'1-hit' event provides new opportunity for colon cancer prevention, say Fox Chase researchers

September 15, 2008

More than 30 years ago, Alfred Knudson Jr., M.D., Ph.D., revolutionized the field of cancer genetics by showing that a person must lose both their paternal and maternal copies of a particular class of cancer-inhibiting genes, called tumor-suppressor genes, in order to develop cancer. This theory, called the two-hit hypothesis, guided scientists around the globe in their quest for tumor suppressor genes. Now Knudson, a Fox Chase Cancer Center Distinguished Scientist and senior advisor to the Center president, and colleagues offer evidence that a "one-hit" event is enough to change the cells and increase the likelihood they would become cancerous.

By studying people who have inherited the first hit in every cell in the body, the Fox Chase researchers believe they may have discovered a source for some of the earliest known molecular changes that signal the presence of colorectal cancer, the second leading cause of cancer-related death in the United States. Their findings are presented in the September 15 issue of the journal Cancer Research.

"We hypothesized that an inherited one-hit gene mutation can, by itself, lead to changes in the proteins of normal-looking cells" says Anthony Yeung, Ph.D., lead author of the paper and a tenured member of the Fox Chase scientific staff. "While these cells are just another hit away from becoming cancerous, their altered patterns of protein production may represent new biomarkers of cancer and novel targets for preventive and therapeutic drugs - a chance to strike at cancer before a second hit can happen."

The Fox Chase researchers studied patients with familial adenomatous polyposis (FAP), an inherited disorder that also serves as a classic model in support of the two-hit hypothesis. Patients with FAP, which predisposes people to colon cancer, carry mutations in one of their two copies of the adenomatous polyposis coli (APC) tumor-suppressor gene. The APC gene acts to prevent the colon cells from growing out of control and becoming cancerous. The APC gene is also mutated in most cases of sporadic colorectal cancer.

According to Yeung, the proteome, the sum total of proteins a cell will create from the genome, offers an insight into the physical state of cells. "We see that a single hit, in this case an inherited mutation, can have many repercussions within the entire cell even if it doesn't cause cancer itself," Yeung says. "The 'one-hit' event makes a second mutation that much more likely to push the cell over the edge into cancer."

This is the first time the human colon proteome has been characterized to this depth, made possible by samples of high quality and purity donated by research participants. Approximately 13 percent of 1,695 identified proteins were abnormally produced in the colon of APC mutation carriers, indicating that a colon cell under the one-hit state is already abnormal. Many of the changes affect molecular pathways consistent with the function of the APC protein as a tumor suppressor, including how the cell moves, interacts with other cells, divides, responds to free radical damage and, ultimately, self-destructs when growth threatens to go out of control.

"The two-hit hypothesis is applicable to most cancers because there are hundreds of tumor-suppressor genes," Yeung says. "The knowledge acquired in this study on the proteome of precancerous one-hit cells could be an opportunity to devise rational strategies, based on drugs or dietary changes, that may delay a second hit from occurring and thus prevent cancer from happening entirely."

Fox Chase Cancer Center

American Cancer Society's Complete Guide to Colorectal Cancer
by American Cancer Society (Author), Bernard Levin (Editor), Terri Ades (Editor), Katie Couric (Editor)

Created by a prestigious panel of experts, this new book offers comprehensive coverage of colorectal cancer, the second most prevalent form of cancer in the world, which, with proper screening, is almost entirely preventable. It provides up-to-date, essential information about the disease, including prevention, detection, diagnosis, treatment options, complementary and alternative therapies, coping, living well with cancer, caregiving, and much more. Throughout the text real cancer survivors offer their experience dealing with this disease, from diagnosis to treatment and beyond.

ABC of Colorectal Cancer (ABC Series)
by Annie Young (Editor), Richard Hobbs (Editor), David Kerr (Editor)

Colorectal cancer is a common cause of morbidity and mortality in which prevention, screening and early detection are vital. Beginning with the patient perspective and following the patient pathway, this new second edition covers epidemiology and prevention, screening programmes, decision support networks, the role of primary care, and supportive care for patients with colorectal cancer.The ABC of Colorectal Cancer provides the core knowledge on clinical genetics, diagnosis, imaging, therapy and surgery options and the latest evidence based guidelines for treating and managing colorectal cancer patients within the multidisciplinary team. Highly illustrated and accessible, it covers the full spectrum of the disease to provide the basis to make a real difference to clinical management.This...

On The Far Side of The Curve: A Stage IV Colon Cancer Survivor's Journey
by Wayne Cooke (Author), Dr. Peter I. Yi MD (Foreword)

On the Far Side of the Curve: A Stage IV Colon Cancer Survivor’s Journey is cancer survivor Wayne Cooke’s dramatic and comprehensive book about overcoming the odds—making it to the far side of the survival curve—moving on with his life, and his easy-to-follow lessons for coping…and surviving. Following a Stage IV colon cancer diagnosis, the author underwent three major surgeries and more than seventy cycles of chemo and infusional therapy. Six years later, he is sharing the lessons, coping techniques, wisdom, humor, and enthusiasm that supported him throughout his lengthy treatment. Whether one is diagnosed with colon cancer or another type of cancer, patients, caregivers, family, and friends will benefit from the lessons described in this book. From the vital role played by...

What Your Doctor May Not Tell You About(TM) Colorectal Cancer: New Tests, New Treatments, New Hope
by Mark Bennett Pochapin (Author)

- What Your Doctor May Not Tell You About Colorectal Cancer was published in Warner hardcover (0-446-53188-X) in 3/04. The book features a foreword by Katie Couric.
- Dr. Pochapin made an appearance on the Today show in conjunction with the hardcover publication of this book. Previously, he had been chosen by Katie Couric to be the Medical Director of the Jay Monahan Center for Gastrointestinal Health, named in honor of Ms. Couric's late husband.
- The author is an associate professor of clinical medicine at the Weill Medical College of Cornell University and Chief of Gastrointestinal Endoscopy at New York Presbyterian Hospital's Weill Cornell Medical Center.
- There are approximately 100,000 new colorectal cancer cases diagnosed annually, making it the second leading cause of...

Positive Options for Colorectal Cancer: Self-Help and Treatment
by Carol Ann Larson (Author), Kathleen Ogle (Foreword)

Colorectal cancer develops slowly over a period of several years, undetected, usually as polyps. It is a preventable and treatable disease if caught in time, yet most know little about how to read its symptoms. Written for the layperson, this book covers all the uncomfortable questions and answers about the disease, from prevention and warning signs, to screening and diagnosis techniques, to making decisions and developing treatment plans. Also included are positive stories about life after cancer by 12 survivors.

Colon & Rectal Cancer: From Diagnosis to Treatment
by Paul Ruggieri MD (Author), Addison R. Tolentino MD (Author)

This handy, reassuring guide helps recently diagnosed patients answer pressing questions, such as How far advanced is the disease? What tests are involved? and What treatments will be recommended? and understand the often confusing and intimidating medical jargon. In addition, this fully updated second edition is a quick, reliable reference to the most current procedures and treatment options. Among these are the increasingly popular trend of using chemotherapy and radiation prior to surgery, targeted therapies involving newer drugs that limit their focus to the cancer cells, the use of laparoscopic surgery, and latest approaches in radiation therapy and chemotherapy drugs. This work also reviews symptoms and risk factors for colon cancer, how the disease may be prevented, and pros and...

Be a Survivor Colorectal Cancer Treatment Guide
by Vladimir Lange (Author)

Dr. Lange’s comprehensive overview of cancer and treatment options offers detailed information using simple, concise language and a wide variety of color photos and drawings. Colorectal cancer patients need to know more about their disease, yet there is an overload of information. Be a Survivor gives the patient the specific, reliable and necessary information to make good decisions about their cancer and treatment options. Annually, 150,000 Americans are told they have colorectal cancer, making it one of the top three most common cancers in the United States. Diagnosed early, colorectal cancer is treatable, often curable, and vey preventable. This resource covers all aspects of colorectal cancer—from diagnosis to recovery, including a chapter for the patient's spouse.

Colon Cancer : Holistic Approach

This piece of writing is all about colon cancer. It explains things such as what exactly is the disease, its signs and symptoms, and several risk factors or causes. One would also be able to learn more regarding traditional modes of colon cancer treatments as well as a variety of alternative or complementary therapies to fight or at least augment the conventional cures. Discovering Colon Cancer aims to help everybody to try and combat this condition by imparting valuable facts and information.

The Cancer Survivor's Guide: Foods That Help You Fight Back
by Neal Barnard (Author), Jennifer K. Reilly (Author)

The Cancer Survivor's Guide explains how foods influence the hormones that fuel cancer and how a dietary change to a low-fat, plant-based diet can be beneficial to anyone diagnosed with cancer. Each section describes specific nutrients and how they work in your body, which foods are the best sources, recommended recipes, and offers simple, practical steps you can take during the week to increase consumption of these foods. Includes over 60 pages of recipes for satisfying and flavorful meals to help implement the recommendations.

Living with Colon Cancer: Beating the Odds
by Eliza Wood Livingston (Author), David Spiegel (Foreword)

Despite the efforts of Katie Couric to draw attention to the importance of colonoscopy screening for the detection of colon cancer, this cancer still does not receive the publicity devoted to breast, lung, and prostate cancer. Yet colorectal cancer is the third most common malignancy in the world and is the second leading cause of death from cancer next to lung cancer. As a result of the silence surrounding this disease, colon cancer patients and their families can feel isolated, without the support and information networks available to those coping with more publicised illnesses. In this helpful and inspiring book, Eliza Wood Livingston provides a wealth of practical information about colon cancer while telling of her own heroic battle against this challenging disease and her survival...