation or if a genetic counselor deems the family history extreme enough to warrant preventive action.

A Bit of Background

BRCA2 is a member of a group of genes that control the “DNA damage response,” aka “DNA repair.” These genes normally fix errors that happen when DNA replicates. If they fail or are removed, protection against damage is derailed, which enables mutations that directly cause cancer to persist. The runaway cell division that is cancer ensues.

Each cell has two copies of each gene, because two genomes are stuffed into all cells except sperm and eggs, which have one. A person who has a BRCA2 mutation in every cell also has a normal copy of the gene. When the normal copy mutates, cancer begins. That’s why BRCA2 is dubbed a “tumor suppressor” – a second mutation lifts the normal function of preventing cancer. It’s opposite for an oncogene, which causes cancer when overactive.

BRCA2 protein interacting with another DNA damage response protein, PALB2.

Of all the oncogenes and tumor suppressors, mutations in the BRCA genes carry the highest risks. Mutations in other genes, such as ATMTP53, PALB2, CHEK2, and PTEN and dozens of others, moderately increase risk. I was tested for variants (a nice word for mutation) of 108 genes when I was diagnosed in late 2017, thanks to my cancer-drenched family history. However, a recent study calculated the number of lives that would be saved if every woman had these tests, irrespective of family history.

The new investigation was simple in concept, but complex to carry out. The researchers sequenced the genomes of single cells from mammary gland milk ducts, where many cancers arise. They compared the sequences from cells in BRCA2 breasts to those from women undergoing breast reduction.

Anatomy of a Milk Duct

A double layer of cells forms a milk duct. The inner layer is luminal cells (lumen means “open space,” anatomically speaking) with a few progenitor cells nestled among them. Progenitor cells divide, which is vital during pregnancy when the ductile system blooms, transforming a fatty breast into a milk machine. The outer basal myoepithelial cells are tile-like and harbor the contractile proteins of muscle, enabling them to form a pulsatile ring that shoots milk out of the nipple when a baby sucks.

The researchers looked at 8 to 20 cells from each of 28 women with BRCA2 mutations and from 26 women who’d had reduction surgery.

First, “highly experienced breast pathologists” examined luminal progenitor cells, deeming them normal in both the women with BRCA2 mutations and the controls. Then researchers sequenced the genomes of individual luminal progenitor cells. Probing the genes in cells one-at-a-time avoids missing an important glitch that might be overwhelmed in a biopsy packed with hundreds of cells, like isolating the contribution of a single instrument in an orchestra.

Capturing Early Changes

Even though the cells from the two groups of women looked alike to trained eyes, changes had already occurred in the genomes of the cells from the women with BRCA2 mutations. Tellingly, the changes had happened before loss of the “good” copy of BRCA2 that was thought to start the cancer. These are:

  •  Loss of several chromosome chunks larger than 10 million DNA bases, a condition called “haploinsufficiency” known to lie behind cancers. The chunks were long stretches of short DNA sequence repeats (copy number variants).
  • Impaired ability of cells to die by apoptosis, which is a built-in protection against cancer.
  • Botched interactions among several DNA damage control genes.
  • Disruption of the cell cycle (how often a cell divides)
  • A pile-up of excess luminal progenitor cells, and the same changes in multiple cells from the same woman, the older the woman, the more extra cells. All point to the genesis of a tumor.

The investigators used a “comet” test to envision the chromosomal havoc that BRCA2 wrought. They embedded cells in agarose gel, sliced open the cells, then zapped them with electricity, a classic technique called electrophoresis. Because DNA is negatively charged, the chromosome fragments migrated on the gels towards the positive charge of the anode, leaving a trail in their wake that resembled the tail of a comet. It was a celestial marker of a cancer’s beginnings.

Overall, the genome-level view seemed to presage the cellular changes that would alert an expert pathologist to cancer.

A breast cancer cell (NHGRI).

The difference between the cells of the women who had BRCA2 mutations and those having reduction surgery were stark and significant. In women with a mutation, 27% of luminal progenitor cells and 13% of basal myoepithelial cells showed DNA damage. But the telltale chromosomal losses appeared in only 1.1% of the cells of either type from the breast reduction group.

“Using these hallmarks of cancer predisposition will yield unanticipated opportunities for improved risk assessment and prevention strategies in high-risk patients,” the researchers conclude. But it’s also important news for the women who have already made the difficult decision to have their breasts removed.

A No Nipple Zone

As long as we’re talking about breasts, I’d like to mention how Facebook does a disservice to the breast cancer community. It’s important that we see what we look like, to help decide about treatment. But Mark Zuckerberg and the Facebook gods have deemed the female nipple not a body part that can in the best of times feed a child and in the worst of times become cancerous and deadly, but an object of male arousal, an obscenity, something to be hidden. Male nipples are kosher.

Recent “free the nipple” campaigns may enlighten the powers-that-be, while we patients surreptitiously post our nip pix in the comments and hope other women realize they’re there. We benefit from seeing what other women who have had breast reconstruction actually look like – not just the cherry-picked images that a surgeon is likely to show off.

It’s bizarre. Those of us who no longer have breasts are free to post our images on our closed Facebook pages, such as Fabulously Flat, but not women who’ve kept their nipples. Using that logic, should Facebook allow images of circumcised male organs, but not the uncircumcised? Free Willy?

My breast cancer Facebook groups have kept me sane, and the no-nipple policy an outrage.

I hope the findings of the new study offer some comfort to women who have chosen the difficult route of removing cancer’s toehold.

 

 

 

 

Discussion
  1. FYI, there has been a slight upward shift in the risk classification for PALB2. December 2019 NCCN Guidelines read: “Testing criteria for high penetrance susceptibility genes… often includes BRCA1/2, CDH1, PALB2, PTEN, TP53 among others…”

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