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Cancer, Dermatology, Research, Science, Stanford News

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

sunbathingA link between the UV rays in sunshine and the development of skin cancer is nothing new. We’ve all (hopefully) known about the damage sun exposure can wreak on the DNA of unprotected cells. But it’s not been known exactly how it causes cancers like squamous cell carcinoma or melanoma. Now, Stanford dermatologists Paul Khavari, MD, PhD and Carolyn Lee, MD, PhD have identified a UV-induced mutation in a protein active during cell division as the likely driver in tens of thousands of cases of skin cancer. Although the protein hasn’t been previously associated with cancer, the work of Khavari and Lee suggests it may actually be the most-commonly mutated oncogene in humans.

Their work was published yesterday in Nature Genetics. As we describe in our release:

Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumor cells with those of normal skin and looked for mutations that occurred only in the tumors. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.

The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.

If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.

The mutation in KNSTRN is a type known to be specifically associated with exposure to UV light. Khavari and Lee found the mutation in pre-cancerous skin samples from patients, but not in any samples of normal skin. This suggests the mutation occurs early, and may be the driving force, in the development of skin cancers. As Khavari, chair of the Department of Dermatology and dermatology service chief at the Veterans Affairs Palo Alto Health Care System, explained in the release:

Mutations at this UV hotspot are not found in any of the other cancers we investigated. They occur only in skin cancers… Essentially, one ultraviolet-mediated mutation in this region promotes aneuploidy and subsequent tumorigenesis. It is critical to protect the skin from the sun.

Previously: Master regulator for skin development identified by Stanford researchers and My pet tumor – Stanford researchers grow 3D tumor in lab from normal cells
Photo by Michael Coghlin

Applied Biotechnology, Cancer, Genetics, Pediatrics, Research

Gene-sequencing rare tumors – and what it means for cancer research and treatment

Gene-sequencing rare tumors - and what it means for cancer research and treatment

Sequencing the genes of cancer patients’ tumors has the potential to surmount frustrating problems for those who work with rare cancers. Doctors who see patients with rare tumors are often unsure of which treatments will work. And, with few patients available, researchers are unable to assemble enough subjects to compare different therapies in gold-standard randomized clinical trials. But thanks to gene sequencing, that is about to change.

Though this specific research was not intended to shape the child’s treatment, similar sequencing could soon help doctors decide how to treat rare cancers in real time

That’s the take-away from a fascinating conversation about the implications of personalized tumor-gene sequencing that I had recently with two Stanford cancer experts. Cancer researcher Julien Sage, PhD, is the senior author of a recent scientific paper describing sequencing of a pediatric tumor that affects only one in every 5 million people. Alejandro Sweet-Cordero, MD, an oncologist who treats children with cancer at Lucile Packard Children’s Hospital Stanford, is leading one of Stanford’s several efforts to develop an efficient system for sequencing individual patients’ tumors.

In their paper, Sage’s team (led by medical student Lei Xu) analyzed the DNA and RNA of one child’s unusual liver tumor, a fibrolamellar hepatocellular carcinoma. The cause of this form of cancer has never been found. Curious about what genes drove the tumor’s proliferation, the scientists identified two genes that were likely culprits, both of which promoted cancer in petri dishes of cultured cells. One of the genes, encoding the enzyme protein kinase A, is a possible target for future cancer therapies.

Though this specific research was not intended to shape the child’s treatment, similar sequencing could soon help doctors decide how to treat rare cancers in real time. Sweet-Cordero is working to develop an efficient system for getting both the mechanics of sequencing and the labor-intensive analysis of the resulting genetic data completed in a few weeks, instead of the two to three months now required. “We’re trying to use this kind of technology  to really help patients,” Sage said. “If you’re dealing with a disease that may kill the patient very fast, you want to act on it as soon as possible.”

In addition to giving doctors clues about which chemotherapy drugs to try, gene sequencing gives them a new way to study tumors.

“What’s really important is that, instead of categorizing tumors based on how they look under a microscope, we’ll be able to categorize them based on their gene-mutation profile,” Sweet-Cordero said. Rather than setting up clinical trials based on a tumor’s histology, as doctors have done in the past, scientists will group patients for treatment trials on the basis of similar mutations in their tumors. “In my mind, as a clinical oncologist, this is the most transformative aspect of this technology,” he said. This is especially true for patients with rare tumors who might not otherwise benefit from clinical trials at all.

And for childhood cancers, knowing a tumor’s gene mutations could also help doctors avoid giving higher doses of toxic chemotherapy drugs than are truly needed.

“The way we’ve been successful in pediatric oncology is by being extremely aggressive,” Sweet-Cordero said. Oncologists take advantage of children’s natural resilience by giving extremely strong chemotherapy regimens, which beat back cancer but can also have damaging long-term side effects. “We end up over-treating significant groups of patients who could survive with less aggressive therapy,” Sweet-Cordero said. “If we can use genetic information to back off on really toxic therapies, we’ll have fewer pediatric cancer survivors with significant impairments.”

Meanwhile, Stanford cancer researchers are also tackling a related problem: the fact that not all malignant cells within a tumor may have the same genetic mutations, and they may not all be vulnerable to the same cancer drugs. Next month, the Stanford Cancer Institute is sponsoring a scientific symposium on the concept, known as tumor heterogeneity, and how it will affect the future of personalized cancer treatments.

Sage’s research was supported by the Lucile Packard Foundation for Children’s Health, Stanford NIH-NCATS-CTSA UL1 TR001085 and Child Health Research Institute of Stanford University. Sage and Sweet-Cordero are both members of the Stanford Cancer Institute, and the National Cancer Institute-designated Cancer Center.

Previously: Smoking gun or hit-and-run? How oncogenes make good cells go bad, Stanford researchers identify genes that cause disfiguring jaw tumor and Blood will tell: In Stanford study, tiny bits of circulating tumor DNA betray hidden cancers

Cancer, Men's Health, Stanford News, Videos

Stanford experts talk new diagnostic technology for prostate cancer

Stanford experts talk new diagnostic technology for prostate cancer

This month is National Prostate Cancer Awareness Month, and Stanford urologic oncologists are sharing their knowledge about prostate cancer diagnosis and treatment, both online and in person. This Saturday, at a free community talk hosted by the Stanford Cancer Center, several experts will be on hand to answer questions and discuss prostate cancer screening, “watchful waiting,” diagnostic advances, and treatment options. In an online Q&A and the video above, Eila Skinner, MD, chair of urology, and James Brooks, MD, chief of the urologic oncology division, and others provide more insight on the disease. And during the month of September, more information about prostate cancer, including the benefits of targeted prostate biopsy, will be offered on Twitter via @StanfordHosp.

Previously: Managing a prostate cancer diagnosis: From leader to follower, and back again, New technology enabling men to make more confident decisions about prostate cancer treatment, Six questions about prostate cancer screening, Ask Stanford Med: Answers to your questions on prostate cancer and the latest research and Making difficult choices about prostate cancer

Cancer, Research, Stanford News, Surgery, Women's Health

Breast cancer patients are getting more bilateral mastectomies – but not any survival benefit

Breast cancer patients are getting more bilateral mastectomies - but not any survival benefit

woman looking out window2The most common cancer diagnosis you or a woman you love is likely to receive is early stage breast cancer, probably after detection by mammogram. One would think that given the regularity with which it’s diagnosed, treatment options for early stage breast cancer would be streamlined. Unfortunately, this isn’t the case.  There’s a staggeringly large menu of potential surgeries and treatments from which a patient and her doctor must choose, each with their own risks and benefits. Not including all of the different hormone blocking and chemotherapies, patients must pick one of three surgeries, shown here in order of escalating invasiveness and risk of complication:

  • Breast-conserving surgery (removal of the tumor only), followed by radiation
  • Single mastectomy (removal of the entire affected breast and any affected lymph nodes)
  • Bilateral mastectomy (the above plus the the unaffected breast)

One also would assume that the medical evidence base providing the benefits to the risk/benefit equations for each surgery would be large and up-to-date. Surprisingly, it is not. The randomized trials comparing lumpectomy and single mastectomy were conducted 30 years ago, and they showed similar risks of death. There has not been (and probably will never be) a randomized trial comparing bilateral mastectomy to one of the less invasive choices for healthy women. Angelina Jolie and other women positive for the breast cancer genes (BRCA1 and BRCA2) are in a different situation. For these women, clinical studies have observed a survival benefit after prophylactic mastectomy. For the 99 percent of women without mutations in these or other high-risk genes, existing trial data do not speak to current trends.

Even after accounting for [numerous factors], we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery

The complexity of choosing a breast cancer surgery – and how evidence should play into that choice – has been a hot topic in the last two months, after the publication of a large study calculating (based on predictive models) that bilateral mastectomy ultimately provides little to no improvement  in life expectancy as compared to a single mastectomy. Soon thereafter, on the New York Times’ opinion page, journalist Peggy Orenstein discussed the emotional reasons why women remove their remaining healthy breast, but firmly labeled bilateral mastectomy as  the wrong approach to breast cancer, saying, “It’s hard to imagine… that someone with a basal cell carcinoma on one ear would needlessly remove the other one ‘just in case’ or for the sake of ‘symmetry’.” Other journalists shared why they chose bilateral mastectomy knowing that it wouldn’t necessarily save their life.

To improve the evidence regarding outcomes after the three surgery types, our team at the Stanford Cancer Institute and the Cancer Prevention Institute of California used one of the largest cancer databases available: the cancer registry for the entire state of California. We tracked all 189,734 women diagnosed with stages 0-III breast cancer from 1998-2011 to learn which surgeries they were undergoing for breast cancer treatment and how long they survived afterwards.  These are all women who should have been eligible for breast conserving surgery with radiation. Our results were published today in the Journal of the American Medical Association today and have already received media attention.

We found that bilateral mastectomy for early stage breast cancer increased from 2 percent in 1988 to more than 12 percent in 2011.  The rate of increase was fastest among women younger than age 40 at diagnosis, among whom over one-third of those diagnosed in 2011 had a bilateral mastectomy. Bilateral mastectomy was more often chosen by non-Hispanic white women, those with private insurance, and those who received care at a National Cancer Institute-designated cancer center; while unilateral mastectomy was more often chosen by non-white women and those with public/Medicaid insurance. Even after accounting for characteristics of the women themselves, their tumor types, and their hospitals, we found no evidence of lower mortality for women who had bilateral mastectomy in comparison to breast-conserving surgery. Surprisingly, we found that women who underwent unilateral mastectomy had higher mortality than those who had the other two surgery types. We concluded that despite the growing popularity of bilateral mastectomy, it likely does not provide a better outcome than a less invasive procedure.

These data and the public response to them underscore the need for more updated and more personalized information regarding outcomes after common surgeries. Ideally, these would be accessible real-time by patients and their doctors in easily-understood formats.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: At Stanford event, cancer advocate Susan Love talks about “a future with no breast cancer”, Exploring the reasons behind choosing a double mastectomy and Researchers unsure why some breast cancer patients choose double mastectomies
Photo by Alex

Cancer, Parenting, Pediatrics, Public Health, Research

Study shows number of American teens using sunscreen is declining

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Despite an increase in cases of melanoma, the most dangerous type of skin cancer, growing percentage of high school students get a failing grade when it comes to using sunscreen. HealthDay reports:

The number of U.S. teens using sunscreen dropped nearly 12 percent in the last decade, a new report shows.

During that same time period, the number of teens using indoor tanning beds barely decreased. Both indoor tanning and failure to use sunscreen increase the risk of skin cancers, including deadly melanomas, the researchers noted.

“Unfortunately, we found a decrease in the overall percentage of teens who reported wearing sunscreen, from 67.7 percent in 2001 to 56.1 percent in 2011,” said lead researcher Corey Basch, an associate professor in the department of public health at William Paterson University in Wayne, N.J.

“Using sun-protective behaviors like applying sunscreen and avoiding intentional exposure to tanning devices will be key [to lowering cancer risk],” she added.

Use of indoor tanning devices by white girls decreased only slightly, from 37 percent in 2009 to 29 percent in 2011, she said.

Study authors say more research is need to understand why teens aren’t following national guidelines regarding sun protection.

Previously: Melanoma rates exceed rates of lung cancer in some areas, Beat the heat – and protect your skin from the sun, Working to protect athletes from sun dangers and Stanford study: Young men more likely to succumb to melanoma
Photo by Alex Liivet

From August 11-25, Scope will be on a limited publishing schedule. During that time, you may also notice a delay in comment moderation. We’ll return to our regular schedule on August 25.

Cancer, Men's Health

Managing a prostate cancer diagnosis: From leader to follower, and back again

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; this month’s bonus column comes from patient advocate Jim Rieder.

Caring for others has always been part of my approach to life. I built my career in health care serving as the CEO of a statewide non-profit foundation, in addition to being the CEO of seven diverse types of hospitals. Naturally, I was intimately familiar with the steps necessary for a person to become an empowered patient. But when I was forced into the role of being the patient, the initial transformation was surprisingly more intense and unsettling than I had imagined it would be.

Managing prostate cancer is a battle. Recognize it as such. Invest the time and energy necessary to empower yourself with the knowledge you’ll need to make informed choices about your path of treatment

When a person is diagnosed with any type of cancer, the obvious objective is to get rid of it completely as quickly as possible. After being diagnosed with prostate cancer in 2002 and doing my due diligence, I ultimately decided that a radical prostatectomy was the best course of treatment for me. I had the surgery in 2003, and I’m very happy to report that I’ve been cancer-free ever since. However, it’s important to recognize that there’s not a one-size-fits-all solution for treating prostate cancer.

In response to prostate cancer diagnosis, it’s critical to take a step back, take a few deep breaths, and try to approach the situation calmly and logically. Don’t let anyone rush you. There’s ALWAYS time to evaluate the medical options and get a second opinion from another medical expert who ideally is not affiliated with the same practice as the physician who provided the initial diagnosis or treatment recommendations. Know that watchful waiting or active surveillance can be viable options. Every treatment has side effects, which typically include erectile dysfunction and/or incontinence. The skill of the physician and the amount of experience specific to the procedure being performed are very important in minimizing the presence and ongoing impact of these side effects.

Some guys pursue their treatment and quietly return to business as usual without ever talking about their prostate cancer or its side effects. While I respect the option of maintaining privacy, I encourage anyone who’s facing a diagnosis of prostate cancer to reach out for help from others who have already traveled the same path, and to reciprocate down the line by helping others who will be grappling with the involuntary transition into joining the prostate cancer community. Also recognize that prostate cancer affects spouses or partners, as well as family members. Their support is also very important.

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Cancer, Genetics, Research, Science, Stanford News

Unraveling the secrets of a common cancer-causing gene

Unraveling the secrets of a common cancer-causing gene

The Myc protein can cause a lot of trouble when it’s mutated or expressed incorrectly. Under those condition it’s called an oncogene, and it’s associated with the development of more than half of all human cancers. But because its cellular influence is vast (it controls the expression of thousands of genes and regulatory molecules), it’s been tough for scientists to learn which of its many effects are cancer-causing.

Now oncologist Dean Felsher, MD, PhD, and his colleagues have found that just a handful of genes are responsible for the Myc oncogene’s devastating outcomes. Their work was published today in Cancer Cell. As I wrote in our release:

The genes identified by the researchers produce proteins that govern whether a cell self-renews by dividing, enters a resting state called senescence or takes itself permanently out of commission through programmed cell suicide. Exquisite control of these processes is necessary to control or eliminate potentially dangerous tumor cells.

In particular, the researchers found that Myc works through a family of regulatory RNA molecules that govern how (and when) tightly packaged genes in the DNA/protein complex called chromatin are made available for transcription into proteins that do much of the work of the cell. Understanding this process might help researchers find ways to throw a molecular wrench into the Myc mechanism.

“One of the biggest unanswered questions in oncology is how oncogenes cause cancer, and whether you can replace an oncogene with another gene product,” Felsher told me. “These experiments begin to reveal how Myc affects the self-renewal decisions of cells. They may also help us target those aspects of Myc overexpression that contribute to the cancer phenotype.”

The reliance of many cancer cells on oncogenes like Myc is called oncogene addiction. In many cases, blocking the expression of an oncogene, or tinkering with its activity, causes cancer cells to stop growing and tumors in animals to regress. Recently Felsher and his colleagues published an article in the Proceedings of the National Academy of Sciences describing how inactivating two oncogenes at once can work better to fight cancer in animal models by making it more difficult for the cancer cells to develop resistance to therapy.

Previously: Tool to identify the origin of certain types of cancer could be a “boon to doctors prescribing therapies” and  Smoking gun or hit-and-run? How oncogenes make good cells go bad

From August 11-25, Scope will be on a limited publishing schedule. During that time, you may also notice a delay in comment moderation. We’ll return to our regular schedule on August 25.

Cancer, Health Costs, In the News, Stanford News, Videos

TV spot features a more humane approach to late-stage cancer care

Updated 8-4-14: The video is no longer posted on the Al Jazzera website, but the online story is still available.

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7-30-14: Is it possible to cut the costs of late-stage cancer care by 30 percent and provide a much better experience for patients?

That’s the question that recently brought an Al Jazzera America TV news crew out to the VA Palo Alto Health Care System, to interview patients enrolled in a new Stanford-designed pilot study on cancer care. You can watch their 9-minute video on this topic here.

The guiding principle behind this cancer-care program is this: Make sure that patients are fully informed about survival odds and treatment side effects well before they’re on the brink of death, when emotions overwhelm the decision-making skills of patients, their families and clinicians.

“Eighty percent of all cancer patients express a desire to die at home, yet only 10 percent do,” says Manali Patel, MD, the VA hospital oncologist running this study. “These end-of-life conversations, which typically take two hours in the beginning and require many follow-on conversations, are too hard, time-consuming and draining for a busy oncologist to do well.”

For these life-and-death discussions, patients are assigned personal care coaches who help them understand the big picture — treatment side effects, survival odds and pain-relief options. They also have access to a 24-hour symptom-management hotline and an option for in-home chemotherapy.

Architects of this new cancer care model, working with Arnold Milstein, MD, at Stanford’s Clinical Excellence Research Center, estimate that this program will lead to fewer unwanted treatments and expensive emergency room visits, saving the overall heath-care system money, while at the same time improving patient quality of life.

Previously: Communicating with terminally ill patients: A physician’s perspective, Identifying disparities in palliative care among cancer and non-cancer patients, Uncommon hero: A young oncologist fights for more humane cancer care, The money crunch: Stanford Medicine magazine’s new special report and New Stanford center to address inefficient health care

Cancer, Dermatology, In the News, Public Safety, Research, Stanford News

A closer look at new research showing disproportionate rates of melanoma in Marin County

Last week, Cancer Prevention Institute of California/Stanford Cancer Institute researcher Christine Clarke, PhD, shared results of a new report (.pdf) showing that a county in California has higher numbers of melanoma skin cancer than the rest of the state. On this morning’s Forum Clarke joined two other guests, including Stanford dermatologist Susan Swetter, MD, director of the Pigmented Lesion and Melanoma Program at the Stanford Cancer Institute, to discuss the research and to offer skin safety and screening tips for the summer.

It’s worth a listen – especially if you live in the county just north of San Francisco.

Previously: Melanoma rates exceed rates of lung cancer in some areasWorking to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma, New research shows aspirin may cut melanoma risk and Working to prevent melanoma

Cancer, Genetics, Research, Stanford News

Stanford partnering with Google [x] and Duke to better understand the human body

Stanford partnering with Google [x] and Duke to better understand the human body

Most biomedical research is focused on disease and specific treatments for illness, rather than on understanding what it means to be healthy. Now researchers at Stanford, in collaboration with Duke University and Google [x], are planning a comprehensive initiative to understand the molecular markers that are key to health and the changes in those biomarkers that may lead to disease. The project was featured in a Wall Street Journal article today.

The study is at the very early stages, with researchers planning to enroll 175 healthy participants in a pilot trial later this year. The participants will undergo a physical exam and provide samples of blood, saliva and other body fluids that can be examined using new molecular testing tools, such as genome sequencing.  The pilot study will help the researchers design and conduct a much larger trial in the future.

“We continue as a global community to think about health primarily only after becoming ill,” Sanjiv Sam Gambhir, MD, PhD, professor and chair of radiology, told me. “To understand health and illness effectively, we have to have a better understanding of what ‘normal’ or ‘healthy’ really means at the biochemical level.”

“The study being planned will allow us to better understand the variation of many biomarkers in the normal population and what parameters are predictive of illness and may eventually change as a given individual transitions from a healthy to a diseased state. This will be a critical study that will likely help the field of health care for decades to come,” said Gambhir, who also directs the Canary Center at Stanford for Cancer Early Detection.

The researchers hope the work will provide insights on a variety of medical conditions, such as cancer and heart disease, and point to new methods for early detection of illness. Their studies will focus on the genetic basis of disease, as well as the complex interplay between genes and environment.

These kinds of studies haven’t been done before because of the cost and complexity of molecular measurement tools, the scientists say. However, the cost of some technologies, such as DNA sequencing, has been steadily declining, while some new tools and new ways of analyzing large quantities of data have just recently become available. So a first step in the study is to determine how best to use these technologies and determine what questions need to explored on a larger scale.

The work is sponsored by Google [x] and will be led by Andrew Conrad, PhD, a cell biologist and project manager at the company.

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