Genome sequencing studies can be boring. It’s not that there are too many of them, although that will surely happen, but sometimes they just don’t tell us anything new. That was the case when last week Medscape asked me to write up a paper in an upcoming New England Journal of Medicine report about sequencing the genomes of uterine fibroids.
I never expected to read “fibroid” and “genome” in the same sentence.
SEQUENCING FIBROID GENOMES
Fibroids are big benign tumors that grow, often in groups like grapes, in the uteruses of about three-quarters of all women. I encountered them personally whilst on the operating table, my obstetrician pulling my middle daughter from my middle, the vertical C-section like bisecting a spaghetti squash.
“Oh my! Here give me some help,” said my doctor to a nurse standing by with a tray. I thought Sarah might have had a twin.
“Ricki, we’ve got some fibroids here. This one’s the size of a baseball!” I hoped she wasn’t talking about my daughter’s head. I suppose I was lucky to get the things out before they made their presence known.
I hadn’t thought about fibroids again until the Medscape assignment. The researchers, from the University of Helsinki, did all sorts of analyses: Whole genome sequencing to spot the point mutations, but also identifying the types of mutations that sequencing misses – copy number variants, indels (insertions and deletions), and rearrangements.
The researchers examined 38 fibroids from 30 women. Two mutations were already known to inhabit fibroid cells – one in an oncogene, one in a tumor suppressor gene. The researchers selected tumors to scrutinize that had either of those, to compare to tumors that didn’t have them.
All of that work ultimately showed that fibroids are very much alike, even in different uteruses. But within one woman, they are clonally connected, like those trees (poplars? I am a botanical dunce) all linked under the ground. The fibroids in a uterus tend to be derived from one leader tumor, and researchers decipher the lineages by aligning genomes from different fibroids according to shared chromosome abnormalities.
On a DNA level, the newly-reported experiments didn’t find much. No mutations in p53, no point mutations other than the two usual suspects, no indels nor large repeats.
But the chromosomal level was a different story. The researchers discovered what looks like the same chromosomal mayhem that is a hallmark of a cancer cell.
I once opened an article in The Scientist with “In cancer, the genome is shot to hell.” For some reason that phrase has been echoed, or perhaps I inadvertently stole it to begin with. The chromosomal chaos of a cancer cell is termed chromothripsis.
It’s like a cytological mega-orgasm, a few chromosomes experience a thundering, one-time explosive event, shattering into smithereens. Then the DNA repair troops come in, only they screw up. If the chromosomes have actually been pulverized, the cell gets routed towards apoptosis (doom) when it reaches the exit point of the cell cycle. But if only a few chromosomes are broken, the DNA repair enzymes try to patch them together. And fail. The result is a chromosomal mess, the brake on its cell cycle forever lifted.
Since chromothripsis had formerly only been known in cancer cells, not the blobbily benign fibroids, the researchers dubbed what they saw “interconnected complex chromosomal rearrangements,” or “CCRs,” which until now meant to me Creedence Clearwater Revival, the cleancut ‘60s band that everyone’s mother loved.
So that’s new, chromothripsis in benign tumor cells. Hopefully this finding will suggest something that can be done to prevent obstetricians from having to tell patients having Cesarean sections that they’ve given birth to baseballs. But at least my baseballs didn’t have hair and teeth in them.
TERATOMAS: THE ‘MONSTER’ MASSES
Last week’s writing about fibroids reminded me of a much more interesting benign growth, a teratoma. Greek for “monster mass,” a teratoma is an outcropping of normal embryonic parts in a person, including representatives of the three layers of the embryo. A teratoma is encapsulated and clearly in the wrong place, such as an ovary.
A teratoma might include hair, teeth, skin, and an occasional bit of gland, a digit, or an eyeball. It usually develops from a wayward sperm or egg that erroneously activated its developmental program, or a somatic cell escaped from an early embryo that didn’t realize it was no longer a part of the whole. Remnants of a twin might also appear to be a teratoma but isn’t quite the same thing.
Teratomas are important in the history of science because their study led to the discovery of human embryonic stem cells (hES), which I chronicled a few years ago in The Scientist and in an essay collection. A quick google just found myself credited with unearthing these facts in a doctoral dissertation.
The stem cell era is usually dated to 1981, when ES cells were derived from mice. That paper has nearly 4,000 citations. But the term “embryonic stem cell” actually first appears in a 1970 paper from a researcher at the Jackson Lab, Leroy Stevens (464 citations), who began isolating the cells from mice with teratomas in the 1950s.
My essay book is called Discovery: Windows On The Life Sciences, published by Blackwell in 2000. Eight people on the planet read it, although a lone review hints that it isn’t as terrible as its Amazon rank might suggest. And Amazon got the title wrong. Anyway, “Discovery” includes one of my favorite descriptions, and because Wiley phagocytized Blackwell and I don’t know who to ask for permission to quote my own work, here it is:
“It is the stuff of talk shows. An 800-pound mass in a woman’s abdomen contains teeth and hair and a jumble of tissue types. A TV program called “The World’s Most Frightening Video” features a man with a second face – an extra nose and mouth that move in unison with his normal ones.
The medical literature offers equally strange reports: a newborn girl with “the underdeveloped lower half of a human body” in her lower back, a young man with a “large greenish mass replacing the left eye” that contains pieces of an embryo’s cartilage, fat, muscle, intestine, and brain.
In another case, an x-ray clearly shows a perfect set of molars embedded in what appears to be a jaw – in a woman’s pelvis. And about a dozen reports describe young men who reached puberty early, then grew the distinctive cell layers of an embryo in their pineal glands, located in their brains! More common are pregnant women who carry not an embryo or fetus, but disorganized masses of specialized tissues, delivering amorphous lumps that sometimes include teeth and hair. Similar growths arise in men, in certain testicular tumors.”
To update my knowledge, I googled teratomas, finding lots of papers from the 1980s, book chapters, and research contract labs that place clients’ hES cells and induced pluripotent stem (iPS) cells into mice. If teratomas form in the rodent’s bellies, then the transplanted cells fulfilled their defining criterion of pluripotency because they give rise to all three tissue layers of the embryo: ectoderm and endoderm sandwiching mesoderm.
How do fibroids and teratomas differ, other than in appearance? It seems that fibroids are fueled by changes in genes, albeit familiar ones, whereas teratomas evolve by changes in gene expression. A fibroid’s genes mutate, and its chromosomes shatter. A teratoma was once a single cell that tried to turn itself into an organized embryo as it divided, only to produce just a tooth or tuft, wrapped in some sort of covering like a California roll.
Both types of growths – fibroids and teratomas — are quite fascinating. They make me wonder anew at how a fertilized egg is able to access its genome, and for all its descendant cells to do so, in a way that forms something as marvelously complex and beautiful as a human body.