Blood Matters Page 13
In 1994 scientists pinpointed the two chromosomes harboring the two genes that suffered the mutations that likely caused Lynch syndrome (three more mutations have been found since). Later that year scientists managed to clone two defective genes, making an early test available for potential carriers. In an article in Anticancer Research, Lynch and his wife, colleague, and coauthor, Jean (a nurse), proudly reported that more than twenty-five years after identifying the syndrome, they were now in a position to suggest that their patients do something about it: have the colon removed prophylactically rather than wait for the cancer to develop. The surgery remained controversial for years. After all, the Lynches were suggesting that young, apparently healthy people have major surgery that would certainly lower their quality of life, risking frequent defecation at best and incontinence and nutrition problems at worst. Lynch continued to dismiss the idea of nondirective genetic counseling, in his gentle, nonjudgmental, but very insistent way. He was known to call some of his patients regularly, just to remind them to consider the option of a preventive surgery.
Lynch’s hobby of collecting information on what he called “cancer families” grew into a scientific preoccupation, and eventually into what may be the world’s largest collection of such information. By the late 1980s his papers would make reference to families that had been under investigation for two decades or more. He found families with outstanding epidemiological features, like six siblings with cancer (five brothers with colonic cancer and one sister with uterine and laryngeal cancer, which the woman’s son also developed). He described a Navajo family that he observed for thirteen years, before identifying the mutation that caused the family’s colorectal cancers and drawing blood from fifty-one members of the family. Of the twenty-three who wished to learn their results, seven were positive for MHL1, one of the Lynch syndrome mutations. “Reactions ranged from full acceptance,” wrote Lynch, “to traditional Navajo reasoning such as the family had been cursed.” Lynch tracked more than 170 families with Lynch syndrome. Soon enough he was even able to generalize about patients’ decision making. He reported in 1996 that more than half of those who discovered they carried an MSH2 mutation considered the option of a prophylactic subtotal colectomy (it was too early to tell how many would actually go through with the surgery).
In 2003 he published the results of a huge study involving over ten thousand members of seventy-five families with breast and ovarian cancer and forty-seven families with Lynch syndrome. In the course of the study, 1,408 people were tested for cancer-causing mutations, and Lynch and his team then analyzed the consequences for the families as a whole. As it turned out, the results of those 1,408 tests affected 2,906 people—all the people who were tested plus their direct descendants. Lynch’s team came to a startling conclusion: 77 percent of those affected went from “at risk to non-carrier status.” It was a bit of a statistical hat trick. Members of any cancer family are reasonably assumed to have a 50 percent chance of having inherited the mutation. If 1,408 people were tested, roughly half of them should have tested negative. All their children would then automatically shed their “at-risk” status. That’s how the researchers got their 77 percent figure. But the study still made an important point. If you take a cancer family and study it, you will inevitably be the bearer of good news. Everyone in a cancer family is, as the Wisconsin teenagers put it thirty years ago, a card-carrying “cancerphobe”—that is, everyone believes he or she will get cancer. Those who learn they are mutation carriers will only have their fears confirmed; the other half will be able to celebrate its liberation from the legacy.
Along the way, Lynch seems to have coined two terms, a poetic one and a technical-sounding one. A person’s cancer destiny is what he believes the various mutations predict—in theory, at birth, or even earlier. And family information services, he believes, can help confront or even change that destiny. A family information service, a Lynch invention, is a surreal experience: generally a weekend when the many members of a family Lynch and his colleagues have studied and mapped meet to hear lectures on their particular family syndrome—and to give blood. These are invariably family reunions of sorts: People who haven’t seen each other in years, have never seen each other, and, sometimes, have never even suspected one another’s existence, come together to exchange niceties and some of the most intimate information about one’s health anyone is ever likely to divulge. Most of them learn something new about their family and about the cancer that makes it different from all others. Most of them will also learn something about their destiny. Lynch’s hat-trick paper on “risk adjustment” is one of the best arguments in favor of these odd gatherings. For most participants, they will ultimately yield good news. For the rest, they will likely provide essential, possibly life-saving knowledge.
***
In November 2005 I lucked into the largest of these family information services Lynch had ever conducted. I arrived in Green Bay, Wisconsin, a bit late—the Packers were playing that weekend, and last-minute travel arrangements were tricky. On the Friday night before the weekend’s family reunion, Lynch was speaking at a dinner with a group of local physicians. He was well into his lecture when I got to the restaurant. He hovered just outside the door to the small dining room—most likely because this afforded his aging eyes enough distance to see his own PowerPoint presentation, but it gave the impression that he was too large to fit in the room. Extremely tall, with a broad frame rendered a bit shapeless by age, at seventy-seven he had enough uncertainty of movement that he occasionally looked like he might topple over, like a tower. His face was similarly obscured by signs of aging: One eye squinted a bit behind gold-rimmed aviator glasses, and while the eyes seemed to be smiling, the mouth was frozen in a sort of permanent frown. His speech was loud, certain, and clear, with that rare ring of something that has been repeated countless times yet has not grown automatic.
Lynch was talking about hereditary cancers and the importance of knowing patients’ family histories. The eighteen doctors in the room seemed marginally familiar with the topics: Lynch’s ideas were not revolutionary for them—indeed, it seemed a given that they were the new medical mainstream—but none of them seemed to have personal experience in applying them. They asked whether it was all right to put women on hormone-replacement therapy following a prophylactic oophorectomy. The jury was still out, explained Lynch and his assistant. The doctors asked more questions about prophylactic surgery: of the ovaries, the uterus, the breasts, the colon (not as big a deal as it may seem, Lynch made sure to add), and even the pancreas.
Then a shiny young man and young woman from Myriad, the company that holds several international patents on BRCA mutation testing, worked the room, giving a well-informed and informative unabashed sales pitch for testing and prophylactic surgery, both oophorectomies and mastectomies. They did their own PowerPoint presentation, handed out cards, chatted with individual doctors, and paid for dinner. Lynch’s assistant stole a peek at the bill and made an impressed face; then someone sitting nearby pointed out that just a few full BRCA tests, at roughly five hundred dollars a pop, would cover the expense. As I found out the next day, the sly Dr. Lynch, who for years had pursued his family information services as an unfunded extracurricular activity, did not himself use Myriad, which had been waging a fight in essence to monopolize testing. He sent his blood samples to Ontario, where a research lab did the sequencing for free.
Early the next morning, Sumedha Ghate, a local genetic counselor, swung by my motel in the hospital’s minivan, on her way to pick up the Lynch party: the doctor, his assistant, and Jean. Lynch veritably bounced out of the hotel. “This is so wonderful,” he boomed, folding himself into the minivan. “I’ve never seen anything like this! How many physicians were there? Seventeen? Eighteen? And they were not doing it for money, and they were not doing it for credit—they just came because they were interested.” This from an international medical star who for a while now had been collecting several awards a year—many of them with
words like lifetime achievement in the title. But after decades of being the object of his colleagues’ ridicule and suspicion—the crazy man who thought cancer ran in families; the rogue oncologist who suggested cutting off parts of one’s body before cancer struck—Lynch seemed sincerely surprised and excited to discover that the medical mainstream had finally caught up to him. He had spent so long trying to convince his profession that genetic medicine was its future that he had missed the moment when the future actually arrived.
***
The halls of Green Bay’s St. Vincent’s Hospital were plastered with arrows pointing to the family information service, a token not only of Sumedha’s enthusiastic diligence but also the relative scale of the event: It was not every day that as many as a hundred people would gather in a single room at St. Vincent’s. At the end of the labyrinth, Karen, a woman in her forties who had once been one of the “cancerphobe” cousins, sat at a folding metal table covered with flyers, sign-up sheets, name badges, and colored dots to place on them to identify the wearer as belonging to one of four branches of the family. She greeted all comers, many of whom she had met over the phone, handing out the materials and making conversation.
“You know,” she was telling someone, “Mamie died in childbirth, and she had a daughter, Annie, and I thought it ended there. But it turns out she had two children. The guy married and moved away. And I contacted them, and what do you know: The girl has breast cancer young, and the guy had prostate cancer young. And I called the guy’s wife, just cold-called her, and she was so receptive. She said, ‘I have kids, I’ll be there.’” The listener was a woman who was one of the semiofficial family historians: Every branch had one.
One of the branches, this one distinguished by huge clear-blue eyes and red paper dots on their name badges, brought a family history typed in caps by one of its matriarchs, and a photograph from the early 1900s of Frank and Nellie, the Dutch immigrants who were ancestors to everyone present. The family story was a fascinating document in the way of all family stories, with its casual unfolding of generations of a fast-growing dynasty: Couples generally had between six and twelve children. But I also found it captivating for what was utterly absent from the story—the family curse, the mutation that had crowded more than eighty people into a single basement room in the hospital. Among the droughts and thunderstorms in the document, Pearl Harbor and the Depression, suicide and tuberculosis, there were only three references to cancer—certainly no more, and no more significant, than you would find in any other family narrative of similar scope.
Frank came to the United States from Holland in 1843 at the age of twelve. His future wife, Petronella (Nellie), was born in Holland that year and brought to America a few years later. They married in 1865. One of them carried a mutation that causes breast and ovarian cancer and possibly raises the risk of some other cancers. It is likely to have been Frank, who lived to eighty-seven: Being a man, he would probably have carried the mutation and not developed cancer. On the other hand, Nellie, who lived to seventy-five, may have had cancer: The family history, written by one of her granddaughters, says nothing about the cause of her death but indicates that she had been ill. Frank and Nellie had six children; two daughters died very young, and three sons and a daughter lived to adulthood. In a bit of bad genetic drift, all four of them inherited the cancer-causing mutation.
The family history I read happened to cover the family of Frank and Nellie’s second son, Bill. He died at seventy-six of throat cancer, which may not have been related to the faulty gene. He and his wife had twelve children. Two daughters died in childhood; one son lived to eighty-three but never married. Another daughter, Frances, had epilepsy. In her twenties she was engaged to be married, but, wrote her younger sister, “the doctor told her she should not get married since there was a chance that the children would have seizures. So she gave up that plan.” Frances stayed at her parents’ house, up the hill from the sand-and-gravel pit that was her father’s business, until her death at fifty-six. This bit of genetic guesswork from the 1930s is a remarkable detail. In fact, familial epilepsy is rare—the risk of a person with epilepsy having a child who develops epilepsy is 4 percent or less—and there is no indication that Frances’s epilepsy was the result of a genetic mutation that she could pass on to her children. The potentially deadly mutation in Frances’s family—the one that was passed on with a 50 percent probability—was at that point unknown, unnoticed, and consequently undescribed.
Eight of Bill’s twelve children went on to have children of their own—forty-four of them in all. This was the oldest generation of the family represented at the meeting in Green Bay, and many of them by this point had great-grandchildren. Altogether Dr. Lynch’s office had data on more than a thousand members of this family—including the descendants of Bill’s siblings.
“Mother lived with us from 1951 to 1964,” I read in the family story, eight single-spaced pages, typed in capital letters. “She had broken her hip in the early 1960s. This took the spunk right out of her. And then when Christy died in January 1962, she had a hard time dealing with it. They had been very close for a mother and daughter, even raising their children together. Mother felt it should have been her that died, not Christy.”
Christy, Bill’s oldest daughter, died at sixty-seven—young by the standards of this family, apparently made of enviable genetic stock. For a detective seeking traces of the cancer mutation, this mention of her death would be the only clue. Although her much younger sister does not write this—and may well have not know this—Christy died of ovarian cancer.
Christy had fourteen children—nine daughters and five sons. Starting in 1985, three of the daughters were, one after another, diagnosed with breast cancer. In 1993 Joyce, the second-youngest daughter, was diagnosed with advanced ovarian cancer. This was when a researcher in Madison, Wisconsin (not the graduate student from the 1970s), who had started to put together a pedigree of Frank and Nellie’s children, suggested Joyce get tested for a BRCA mutation. She agreed—and tested negative. As it turns out, she was tested for the known “Jewish” mutations. A year later, when researchers in Holland had documented another mutation with apparent roots in Holland—a sizable chunk missing from the BRCA1 gene—Joyce was tested again, and this time turned up positive. Vonnie tested positive a year later; Rita tested in 2001. In the end, ten of Christy’s eleven surviving children got tested for the mutation; six turned out positive. With their permission, the Madison researcher shared their status information and contact details with cousins they had never met (or, in one case, whom they had known as neighbors but had not suspected of being relatives).
Four of the sisters, one with her daughter, now sat in metal folding chairs in the hospital conference room. There was something that came close to being unique about these women, even by the standards of Lynch’s remarkable “family information services.” It was their ages. Here was eighty-two-year-old Rita, a former dairy farmer, who had survived breast cancer. Next to her sat seventy-two-year-old Vonnie, who battled breast cancer twice but had been cancer-free for nearly twenty years. Then there was sixty-five-year-old Joyce, who by this time had lived twelve years past her diagnosis of Stage III ovarian cancer—a virtually unheard-of feat. (Seventy-nine-year-old Bernice, who tested negative for the mutation, came just to meet new relatives.) “I think we have bad genetic genes,” explained Joyce, “and good fighting genes.”
“We know something that everybody doesn’t know,” added her older sister Vonnie. “We need to share the survivorship. I had really severe chemo, nineteen drugs a month, and I made it. That’s because we don’t just sit back and listen to the doctor.” The doctor would probably beg to differ. Lynch suspected there was something about this blue-eyed branch of the family that improved their odds of survival. Their cancer seemed to develop later, and, with the long-ago exception of their matriarch, Christy, they did not seem to die of it. The later onset may have been the reason: The older the patient, the less aggressive and slower-gr
owing her cancer is likely to be. Alternatively, there may have been something about these women’s bodies that made them resistant to cancer in spite of their defective BRCA1 gene—and this may explain why the cancer came on late and, apparently, weak. It was Lynch’s hope that the vials of blood his staff carried away from the family information service would shed some light on the difference between this branch of the family and the others.
***
Standing in front of this large gathering of people of different ages, professions, states of health and general well-being, holding a microphone his booming voice hardly required, Lynch looked like a preacher. He talked like one, too. He was here to teach. He covered the basics of Mendelian inheritance in less than five minutes and got into specifics. “What we call the natural history of the disease is simply when is it going to occur on average, and the answer is: early. Much earlier, as a rule, than the population expectations. The average age of onset of breast cancer in patients with BRCA1 and BRCA2 is about forty to forty-five years of age. We have patients as young as the age of twenty. Unusual, but we do have them. In the twenties and thirties it becomes more common, and then it gets to the forties and fifties, and then less common when we get to the sixties and seventies, but even there we will have individuals affected. And there is a branch in your family where there is a much later onset in several members of the family. If we followed the American Cancer Society or the National Cancer Institute recommendations for starting mammography, say, at the age of fifty, we’d miss all those individuals of the young age. We would recommend starting mammography at age twenty and doing it annually from then on.