Blogging the Human Genome: MHC genes, and how a daughter inherited her mother’s cancer.

How Emiko inherited Mayumi’s cancer.

Blogging the Human Genome Entry 13

Illustration by Andrew Morgan

Yesterday’s post examined a case in which a mother in Japan, Mayumi, gave cancer to her unborn daughter, Emiko, thanks to a disastrous exchange of DNA between chromosomes 9 and 22. But we left off at a cliffhanger, because the scientists involved didn’t understand how the cancer cells could have slipped by the placenta and invaded Emiko’s body. To answer that question, they had to interrogate chromosome 6.

On the short arm of chromosome 6 there resides a special stretch of genes called the major histocompatibility complex, or MHC. (In humans, this stretch is often called the HLA.) The MHC fights diseases and performs other immune functions, and it’s some of the most diverse DNA in our repertoire—more than 200 genes packed into a small space, some of which have well over 1,000 different varieties in humans, offering a virtually unlimited number of combinations to inherit. Even close relatives can differ substantially in their MHC, and the differences among random people are a hundred times higher here than along most other stretches of DNA.

MHC genes fight diseases in a few ways. Some produce proteins that grab a random sampling of molecules from inside a cell and put them on display on the cellular surface. This display lets immune cells know what’s going on inside. And if the immune cells see abnormal material—fragments of bacteria, cancer proteins, other signs of malfeasance—they can attack. The sheer diversity of the MHC helps us here because different MHC proteins fasten onto and raise the alarm against different dangers, so the more diversity in the MHC, the more things creatures can combat.

The MHC also has a second, more philosophical function: It allows our bodies to distinguish between self and non-self. The MHC causes little beard hairs to sprout on the surface of every cell, and the diversity of MHC genes helps ensure a distinct arrangement of coifs and curls in each person. Any non-self interlopers in the body (like cells from animals or from other people) of course have their own MHC genes sprouting their own unique beards. Our immune system is so precise that it can recognize those beards as different, and—even if those cells betray no signs of diseases or parasites—marshal up troops to kill the invaders.

Destroying invaders is normally good. But the MHC’s vigilance can also prevent our bodies from accepting transplanted organs, unless the recipients take drugs to suppress their immune systems. Sometimes even that doesn’t work. Transplanting organs from animals could help alleviate the world’s chronic organ-donor shortages, but animals have such bizarre (to us) MHCs that our bodies reject them instantly. We even destroy tissues and blood vessels around implanted animal organs, like retreating soldiers burning crops so that the enemy can’t use them for nourishment either. By absolutely paralyzing the immune system, doctors have kept people alive on baboon hearts, kidneys, and livers for a few weeks, but so far the immune system always wins.

For similar reasons, the MHC made things difficult for mammal evolution. By all rights, a mammal mother should attack the fetus inside her as a foreign growth since half its DNA, MHC and otherwise, isn’t hers. Thankfully, the placenta mediates this conflict by restricting access to the fetus, and no blood actually crosses through to the fetus, just nutrients. As a result, a baby like Emiko should remain invisible to Mayumi’s immune cells. And even if a few cells do slip through the placental gate, Emiko’s own immune system should recognize their foreign MHC and destroy them.

But when geneticists examined the MHC of Mayumi’s cancerous blood cells, they discovered something that would be almost admirable in its cleverness, if it weren’t so sinister. Again, the MHC is located on the shorter arm of chromosome 6. But the scientists noticed that this short arm in Mayumi’s cancer cells was even shorter than normal—because the cells had deleted their MHC. Some unknown mutation had simply wiped it from their genes. This left the roaming cancer cells functionally “invisible” on the outside, and Emiko’s immune system could not classify or recognize them. Her body had no way to scrutinize them for evidence they were foreign, much less that they harbored cancer.

Overall, then, scientists could trace the invasion of Mayumi’s cancer to two causes: the Philadelphia translocation that set the detonator and made certain cells malignant, and the MHC mutation that allowed them to trespass and burrow into Emiko’s cheek. The odds of either thing happening were low; the odds of both happening in the same cells, at the same time, in a woman who happened to be pregnant, were astronomically low. But not zero. In fact the scientists involved now suspect that, in most historical cases in which mothers gave cancer to fetuses, something disabled or compromised the MHC.

Believe it or not, there was one more scientific twist in this case—although I’ll have to refer you to The Violinist’s Thumb for all the details, including the fate of Mayumi and Emiko. I can’t promise you that everyone pulls through—again, in virtually every historical case in which a fetus and mother came down with cancer together, both succumbed quickly, normally within a year. But the story does end with surprise that, in one small way, allowed both Emiko and Mayumi to live on.