Cancer

We always want what we don’t have. My teenage daughter is tall and beautiful (in my naturally biased and loving view). But she’s always complaining about her thighs. She thinks they’re too big and don’t look good in skinny jeans. What I see is a young girl with a fresh face, beautiful curves and a youthful spring of energy.

As a molecular epidemiologist, I see one more thing. She has a so-called “pear-shaped” body, which means she has larger thighs relative to a smaller waist, with most of her fat deposited in the lower body. In contrast, people who have “apple-shaped” bodies are heavier in the middle and have their body fat accumulated around the waist, closer to the heart, putting them at a higher risk for abdominal obesity. Many studies have shown that abdominal obesity has a more detrimental effect than overall obesity (as measured by body mass index, the metric calculated using height and weight) on a number of diseases, including type II diabetes, cardiovascular disease and certain cancers (such as those of the breast, ovary, gallbladder and kidney). The specific biological mechanisms are not entirely clear, but we do know from recent research that fat (adipose tissue) is an endocrine organ that actively secretes a variety of chemicals, such leptin, adiponectin, estrogen and other hormones, and inflammatory cytokines. These markers have been linked to growth and proliferation of cancer cells.

The Stanford Cancer Institute and its affiliated research partner, the Cancer Prevention Institute of California (CPIC), currently are conducting studies to understand more clearly the molecular mechanisms underlying the adverse effects of abdominal obesity on cancers. A better understanding of how leptin and inflammatory markers associated with abdominal obesity can influence cancer risk at the molecular level will help clarify the specific steps involved in carcinogenesis, which in turn can aid the development of effective preventive strategies to stop or slow down cancer development.

Our genetic makeup determines largely which body type we are born with, pear or apple. But our eating habits, physical activity and weight management can also affect fat distribution and disease susceptibility. Regular exercise (three times a week) helps increase muscle mass, which in turn can enhance metabolism and lower the risk of metabolism-related conditions, including certain cancers. Whether cancer prevention and weight reduction guidelines differ for those with different body types is another important topic for future studies.

My daughter is the apple of my eye. But I’m glad that, unlike me, she’s a pear. She inherited her father’s body type. In theory, her risk of certain hormone-related cancers or metabolic disorders is lower than mine. So next time she complains about her thighs, I’ll share with her my recent work on abdominal obesity and cancer and try to convince her that she’s lucky to have “big” thighs.

Ann Hsing, PhD, MPH, is director of research for the Cancer Prevention Institute of California (CPIC). Part of the Stanford Cancer Institute, the CPIC conducts population-based research to prevent cancer and reduce its burden where it cannot yet be prevented.

Photo by KDL Designs

In a novel combination of biochemical experimentation and data mining, Stanford researchers and postdoctoral scholars Cigall Kadoch, PhD, and Diana Hargreaves, PhD, have identified a large protein complex that appears to be significantly involved in cancer development in humans.

The multisubunit is a member of a family of chromatin-regulatory complexes that keep DNA tightly packed in a cell’s nucleus. Originally thought of as a kind of housekeeping, or maintenance, protein in the cell, it’s now becoming apparent that these complexes are really important in development and cancer.

Kadoch, working in the laboratory of developmental biologist Gerald Crabtree, MD, used biochemical techniques to identify seven previously unidentified members of the complex, which is called BAF (or mSWI/SNF). She and Hargreaves then analyzed 44 pre-existing studies that detailed the DNA sequences of primary human tumors of all types. They calculated the likelihood that any protein component of the large group was mutated. (The approach varies from others that analyze the mutation rates of individual proteins.)

As described in our release:

The results, once the newly discovered members were included, were surprising: 19.6 percent of all human tumors displayed a mutation in at least one of the complex’s subunits. In addition, for some types of cancers (such as synovial sarcoma), every individual tumor sample examined had a mutation in a BAF subunit. The results suggest that the BAF complex, when unmutated, plays an important protective role against the development of cancer in many different tissues.

Crabtree, who is also a Howard Hughes Medical Institute investigator, described his lab’s long-standing interest in BAF and other similar protein complexes:

Somehow these chromatin-regulatory complexes manage to compress nearly two yards of DNA into a nucleus about one one-thousandth the size of a pinhead. And they do this without compromising the ability of the DNA to be replicated and selectively expressed in different tissues - all without tangling. In 1994 we reported that complexes of this type were likely to be tumor suppressors. Here we show that they are mutated in nearly 20 percent of all human malignancies thus far examined.

The work was published yesterday in Nature Genetics. The researchers are now working to understand exactly how the mutations they’ve observed affect the function of the BAF complex.

Previously: Dumb, dumber and dumbest? Stanford biologist suggests humans on a downward slide and New clues arise in pancreatic cancer from Stanford researchers
Photo of (left to right) Cigall Kadoch, Gerald Crabtree and Diana Hargreaves, by Nathaniel Hathaway

As a reminder, today is the final day of our Ask Stanford Med installment focused on breast cancer. Questions related to breast cancer screening, dense breast notification legislation and advances in diagnostics and therapies can be submitted to Stanford surgeon Fredrick Dirbas, MD, by either sending a tweet that includes the hashtag #AskSUMed or posting your question in the comments section of our previous entry. We’ll accept questions until 5 p.m. Pacific time.

We provided details about Dirbas’ clinical work and research in our earlier post:

As head of the Breast Disease Management Group at the Stanford Women’s Cancer Center, Dirbas works with an interdisciplinary team of radiologists, oncologists, pathologists, researchers and support programs to provide patients with a comprehensive treatment approach. His research focuses on improving breast cancer therapy by refining existing diagnostic and treatment options and introducing new methods that reduce side effects and improve patients’ quality of life.

A 2011 Stanford Hospital Health Notes article describes how Dirbas and colleagues are at the forefront of exploring new ideas for delivering radiation in a more targeted and accelerated fashion, including methods such as intraoperative radiotherapy and another approach using external radiation therapy after surgery.

Previously: Ask Stanford Med: Surgeon taking questions on breast cancer diagnostics and therapies, California’s new law on dense breast notification: What it means for women and Five days instead of five weeks: A less-invasive breast cancer therapy
Photo by Wellcome Images

This month, a new California law went into effect requiring doctors statewide to notify women if their breast tissue is dense. Dense breast tissue has been linked to an increased risk of breast cancer because it can make tumors more difficult to spot. As Stanford breast cancer surgeon Fredrick Dirbas, MD, and colleagues explained in a recent Stanford Hospital & Clinics video, this notification isn’t meant to alarm women, but rather to educate them about their bodies and empower them in making better health-care decisions.

To expand on the conversation on the breast density notification law and clear up confusion over recommendations regarding mammograms, we’ve asked Dirbas to respond to your questions about breast cancer screening and advances in diagnostics and therapies. As head of the Breast Disease Management Group at the Stanford Women’s Cancer Center, Dirbas works with an interdisciplinary team of radiologists, oncologists, pathologists, researchers and support programs to provide patients with a comprehensive treatment approach. His research focuses on improving breast cancer therapy by refining existing diagnostic and treatment options and introducing new methods that reduce side effects and improve patients’ quality of life.

A 2011 Stanford Hospital Health Notes article describes how Dirbas and colleagues are at the forefront of exploring new ideas for delivering radiation in a more targeted and accelerated fashion, including methods such as intraoperative radiotherapy and another approach using external radiation therapy after surgery.

Questions can be submitted to Dirbas by either sending a tweet that includes the hashtag #AskSUMed or posting your question in the comments section below. We’ll collect questions until Wednesday (May 1) at 5 PM Pacific Time.

When submitting questions, please abide by the following ground rules:

• Stay on topic
• Be respectful to the person answering your questions
• Be respectful to one another in submitting questions
• Do not monopolize the conversation or post the same question repeatedly
• Kindly ignore disrespectful or off topic comments
• Know that Twitter handles and/or names may be used in the responses

Dirbas will respond to a selection of the questions submitted, but not all of them, in a future entry on Scope.

Finally – and you may have already guessed this – an answer to any question submitted as part of this feature is meant to offer medical information, not medical advice. These answers are not a basis for any action or inaction, and they’re also not meant to replace the evaluation and determination of your doctor, who will address your specific medical needs and can make a diagnosis and give you the appropriate care.

Previously: California’s new law on dense breast notification: What it means for women and Five days instead of five weeks: A less-invasive breast cancer therapy
Photo by Army Medicine

Adam de la Zerda, PhD, likes to tell his students that the sky’s the limit - something he most likely told himself many times over. At just 28 years old, he already has a pretty impressive laundry list of accomplishments: He’s co-founder of a Silicon Valley startup, he was recently listed in Forbes magazine’s “30 under 30″ in science and health care, and he has garnered numerous other awards, including ones from the Damon Runyon Cancer Research Foundation and the National Institutes of Health.

A story in today’s Inside Stanford Medicine profiles the young Stanford faculty member and a technology he developed called photoacoustic molecular imaging, which allows researchers to see cancerous tumors hiding under tissues. As writer Elizabeth Devitt explains, the imaging technique holds promise for cancer detection and other diseases:

The unique advantage of photoacoustic molecular imaging is that it allows scientists to see tumors hiding under other tissues and structures. It can also outline tumor boundaries during surgery, which helps surgeons see what to cut out and what to leave in — avoiding mistakes either way. “It’s like having Superman vision,” said de la Zerda.

“There may be a million different things we can do with this,” he added. “We can study basic tumor biology. We can monitor the treatment of cancer patients. We can even apply this technique to diseases other than cancer.”

Previously: Stanford structural biologist named one of Forbes Magazine’s 30 under 30 rising stars
Photo by Norbert von der Groeben

…Make that lots and lots of freezers.

Freezers storing blood from thousands of generous research volunteers who donate samples when they are healthy - years or even decades before they might develop cancer, diabetes or other chronic diseases - can be found across the country. For scientists, these “pre-diagnostic” blood samples are likely to contain new biological clues of disease, perhaps molecular flags that cancerous cells are multiplying, or immunological rumblings as the immune system responds to the first signs of disease. Finding these signals is critical to future prevention, as they could represent the basis for blood tests or other means of ultra-early detection of disease.

The statistics involved in gathering enough pre-diagnostic blood samples to make them useful to research are daunting, though. For example, to study the blood of 100 women who go on to develop ovarian cancer in the next year, more than 200,000 samples from healthy women must first be stockpiled.

This month, Stanford’s partner, the Cancer Prevention Institute of California, along with their colleagues in Southern California at the City of Hope National Medical Center and UC Irvine, embark on an epic research effort: asking more than 50,000 female teachers, retired teachers and school administrators all over California - participants for the last 16 years in the long-term follow-up California Teachers Study - to provide a blood sample to be stored away for future research. This is no small logistical feat. First, teachers aged 50 to 79 from all over the state will be asked to participate and provide a convenient time and place for a phlebotomist to visit them for a blood draw. The samples will then be express shipped to a state-of-the-art biobank where they will be frozen in large banks of closely monitored freezers, alongside similar samples from other long-term studies.

The Teachers Study will continue its long-standing routines for tracking the health outcomes of each participant by continuously linking their names and other identifying information to California health databases, including death certificates, cancer registries and hospitalization discharge summaries. With time, the stored blood samples will turn into scientific gold, as we learn which of them were drawn from women who later developed cancer. In addition to looking for early proteomic markers of breast, ovarian and other cancers, the samples of women who ultimately developed cancer will undergo intense testing for chemical pollutant levels.

DNA will also be extracted from the blood, and from saliva samples donated by mail from teachers who live too far from the phlebotomists’ routes, or who volunteer to participate in that way. These DNA samples will likely be analyzed with others from very large prospective studies, like the ongoing study of more than 100,000 Northern California Kaiser Permanente members, whose saliva samples have been banked.

Some new clues to cancer can only be discovered when scientists study massive numbers of samples at the same time. To date, gene hunting has yielded a few blockbuster findings - most famously the rare BRCA1 and BRCA2 genes with very high risk for breast cancer - but no common genes or gene combinations amenable to broader risk profiling. This may be because past efforts didn’t have the statistical power to find the most likely culprits, subtle combinations of many gene mutations that together may provide some meaningful differentiator of risk. Very large datasets, containing not thousands but millions of genomes, will be required to establish reliable genomic markers of disease.

Genomic prediction for chronic disease and ultra-early blood tests for cancer aren’t here yet, but they’re getting closer. And when they do arrive, we can thank the volunteers with the foresight to file away their precious blood samples in many, many freezers.

Christina Clarke, PhD, MPH, is a research scientist at the Cancer Prevention Institute of California (CPIC) and a member of the Stanford Cancer Institute. Part of the Stanford Cancer Institute, the Cancer Prevention Institute of California conducts population-based research to prevent cancer and reduce its burden where it cannot yet be prevented.

Photo by Shutterstock

Effective today, radiologists across California will be required by law to notify women when their mammography screening shows they have dense breast tissue. Approximately 50 percent of women have dense breast tissue - more fibrograndular tissue than fatty tissue as seen on a mammogram - so falling into this category is quite normal.

If you’re a woman with dense breast tissue, you’ll receive a letter in the mail that includes an explanation that this is a risk factor for developing breast cancer and that having such tissue may make it more difficult to detect a tumor. (However, having dense breast tissue is only a small risk factor for developing breast cancer and mammography is still considered the gold standard in breast-cancer screening.)

While this notification is meant to educate women about their own bodies and empower them to make better health-care decisions, it could also result in needlessly alarming or confusing patients. It’s important that women understand why they’re receiving this information and what they can do about it, which is why Stanford Hospital prepared the video above.

We’ve partnered with Inspire, a company that builds and manages online support communities for patients and caregivers, to launch a patient-focused series here on Scope. Once a month, patients affected by serious and often rare diseases share their unique stories; the latest comes from cancer survivor Dan Adams.

This past November I had my semi-annual cystoscopy. My visit was an early Christmas present, as I wound up receiving an “all clear” from my urologist. This coming May, if I get another “all clear,” it will mark five years of cancer-free living.

I had a resection to remove a bladder tumor in April 2008. I received an inconclusive pathology report following that procedure and a lot of hesitation from my first urologist. That’s when I sought a second opinion from a urologist at a major university hospital. Another resection and a couple of rounds of immunotherapy, and my bladder cancer was gone.

My follow-up cystoscopies were initially every three months, and now I’m comfortable with a six-month schedule. If something is going on in there, I want to catch it early. I’m not ready to move to an annual checkup. I don’t know if I will ever be ready.

It’s been a bumpy road; a few “red spots” in the bladder that required biopsies and a perforated bladder (those damn catheters) elevated my anxiety above and beyond what might be the norm following a cancer diagnosis. Having a cancer with a high reoccurrence rate also contributes to my feelings of anxiousness.

During the first couple of years in this war with bladder cancer, anxiety consumed my everyday living. Cancer was always on my mind, but I was unaware that anxiety was running my life. It took a long time, but eventually I learned to recognize changes due to anxiety, things that aren’t really “me.” Inattention to details, aimlessly daydreaming and becoming much more emotional were some of the telltale signs. I realized things weren’t right and I sought the professional help I needed. Thankfully, this help and the encouragement and support of a close family brought me through a very trying period.

While my anxiety is more or less under control, I’m still very aware that it’s there - and I’ve come to realize that knowing you have anxiety issues is essential to dealing with them. I know my anxiety level increases as I approach my next cystoscopy, and so I now slow down in the weeks leading up to the procedure and defer major decisions to a less anxious time.

I’m very aware now of anxiety and how it has affected my life beyond cancer. In this nearly five-year battle, anxiety has been the one medical issue, or side effect, that no one brought up; no one mentioned it as an issue to be aware of or offered treatment. I wish someone, in the beginning, had told me that cancer is a game changer, that my life will never be the same. I wish someone had explained that I need to be aware of how powerful anxiety can be, how it can affect your life, your relationships, your work.

I’ve been a bladder cancer warrior for almost five years, but it’s been only the last few years that I’ve come to realize that anxiety - not just the disease - is something I need to conquer.

Dan Adams lives along the Southern New Jersey Shore where he and his wife of 35 years raised three children and recently became grandparents for the first time. Dan is committed to raising awareness of bladder cancer and supporting those who are newly diagnosed through the Inspire/BCAN Support C0mmunity.

Hot on the heels of my Friday post about the elevator-pitch throwdown organized by the California Institute for Regenerative Medicine comes news that Stanford postdoc and clinical instructor Michael Rothenberg, PhD, was awarded third place in the organization’s “non-lead scientist” category. (Awards were given in two categories - non-lead scientist and lead scientist - to acknowledge the vast range of experience and training of the scientists who chose to compete. )

Rothenberg works in the laboratory of Michael Clarke, MD, at Stanford’s Institute for Stem Cell Biology and Regenerative Medicine, and he studies… well, why don’t I let him tell you himself? Watch the video above to see how winning science communication is done. And then check out a few more of the winners (links in the CIRM announcement).

Videos longer than 35 seconds lost points. All had to clearly explain in plain language what their CIRM-funded research was about. Humor helped, but it wasn’t necessary. And although the contest was lighthearted, the purpose was serious. From CIRM’s release:

The goal of the Elevator Pitch Challenge was to help researchers who get funding from the stem cell agency, the California Institute for Regenerative Medicine (CIRM), do a better job of communicating with the public. After all, we are a publicly funded agency and the money we use to fund research comes from the people of California, so it’s only reasonable to expect researchers to be able to explain the importance of what they do to Californians, and anyone else they might meet.

Congratulations Michael!

Previously: Learning and laughing: CIRM’s elevator pitch contest and A call to fix the “crisis of communication” in science

We’ve written before about the increasing number of breast cancer patients who opt to have both breasts removed, despite having cancer in only one. A CNN.com article today explores the reasons for these rising numbers and mentions a Stanford-developed online support tool, which was designed to help patients weigh their treatment options.

Previously: BRCA patients use Stanford-developed online tool to better understand treatment options, A closer look at preventive breast cancer surgery and Researchers unsure why some breast cancer patients choose double mastectomies