The Wandering Gene and the Indian Princess

by Jeff Wheelwright

  Joseph Medina has a black-and-white photograph of Luis and Andrellita Martinez. The picture, of the couple in profile, delineates the arching Castilian nose and brow of his handsome grandfather and the more rounded features of his grandmother. In the old days a Castilian profile (think Javier Bardem) was a fine thing to have; Andrellita’s face seems more mestiza. Discussing the photo, Joseph remarked that his grandfather came from Castile. This couldn’t be, since Luis’s father, according to the family pedigree, was born and baptized in northern New Mexico in 1867. The pobladores (little landowners or settlers) of New Mexico didn’t flit back and forth to Albuquerque, let alone Europe. Still, you do sometimes hear Hispano people say that their nineteenth- or early twentieth-century relatives emigrated directly from Spain. That is what I have been told, they will say with a shrug. Perhaps they have a vestige of the old españole snobbery or maybe they say from Spain simply as shorthand for Spanish ancestry. But all told, pure heritage doesn’t matter anymore to the modest people of Culebra, just as claims of limpieza de sangre (pure blood that was free of Moorish, Jewish, African, or Native American taint) are long gone from the ex-Kingdom of New Mexico. Nobody would raise an eyebrow if you pointed out that Medina originally was an Arab name.

  The reason that family members have gathered at T-ana’s Restaurant this Sunday afternoon in 2007 is to learn about their genetic, not cultural, heritage. A genetic counselor named Jeffrey Shaw is coming down from Colorado Springs to speak to the group. Relatives have returned to Culebra from cities north and south because of the breast and ovarian cancer running in the family since at least Andrellita’s generation. Our inherited imperfection, Shonnie might have said.

  The session with the genetic counselor was a long time in the making. After Shonnie died, Marianne Medina, who is something of a genealogist herself, would take out the piece of paper with her daughter’s DNA test result. Brooding over the finding, BRCA1.185delAG, she made a mental list of the cancers she’d heard about among her husband’s female relatives. About the same time but acting independently, two of Joseph’s cousins in the Denver area started to collect health histories from their parents, uncles and aunts, and other relatives. When the cancer records were superimposed on the Medina-Martinez family tree, the picture was terrifying.

  The woman at the top, Andrellita Medina Martinez, the sixteen-year-old bride, developed breast cancer late in life. A midwife cut out the lump, according to one story; another account says that she had a mastectomy and radiation. Andrellita survived and died in her seventies of other causes.

  Fourteen of Andrellita’s children grew to be adults. The second generation consisted of six men and eight women. Of the eight daughters, five had died of breast or ovarian cancer by the time of the 2007 meeting. Their names were Maria Casilda, Eduvigen (Duvie), Susan, Amalia (Molly), and Mary. Another daughter, ninety-two-year-old Bernarda (Auntie Bernie), was a breast-cancer survivor. On the other side of the ledger, Abel and Salamon, two of the sons, had developed prostate cancer, and Abel had died of the disease. To summarize, half of the Martinez children had had breast, ovarian, or prostate tumors. These cancers are linked in having a hormonal component. The number of cases and the similarity of the pathway screamed out that genes were involved. (It probably was not relevant that Luis, he of the Castilian profile, died of cancer of the tongue or throat.)

  Just two of the daughters of Luis and Andrellita were cancer-free: Dorothy and her younger sister Teresa (Teresita), who was seventy-three. Both were attending today’s meeting. None of the Martinez brothers came. When Marianne distributed the invitations, a couple of her male in-laws indicated that they were uncomfortable with the proceedings. They’re in denial, said Marianne, not one to equivocate.

  Now to the next generation. Exponentially more Martinezes occupy the third tier of the family tree. Dorothy Martinez alone had fourteen babies following her marriage to Joe U. Medina. Eleven survived infancy, including Joseph, the second-born. Although none of Dorothy’s offspring had been diagnosed with cancer at the time of the meeting, cancer had already reached around and taken one of her grandchildren, Shonnie. As for Joseph’s first cousins and Dorothy’s nieces, women in their forties and fifties, some of them here today, they were riddled with breast and ovarian cancer. Eight had had the disease; three were dead. After this generation came an expanding number of offspring who were as yet too young for the disease but who were at risk. Genetic counseling was absolutely in order for this group even without the smoking gun of their DNA, for, in addition to Shonnie, two of Joseph’s cousins and one of his sisters had already tested positive for the BRCA1.185delAG mutation. Every member of the clan with a blood connection to Andrellita, the obligate carrier of the mutation, was potentially a carrier.

  Genetic counselors are not doctors, but they work alongside doctors. They are health professionals with master’s degrees who explain the risks of inherited mutations and the pros and cons of DNA testing to patients and families. Jeffrey Shaw, who worked at the Penrose Cancer Center in Colorado Springs, was an experienced counselor, and this was not his first encounter with the family. He had met Marianne just before Shonnie died, in 1999, and three years later he had counseled Marianne, Iona, and two of their female relatives. Iona was supposed to be tested for the mutation then, but she put it off. I can’t pinpoint if I do want to know or don’t want to know, Iona said. What good will it do? I go every other year for a physical breast exam. I’m OK now, and if I get it, I get it. Another time Iona said, Call me crazy, but I still don’t want to know what may be lurking in my body. Like many women in her situation, she imagined the gene, if she carried it, as a tiny bit of cancer in itself, so small that it might be repressed into nothingness. Today, as Jeff Shaw drove down from the Springs and through the mountain wall to Culebra, he thought to himself, She is too sweet to ignore this. On entering T-ana’s, he jocosely scolded Iona, saying to her, You are on my shift list.

  Goateed and a little chunky, with a breezy, affable manner, Shaw wore shorts and a checked shirt to the weekend session. He set up an easel and poster paper at one end of the dining room, where Joseph and Iona had performed the night before. About three dozen family members occupied the tables and booths and rows of extra chairs. Some of the parents had brought their children. Waiting for the event to begin, a teenager trained her video camera on her cousins. Their collars too big and their hair plastered down, the boys scowled back as boys do.

  Joseph, the grave host in sunglasses and a charcoal blue suit, stood in a back corner. During Shaw’s talk he moved about restlessly. With silent reservations he had gone along with his wife’s wishes that this health matter of the family should be brought into the open. But what did he think about taking the gene test himself? It’d be OK, he said, clearly in no hurry. Marianne, having prepared the chips and dip, the lemonade and soft drinks, sat with a bunch of her in-laws. Wearing a dark dress, she looked at ease. Iona, her black hair pulled back with a silver clasp, minded the refreshments, lowering her head as she went in and out of the kitchen. Married not long before Shonnie fell ill, Iona and her husband had forsworn having children—not because of the cancer risk but because of the fraught state of the world, a world they believed was coming to an end.

  The afternoon was warm, and soon the dining room was warm too, creating a run on the lemonade. Joseph’s younger sister Louisa arrived in tight red shorts, definitely the least Hispano of the Medinas. Skittish Louisa had decided that if she were going to have the gene test, she wouldn’t want to know the result, although later she would change her mind. Another sister, Wanda, flashed a friendly smile but looked hollow-eyed and drained from her harsh, therapeutic diet. She believed she already was fighting the disease. A blonde cousin, Linda, was here because her sister Gean had died recently of breast cancer. Shaking her head, Marianne said that Gean had chosen to have her tumor treated with surgery and chemotherapy. She had a biopsy and it went crazy, Marianne said, and still she did conventional m
edicine.

  Joseph’s niece Shannon, representing the fourth generation of the family, came with her thirteen-year-old son. Shannon’s roots were in Culebra, but she, like most of the family, had moved on and branched out. In addition to the names Martinez, Medina, Chavez, Sanchez-Vigil, and Salcido, there were now Kahn-Ortiz, Kramer, Pakalenka, Monarski, Hosack, and Rich-Crane. For the first time in centuries the blood of the Martinezes flowed outward rather than inward, seeping into other landscapes, mingling with other streams. With dilution, a certain genetic disinfection takes place in the American melting pot, especially as families become smaller and better informed about heritable diseases.

  Jeff Shaw spoke to the group that day about the BRCA1 gene. BRCA stands for breast cancer, and in the mid-1990s BRCA1 was the first such gene to be identified, hence the name, followed closely by the discovery of BRCA2. The disease caused by the two genes is called HBOC, for heritable breast and ovarian cancer. A woman who carries a mutation of the genes may contract one or the other or occasionally both of the conditions.

  BRCA1 is not a breast-cancer gene, Shaw said, right off addressing a pervasive misunderstanding. It is a tumor-suppressor gene, which everyone has. The misunderstanding was this: In the nomenclature of medical genetics, the tail wags the dog. A BRCA1 mutation is a rare, flawed variant of the normal gene. The gene was given the name of its mutation after the mutation was discovered. There is some logic to the process because if it hadn’t been for the mutation (the anomaly), the normal type would not have come to light. By the same token, the function of the gene—to keep a cell in good repair, to keep tumors from occurring—wouldn’t have been discovered if the failure of the gene hadn’t manifested itself first. Like a broken pane of glass, the mutation exposed a window into the body that no one had noticed before. Be that as it may, scientists discussing BRCA1 toggle back and forth; from the context, they know which state of the gene is meant, normal or mutated.

  Shaw skipped the fine points, which were more than the attentive Martinezes and Medinas needed to hear. Taking his felt-tip pen to the poster paper, he sketched a squiggly pair of chromosomes—in each human cell, chromosomes come in pairs—and he marked a point on one of the chromosomes where the BRCA1 gene resided. Likewise for the BRCA1 gene on the opposite chromosome. The two genes have separate sources, he observed. Two copies of the gene are passed to you, one from each parent. Joseph, in the back, shifted uneasily.

  Then Shaw started to explain what happens when a mutation occurs inside a cell. I prefer to call it a boo-boo, he said to the group. Granted, mutation was a distasteful word, which Shaw was not alone in disliking. Marker, another term he used, was an improvement but not exact. A mutation simply means a change, a change in the biochemical spelling of a gene, and not all such changes are harmful. This mutation surely was, however.

  The theory is, it takes two hits on the DNA in order for a cell to turn cancerous: two hits meaning that both copies of BRCA1 are disabled. A hit can be inherited, as when a child receives a BRCA1 mutation from a parent. Then they become cells with no backup, Shaw said, making an X on the chromosome he’d drawn. At a later time in life, a second hit occurs—say, from radiation or a toxic chemical or just an accident of nature, and it disables the second copy of BRCA1 in a breast cell. Two more rapid squeaks of the pen. Now both of the tumor-suppressor genes are damaged and they lose control, he said. The rogue cell divides and multiplies until there is an uncontrolled growth of cells.

  The two-hit theory of cancer explains the difference between the breast cancer that most patients get and HBOC, the condition plaguing the Medina-Martinezes. Most breast cancer is called sporadic, a term indicating that it has no familial pattern. Sporadic cancers cannot be assigned to the hard-wired inheritance that was plain in the pedigree of the people here. That notorious number that a woman hears, one in eight, describing her risk over a lifetime, is based on the sporadic cases of breast cancer. Nine out of ten cases of breast cancer are sporadic, their causes unclear. Genes no doubt are involved, but they can’t be very powerful genes, or else scientists would have spotted them by now.

  When a breast cell first takes a wrong turn, tumor-suppressor genes like BRCA1 and BRCA2 step in and try to fix it. You can appreciate that if a woman begins her life with two working copies of an anticancer gene, and one gets knocked out along the way, she’s still covered. The second hit on the repair gene might never happen, or, if it does, the odds are that it will strike later in her life, which is why sporadic breast cancer is generally a disease of older women. In that regard, you could say that Shonnie Medina began her life with one hand tied behind her back. Contrary to all appearances, she had a physical handicap.

  Inheritors of a BRCA1 mutation aren’t absolutely guaranteed to get breast cancer. A range of risk is given: The high-end estimate for carriers in families like the Medinas and Martinezes is more than 80 percent, that is, an 80 percent chance over a woman’s lifetime, while other studies (fewer) have found that the risk may be as low as 35 percent. The risk probabilities for ovarian cancer are lower, in the range of 40 percent, which is still significant. Male breast cancer, normally a very rare condition, takes an upward tick in male BRCA carriers. But with female breast cancer, what distinguishes the heritable cases from the sporadic sort is the skew toward younger women.

  There is a 50 percent chance that if it happens, Shaw said to the group, it will happen before the age of fifty. A family history of breast cancer should be a red flag, he said, and it’s a red flag if a doctor sees a young woman from that family who’s concerned about a suspicious lump in her breast. Shaw obviously was thinking of Shonnie when he quoted the hypothetical physician saying to his patient, Oh, you’re only twenty-four or twenty-five. That has to be a cyst. Go home, get out of here. . . . No! Shaw said. We need to know if you’ve got cancer in the family.

  All this was going down smoothly at T-ana’s. A couple of times, a cell phone rang and was quickly turned off. Now the counselor mounted a very effective demonstration of the inheritance pattern of BRCA1. Borrowing from the refreshments, he used a red Coke can to represent the mutation and three green cans of Sierra Mist to stand for copies of the normal gene. He called up Debbie Rich-Crane, Teresita’s daughter and Joseph’s cousin, to pretend to be his wife. Debbie was an imposing woman about Jeff Shaw’s age. After some ice-breaking banter, he gave her two green cans to hold while he held out a red can and a green one. When he said, Our child will inherit one can from each person, the audience readily grasped the fifty-fifty probability that the red can, the adverse mutation, would be passed along.

  Importantly, Shaw had made himself the carrier, the male who masks the breast- and ovarian-cancer risk and transmits it to the next generation. It doesn’t only pass from mothers to daughters, as when Debbie held the red can. The cancer can skip generations, Shaw said, especially if it goes through men. Most doctors will say your dad’s side doesn’t matter. No. Then Jeff and Debbie exchanged cans. Whatever combination of BRCA1 genes they presented, always there was a 50 percent risk that their child would turn out to be a carrier of the mutation. The counselor added a warning, mindful of the large families present: Remember, a coin can turn up tails four times in a row.

  What if the baby inherits two copies of the mutation? someone asked. That does not happen, Shaw said. A miscarriage would occur and the baby would not make it. Shaw stepped over a permutation that might well apply to the people in this room, however. If two BRCA1 carriers, young and poor and not knowing their risk, met and married, they’d stand an even greater chance of producing carriers in the next generation, while their miscarriages would not be remarked upon. Given the crossed bloodlines in the community, it was not out of the question that both Luis and Andrellita had carried the mutation.

  . . . and now she is sixty-five years old, Shaw was saying to another questioner, and she does not have cancer. Is it possible for her to be a carrier? Yes! Shaw could have been speaking about Jose
ph’s mother, Dorothy. Though disease-free, she, like her oldest son, was an obligate carrier, as in has-to-be, since there was no other way to explain the path of cancer in her family. Dorothy Medina was paying attention to Shaw’s talk mainly out of politeness. Her English wasn’t the best. Urged by her daughters, she did go for DNA testing a couple of weeks later and got her positive result. Joseph, impassive behind dark glasses, never took the test.

  A cousin named Beverly Ortiz raised her hand and asked about screening. Beverly, who lived near Albuquerque, was one of the few who already knew she was BRCA1-positive. She had taken the test because her mother had died of ovarian cancer and her sister had contracted breast cancer. After her childbearing years, Beverly had her ovaries and uterus removed, and today she kept a close watch on her breast health through mammograms and MRI screening. In the eyes of the medical profession Beverly Ortiz was an ideal patient, informed and proactive. Her effort to outflank her genes so far had succeeded. Shaw said to her approvingly, For positives, yes, we’re going to do increased screenings. And there is a huge drop in risk by doing the surgical intervention—by which Shaw meant the ovarian removal. He seemed to recognize that this crowd wouldn’t countenance preventive mastectomy.

  Shaw gestured toward a stack of pink handouts on the table. Here’s the info. You decide. It has my phone number and my e-mail address. I will get back to you promptly if you contact me, but I’m a lot better with e-mail than with the phone. Although genetic counselors are trained not to twist patients’ arms about DNA testing, when you make an appointment with them, they make their preferences ringingly clear. Along with nurse practitioners, physician’s assistants, and other clinical staff short of MDs, they buy into the rationalism of scientific medicine, yet they haven’t become hard of hearing of emotions.