Healing My Family's Future

We paused outside the unit, hand in hand. “We could go home, you know,” I said, glancing at my husband, Chris. We might have been buying a car or questioning whether to sit through a movie. Instead, after more than a year of planning, weeks of daily injections, transvaginal ultrasounds, and an egg retrieval, we stood at the cusp of starting a family. After a final look and squeeze of the hand, we entered.

The waiting area was cold and uninviting. A handful of plasticky chairs with hard armrests occupied a dim corner beside a water dispenser and small, generic plants. Two heavy-looking doors read: “Medical procedures beyond this point.” A check-in desk sat behind a pane of frosted glass. Peeking through a cloud-shaped cutout, I saw staff in blue surgical head covers and scrubs dipping in and out of cramped patient bays. They were attending to others who, like us, hoped to bring a child into the world.

We were led to our own curtained bay, where I changed into a thin hospital gown and oversized grippy socks. Chris pulled a white, disposable suit over his street clothes, as if he were about to begin a shift at a food plant.

The reproductive endocrinologist stepped in and, without preamble, handed me a four-by-six-inch photo. It sent a jolt through my body as I focused on the image of a floating cluster of cells. If all went well, those cells, grown in a petri dish and implanted into my body, would become a warm, wriggling infant. The endocrinologist explained how she would thread a catheter through my cervix, push a gush of saline through its tip, and eject a five-day-old blastocyst into my uterus.

We take the consent form and sign on the line, agreeing to the embryo transfer, hoping for an outcome we might otherwise have initiated in a moment of private intimacy. There was nothing stopping us from conceiving naturally, but we never tried. We couldn’t risk passing on the insidious cancer gene I’d inherited.

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In 1996, when I was just 7 years old, I watched my mother transform from a strong woman to an ashen, bony figure swaddled in blankets, perpetually cold even in the humid Hawaiian air. Over a span of just nine months, she faded from this world and my future.

The culprit was cancer. It struck not only my mother but also, years before I was born, my grandfather and second aunt as well. All died young, tumors gnawing away at their stomachs.

I had no way of knowing that, as my mother became sicker and sicker, another family living five thousand miles away, in Aotearoa, New Zealand, was searching for their own answers to a similar, cancerous curse they called a makutu. Over a span of thirty years, that New Zealand family lost 25 members to stomach cancer, the youngest just fourteen.

I didn’t learn about them until the summer of 2010, when in examining my motivations to pursue a career in biomedical research, I started looking for explanations behind my mother’s disease. Late one evening in my college dorm room, I typed “hereditary stomach cancer” into the PubMed search bar. One of the top results, a 1998 publication in Nature, traced the New Zealand family’s deadly pedigree — solid circles, squares, and slashes flatly representing the encroachments of this devastating disease from generation to generation. I looked at the MacLeods’ family tree with a click of recognition; it could have described my own.

Parry Guilford, the study’s first author, later told me about establishing the trust necessary for the joint effort between his research group at the University of Otago and the MacLeods. It was only in realizing Guilford shared their motivation to get to the mysterious cause of their makutu that they agreed to share samples of their blood — that tapusubstance connecting them to the earth and their ancestors — with the research team, dismantling a century of whānaudistrust in Western influence.

Today, decades after the invention of DNA sequencing, it is easy to take the accessibility of genomic data for granted. In 2007, an undergraduate research student like myself — only months into wielding a pipette in the MIT Cancer Center on Ames Street in Kendall Square — might submit a plastic polypropylene tube with ten microliters of DNA fragments to a sequencing service. Five dollars and less than 24 hours later, the results — a string of letters, permutations of A’s, C’s, G’s, and T’s, representing the four nucleotides, adenine, cytosine, guanine, and thymidine — could land in my email inbox, providing a glimpse into the invisible chemical structures that link our cells to those who came before us.

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But in the early 1990s, when Guilford’s group began collecting blood and tumor samples from the MacLeods, DNA sequencing technology was still costly and unwieldy. Publications on “DNA sequencing technologies” were only just beginning to surge in the mid-1990s — there were more than 2,000 papers on the subject in 1996, as opposed to just two in 1967.

I can imagine Guilford’s group laboriously searching for the genetic change — one in six billion — driving the invasion of rogue cells into the stomach lining, the mechanistic cause of the MacLeod family’s makutu. But they were not the only ones searching for a genetic linkage to gastric cancer in families across the globe. In Britain, Korea, Japan, and elsewhere, similar research was being undertaken to understand the aggressive cancer ravaging generation after generation. In a bittersweet twist, the extent of the MacLeods’ suffering — the large n, or sheer number of those affected across their large clan — is what illuminated the link between a genetic mutation in the gene CDH1 and their cancer.

The mutation Guilford’s group identified, a thymidine at position 1008 where a guanine was expected (G1008T), results in a non-functional, truncated E-cadherin protein. Guilford’s paper marked the first time that researchers found a genetic mutation directly linked to gastric cancer.

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Months after reading about the MacLeods, I flew home to Honolulu for summer vacation. My sisters and I had an appointment at the Genetics Clinic at Queen’s Hospital, where a counselor explained to us the nature of Hereditary Diffuse Gastric Cancer.

My research over the last couple of months had already validated the suspicion I’d had since childhood — that I too was at risk; that my life expectancy might not extend far past forty. Until 2010, I had no evidence for this, but my recent investigation into the topic put more information within reach. Because of partnerships between researchers and families, like Parry and the MacLeods, it was then known that detection of an anomaly in our copies of CDH1 could explain our family’s gastric cancers, marking us with an estimated 80 percent risk of developing gastric cancer in our lifetimes.

Yet CDH1 mutations only partially explain these cancers. Only 25-40 percent of families with hereditary gastric cancers have a mutation in CDH1, and alternative genetic causes had not then, and have not yet, been comprehensively identified. Without one of us testing positive for a CDH1 mutation, a negative result would still leave us in the dark, forcing us to continue to wait for a latent driver of our family’s cancer to show itself.

As we shipped vials of our blood to City of Hope, a cancer center on the outskirts of Los Angeles, I didn’t know which result I wanted more: A positive result for the CDH1 mutation that would arm us with the definitive information to intervene against terrible odds, or a negative result that might eliminate individual risk, but only if at least one of us tested positive.

In December, I received a phone call from the Genetics Clinic in Honolulu. I had a gut feeling that my sisters would receive good news and that I would not. Alone in my dorm room overlooking the Charles River, its banks dotted by skeletal, leafless trees, I learned over the phone that I had inherited a copy of the mutated CDH1 gene from my mother. A guanine had been switched to an adenosine at position 59, a mutation that, like the MacLeod family’s, results in a truncated, non-functional E-cadherin protein. My sisters both tested negative.

Growing up, I’d occasionally look in the mirror with a photo of my mom in hand, trying to pick out features I thought we shared. Did I have her eyes? Her hair? Her nose? In what ways did she live on in me? With the genetic testing results in hand, I now had my answer.

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“You can live without a stomach?” my friends and MIT classmates asked, incredulously, as I shared that, on top of fellowship and graduate school applications, capstone projects, and final exams, I was facing a total gastrectomy in my future. Just as I’d had to inform myself, I had to teach those around me about CDH1 and why such drastic surgery was the recommended intervention.

CDH1 encodes a protein called E-cadherin, which is expressed ubiquitously on the surface of epithelial cells coating our skin and digestive tract. Facilitating the adhesions between these cells, E-cadherin locks them into a single tissue, forming the barrier that protects our insides from the outside. The intercellular connections cue them into their proper place in the context of the whole, to which way is up, and instructing them when and in which direction to divide.

While expression of a single healthy copy of E-cadherin, as is the case for my cells, is sufficient to perform this function, a “second-hit” caused by environmental factors or simple aging can dial down the expression of this remaining copy. The loss of E-cadherin leaves these cells disoriented, disrupting their ability to divide with fidelity. Their nuclei displace to the periphery of the cells, appearing like the flat seal of a signet ring when stained under the microscope, giving these aberrant cells their technical name: signet ring cell carcinoma. No longer one of many in a uniform layer of epithelium, signet ring cells break away and lurk under the surface until triggered by other molecular drivers of cancer to proliferate and infiltrate healthy tissue.

Diffuse gastric cancer is a silent killer. In the earliest stages of cancer, these signet ring cells hide beneath the lining of the stomach, asymptomatic and invisible to endoscopic surveillance. The probability of finding them with random biopsies before they proliferate and invade is minuscule; imagine overlaying two random distributions of dots and betting your life on the chance of their overlapping. More often than not, the cancer is already stage IV, with a five-year survival rate below 10 percent, when it is detected.

Thus, the recommended course of action for CDH1 mutation carriers is prophylactic surgery, or a total gastrectomy with roux-en-y reconstruction. It’s basically a large-scale plumbing job; after complete excision of the stomach, the esophagus is re-routed to the small intestine. The body adapts with behavioral and nutritional changes: smaller meals, more snacks, deliberate chewing, limits on high-fat and high-sugar foods, vitamin supplements. Apparently one canlive without a stomach.

In the months leading up to and after receiving my genetic testing results, I took comfort in becoming an expert in my own condition. Like any other class project, I knew which papers to reference, and the main research groups studying my disease syndrome or the molecular underpinnings of tumorigenesis. But it was a false sense of security, for I didn’t yet understand the human ramifications, the difficulty in interpreting how I felt about the information, and how to decide on when to act on it.

In 2011, I navigated my last semester at MIT numbly, on autopilot — attending classes, working on problem sets, and practicing piano. I was due to move to Oxford, UK, the following fall for a Master’s in Integrated Immunology, which would allow me to pursue research into understanding and manipulating immune recognition of foreign, rogue agents like viral pathogens and cancer. This would set the stage for beginning a MD/PhD program back in the States, where the plan was to spend the subsequent 8-9 years of my career.

Even with this path laid out, doubts crept in. When should I have the total gastrectomy? Should I take time off for surgery before, during, or after medical school? What about the grueling clinical years of medical training? One surgeon told me during a consult, “medical school will be really hard without a stomach.” A professor at MIT, upon learning I had written about my family history and decision to pursue genetic testing — components so central to my perspective, resiliency, and sense of urgency — in my fellowship applications remarked, “they might not want to invest in someone known to have a shortened life expectancy.” Rather than giving me time by freeing me from my mom’s fate, I worried whether knowledge of my CDH1 mutation instead hindered me in other ways.

In the end, I cut my Oxford studies short. I couldn’t envision completing assignments while the anticipation of the surgery and its outcome was ever-present in my subconscious. In 2012, I had a total gastrectomy, removing 115 sites of diffuse-type carcinoma from my body.

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Following my surgery, I didn't get back on the route I had put so much time and energy into. Instead, I returned to Oxford to study music before earning a PhD in protein engineering. I started running half-marathons, partly in defiance of that surgeon’s dismissive comments, partly to prove to myself that I could. Now, over a decade after my surgery, my new normal feels so normal I sometimes forget about my altered anatomy.

But even after my gastrectomy, I’m not completely in the clear. When I turned thirty, I started addressing the secondary cancer risk linked with my CDH1 mutation: a 50 percent risk of developing lobular breast cancer, a type that, like diffuse gastric cancer, doesn’t always present as an obvious, palpable lump. Instead, it tends to escape the breast single-file, one cell lined up after another. In sleuthing for details of my family history, I’d learned that my mom’s cancer began in the breast. The advanced gastric cancer was simply a devastating, secondary finding on an exploratory laparotomy to address the build up of fluid in her abdominal cavity.

Trying to be a responsible patient, I started scheduling the recommended breast cancer screening, alternating mammograms and MRIs every six months. Within 5 years, I’ve endured three breast biopsies — one ultrasound-guided, two MRI-guided. Each biopsy gave a false-alarm, consistent with the high false-positive rates of breast imaging.

With the future promise of biannual screening anxiety and false-positives until a likely inevitable true-positive, I brace myself for a prophylactic double mastectomy in the coming years. I’d rather a proactive intervention than one reactive to a breast cancer diagnosis.

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Even without my stomach or my breasts, barring further intervention, the mutated CDH1 will persist in each of my cells, lying in wait to pass itself on to the next generation.

In 2011, shortly after receiving my genetic testing results, my genetics counselor had mentioned offhandedly: “Massachusetts has great insurance coverage for embryo testing and IVF.” When my baby fever set in around the same time my husband and I moved back to Boston for my postdoctoral fellowship a decade later, I recalled my genetics counselor’s remarks. Family planning wasn’t a factor when we’d made the decision to move back to Boston, but my husband and I soon were grateful for the reproductive options open to us with our insurance coverage. Had we lived elsewhere, the financial burden of IVF and pre-implantation genetic testing (PGT) may have prompted a different decision. Instead, we had access to technology that has enabled us to leave genetics behind, deciding that my generation would be the last to carry my family’s CDH1 mutation.

Nearly two years before our son was born, Chris and I had our blood drawn at Brigham and Women’s Hospital. Five thousand miles away in Hawaii, my dad spit into a tube. We sent the samples to Natera, a genetic testing company where they would use our DNA to build a custom probe for PGT. With just a couple of cells from our future embryos, the probe would be able to determine the lineage of CDH1, tracking which copies were derived from Chris, my mom, or my dad.

Months later, my reproductive endocrinologist would call me at work one morning to share the news that my first round of in vitro fertilization had been successful. I found a quiet corner in an empty hallway of a biotech incubator space to learn that seven of twenty embryos tested were unaffected. We’d have seven shots to start a family and give our offspring just an average risk of developing stomach cancer.

It was strange to think of these embryos — one of which has since become my son — cryopreserved in plastic straws within a liquid nitrogen dewar tucked away in the depths of the hospital. I imagined the vapor wafting from the opening whenever an embryologist, wearing thick, blue, protective gloves removed one. I joked to Chris, “We could have our own village, if we wanted.”

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It amazes me that my son, a toddler now endlessly thrilled by The Very Hungry Caterpillar, is the outgrowth of the clump of cells, thawed the morning of the transfer, depicted in that four-by-six-inch photo. I think about the 13 fertilized embryos that will never grow to have favorite picture books because of our choice to not perpetuate the CDH1 mutation, and of the others equally denied because a mini-village of seven children is impractical. While I wouldn’t assign personhood to each cluster of cells frozen in liquid nitrogen, I still think about their potential.

I also wonder what decisions my mother would have made had this information and technology been available to her. That I value my existence, cherish the sensation of wind on my face, and feel proud of the person I’ve become — despite and, in part, because of the challenges presented by my CDH1 mutation — raises a question: Does a CDH1 mutation cause enough of a “highly serious” adult-onset condition (the bar set by the Ethics Committee of the American Society for Reproductive Medicine) to warrant PGT, the selection of one embryo over another?

To what extent does selecting the implantation of an embryo negative for the CDH1 mutation, conferring an adult-onset disease risk with available interventions, start looking like opting for a designer baby? During the IVF process, my husband and I felt this acutely when presented with the option to decide the transferred embryo’s sex. We chose to transfer the highest-quality embryo, but I couldn’t help but think about how, as the highest-quality embryo happened to be XY, we were also inadvertently choosing to confer the advantages of being male-presenting in our society.

Current PGT protocols screen for aneuploidy (PGT-A), structural chromosomal rearrangements (PGT-SR), and monogenic conditions (PGT-M). Aneuploidy, referring to missing or extra chromosomes, most often results in early miscarriages. Structural chromosomal rearrangements, where portions of chromosomes may be duplicated or deleted, are a common cause of infertility and recurrent pregnancy loss. Finally, monogenic conditions are those caused by known alterations in single genes — like CDH1.

The repercussions of these genetic anomalies, often leading to inviability, are straightforward, cut-and-dry cases of clear one-to-one clinical correlation with well-characterized genetic modifications. Yet, in an age where information is king, and the assumption is commonly “more is better,” the push for more control is seen as the next technological frontier. With advances in reproductive technologies, whole genome sequencing of embryos, and the calculation of difficult-to-validate polygenic risk scores, composite estimates of risk for diseases where many genes may play a role, are on the horizon. I wonder whether this — and my actions, even — might lead us down the slippery slope, where the decision of which embryo to transfer extends to more complex diseases and traits like obesity, heart disease, diabetes, and myopia.

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How does one measure whether a disease is “serious” enough to warrant genetic manipulation  of the next generation? While this enormous question lacks consensus, there are a few factors to consider, including available interventions, penetrance and risk.

Interventions to curb gastric and breast cancer risk exist for CDH1 mutation carriers, which is more than can be said for a disease like Huntington’s Disease, where a faulty copy of the HTT gene marks an individual for a certain, irreversible neurological demise. Yet the interventions available — prophylactic surgeries and enhanced breast screening — carry significant psychological and physical burdens.

Moreover, CDH1 mutations aren’t genetically deterministic. The penetrance rate, or lifetime risk of developing gastric or breast cancer given the presence of a CDH1 mutation, isn’t 100 percent. The actual risk, a number so central to clinical decision-making, is difficult to estimate.

Counterintuitively, expanded genetic testing has diluted our understanding of the severity of inherited CDH1 mutations. Early studies of CDH1 mutation carriers included individuals based on family history of multiple gastric cancer cases, often with extreme family histories such as the MacLeods’, leading the earliest estimates of penetrance to be as high as 80 percent. These risk calculations, however, depend on the study population, and by only including individuals with known family history of gastric cancer, estimates from the earliest studies suffer from ascertainment bias.

More recently, with the inclusion of CDH1 on multigene panel testing widely used to manage many types of cancer risk, the number of individuals being tested for CDH1 mutations without family history of gastric cancer has exploded. One study including individuals without the requirement for family history of gastric cancer estimates the lifetime risk to be on the order of 10 percent — a far cry from 80 percent.

On the surface, the results of this paper appear to buck previous clinical recommendations for CDH1 mutation carriers. The decision to elect for prophylactic total gastrectomy or pursue IVF with PGT given an 80 percent lifetime risk of developing gastric cancer is much easier to make than when the reported risk is 10 percent. If presented with a 10 percent risk today, without any other information, I don’t know what decision I’d make.

Delving into the details of the study, stratification of the study population by family history does show a correlation between estimated penetrance and number of gastric cancer cases in an individual’s pedigree. The upper-risk estimate reaches nearly 65 percent for individuals with three relatives affected by gastric cancer, whereas this number drops to a low of 10 percent for individuals with only one known affected relative. This relationship between disease burden in one’s family history and estimated risk highlights the importance of patient-centered decision-making informed by family history. An individual’s genetic information isn’t sufficient.

That there were three known cases of gastric cancer in my family history and that 50 percent of CDH1 mutation carriers in my mom’s generation have succumbed to disease — combined with the knowledge that surgeons removed 115 lesions in my stomach — confirm that the decisions to pursue prophylactic surgery and IVF with PGT were right for my partner and me.

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Enduring the health interventions my CDH1 mutation has required, including a myriad of gastrectomy-related complications on my way to becoming a mother, has transformed how I view the loss of my own mother. While I had always grieved for my sisters and myself — having lost our mom too young — as a mother, I now also grieve for my mother, who I imagine suffered physically and emotionally as she left her daughters.

As my husband and I settle into the normal chaos of parenthood, we become further and further removed from the technology that has given our son the chance at a normal future. We realize the true gift of genetic testing: It’s spared us from 18 years — the earliest age at which genetic testing is recommended — of wondering whether he carries my mom’s copy of CDH1. It has spared him from the decision of whether and when to have surgery, especially with the increased uncertainties of clinical management of CDH1 mutations, and the potential post-surgical complications that might trail him for years. It’s given us the chance to parent him without the threat of cancer taking me — or him — too soon.

Our understanding of genetics remains incomplete. Yet we are grateful for what we do know and for the accessibility of PGT and IVF that have released us from the intergenerational cycle of grief from losing loved ones too soon, too young, and with too much suffering.

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Jennifer Lai Remmel is a protein engineer whose research in academia and industry joins experimental and computational approaches to design next generation vaccines and biotherapeutics. She is a Rhodes Scholar and Schmidt Science Fellow.

Cite: Jennifer Remmel. “Healing My Family’s Future.” Asimov Press (2025). DOI: 10.62211/82pt-98re

Artwork by Martine Balcaen