The A-T Family Study

A rare disabling disorder led to genetic insight into cancer and coronary heart disease, and to a whole new way of thinking about the genes involved in common diseases.

In 1971, we began studying families of ataxia-telangiectasia patients, a rare genetic condition in which cancer occurs remarkably frequently. Patients get A-T by receiving a mutated A-T gene from both parents. The parents, who carry only one mutated A-T gene, are called carriers or heterozygotes. Close blood relatives such as aunts, uncles, and grandparents have a 50-50 chance of carrying the mutated A-T gene. Neither physical examinations, nor conventional laboratory tests can distinguish carriers from non-carriers.

According to a basic genetic principle, A-T mutations are relatively frequent in the general population. If A-T mutations predispose carriers to a common disease, the frequency of these mutations has obvious public health implications. Because of this, Dr. Swift began to study the incidence of cancer in A-T families.

Cancer in A-T Mutation Carriers

Cancer Research 1976 published the first report showing that carrying a single A-T mutation predisposed carriers to cancer.

Later, a visiting scientist convinced Dr. Swift that the scientific community needed substantial new information about the role of the A-T gene in cancer. In response, his research group extended the study in 1981 to recruit every A-T family in the United States. The goal was to follow changes in the health of each relative to determine the cancer risk of A-T mutation carriers. The study compared the cancer rates in A-T blood relatives, each of whom has a high probability of carrying an A-T mutation, to the rates in persons who married into the families, each with a much lower probability of being a carrier. When the research started, no-one had any idea of the new medical discoveries that would come from this program!

The data showed, for the first time, that A-T mutations predispose female carries to breast cancer. Dr. Swift vividly remembers where he was and what he was doing when a research assistant showed him these data – he saw immediately that the A-T gene is an important previously unrecognized “breast cancer gene”.

An independent study confirmed this finding four years later; the studies appeared in the New England Journal of Medicine in 1987 and 1991. These studies also found:

A T heterozygotes have a higher overall risk of cancer than non-carriers. The following cancers occurred more frequently in A-T blood relatives than in spouse controls:
          - Breast (of course)
          - Lung
          - Prostate
          - Pancreas
          - Stomach
          - Thyroid
          - Gall bladder
          - Kidney and urinary bladder
          - Chronic lymphocytic leukemia

• A T heterozygotes have higher overall death rates as adults.
• A T heterozygotes have higher rates of coronary heart disease.
• Significantly more blood relatives with breast cancer had substantial prior exposures to diagnostic X-rays.

THE NEXT STEP: DNA TESTING TO IDENTIFY A-T MUTATION CARRIERS

Dr. Swift recognized, in the late 1980s, that advancing genetic laboratory techniques would soon permit scientists to determine precisely which A-T blood relatives carry an A-T mutation. He then devised the index-test method for using molecular tests and the A-T clinical family data to demonstrate, beyond any possibility of doubt that A-T mutations predispose to cancer.

This method proved that carrying an A-T mutation increased the risk of breast cancer almost 4-fold (Cancer Genetics and Cytogenetics 1996).

The A-T family study also used DNA testing to demonstrate (Annals of Internal Medicine 2000):

          - Carriers of a mutated A T gene have a significantly increased risk for death at ages 20
             through 79 years.
          - On average, carriers die 7 to 8 years earlier than non-carriers.
          - Carriers die more frequently from coronary heart disease, at earlier ages than non-carriers.

In 1996, a Connecticut radiation oncologist asked Dr. Swift if a 65 year old A-T mother with breast cancer could be safely treated with radiation therapy. He was concerned because he knew that radiation therapy of A-T patients led to severe complications. Dr. Swift’s review of all A-T carrier women who had treated breast cancer with radiation found none had a severe complication of this therapy. The physician did treat her with radiation – she has had no complications or recurrence!

In fact, we later found that radiation therapy of A-T carriers with breast cancer was not only safe but also strikingly effective (Journal of the American Medical Association 2001). Without radiation therapy -- early stage breast cancer treated only by surgery recurred frequently in A-T carriers. On the other hand, the recurrence rate was quite low for those patients who received adjuvant radiation therapy in addition to surgery. Further studies confirming these observations could lead to improved diagnosis and treatment for the thousands of A-T mutation carriers diagnosed with breast cancer each year.

A-T MUTATIONS IN GENERAL BREAST CANCER PATIENTS

In the late 1990s, several research groups began to screen for A-T mutations in breast cancer patients from the general population. These surveys found A-T mutations in 12-18% of breast cancer patients but raised a difficult question that still has not been answered: which changes in DNA sequence found through screening count as true A-T mutations (types of mutations) and which are “harmless?” (Published studies from other labs.)

A high proportion of breast cancer cases carry missense A-T mutations. The surveys referred to above are convincing support for the overall association of A-T mutations with breast cancer, but none of them were able to demonstrate conclusively which individual missense mutations were truly associated with breast cancer and which were harmless normal variants. The Index-Test Method is uniquely suited to answer this question for every common missense mutation.

These population surveys have shown:

- A-T mutations are the most common genetic cause of breast cancer;
- These mutations are present in 2-5% of all men and women.

Types of Mutations

In a mutation, the letters of the genetic code differ from the typical human DNA sequence. A different letter may appear or a portion of the code may be deleted or duplicated. Duplications and deletion have the most severe effect on function – typically they lead to a totally nonfunctional protein. About 60-70% of mutations found in A-T patients completely, or almost completely, abolish the function of the A-T gene product.

DNA sequencing has identified numerous mutations of another type called missense mutations. Missense mutations result from changing a single base in the DNA sequence and often lead to a gene product with altered function. Some missense mutations are found in A-T patients, usually leading to A-T with later onset and slower progression. Many other missense mutations do not seem to cause A-T at all, even if paired with more severe mutation.

Click here to learn more about genetic testing

EARLIER DIAGNOSIS AND MORE SUCCESSFUL TREATMENT

Women who know they have a high risk of breast cancer can do several things to detect the cancer as early as possible. In general, physicians believe that early diagnosis of cancer increases the success of treatment. For A-T mutation carriers in particular, radiation therapy and surgery of Stage I/II breast cancer may bring a lasting remission. Women unaware that they carry a mutated gene may opt for surgery alone, which may lead to a greatly increased risk of cancer recurrence.

Conventional laboratory tests cannot detect a carrier; a specialized DNA diagnostic test is required. Click here to learn more about genetic testing. Clinical testing of women for A-T mutations will find many missense mutations. We must know first which common mutations lead to breast cancer and which do not. Inconclusive test reports do not help women concerned about their risk of cancer.

Cancer chemotherapy agents are currently selected based on the best available clinical trials covering all breast cancer patients. Certain drugs may be more effective for A-T breast cancer patients while others may be less useful or even harmful. Future studies will determine which chemotherapy regimen brings the greatest benefit to A-T carriers with breast cancer.

PREVENTION OF CANCER

The risk of cancer (or coronary heart disease) for A-T mutation carriers could be reduced once scientists fully understands the chain of events that lead from the gene mutation to the actual disease. Specific environmental factors may participate in this chain; identifying and eliminating these factors could prevent disease. Or a drug could be devised to interrupt the chain of events causing the disease. The research needed for this will take place once the scientific community is convinced, through additional studies, how important A-T mutations are in disease.

About A-T

Ataxia-telangiectasia (A‑T) is a rare genetic disorder first described in the late 1950s by two outstanding physicians, Drs. Elena Boder and Robert Sedgwick.  These physicians identified a group of patients in Los Angeles with gait and coordination problems -- ataxia -- and prominent widened blood vessels in the eye and certain skin regions -- telangiectasia.

A‑T patients almost always show difficulty in walking before the age of 2.  They progressively become disabled from decreasing coordination, difficulty in speaking clearly, and, later, muscle weakness.  Some A‑T patients live until their 30s or 40s.

Dr. Boder introduced every A-T family she knew to Dr. Swift for his study.  He visited more than 20 A-T families in 1974-5, when he reported the results of the first family study to them.  One A-T mother who learned about the cancer risk of A-T carriers had successful surgery in 1977 for an early breast cancer – she has had not a recurrence.

RESEARCH HAS IMPROVED THE QUALITY AND LENGTH OF LIFE FOR A-T PATIENTS

As he got to know these and the new families who joined the study, he learned that many A-T children, with their humor and warm personalities, had an excellent quality of life despite their disability. Unfortunately, from the frequent phone calls and questions from the families and their physicians, he also learned about the cancers and chronic lung diseases that ended many lives prematurely. Deeply troubled by his inability to help A-T children and young adults who were dying from these chronic illnesses, he began to recruit help from experts in each field. The following recommendations resulted:

Chronic Lung Disease
Dr. Swift enlisted a pediatric pathologist at Baylor Children’s Hospital, Dr. Claire Langston, to review tissue slides from A-T patients with chronic lung disease. Her evaluation led Dr. Swift to recommend to physicians a new approach to treating this disease. When this treatment was begun early enough, the progression of the lung disease was arrested, or even reversed, as in the following report (Pediatric Pulmonology 2005). A T chronic lung disease caught early enough can be reversed and may not recur. Unfortunately, many doctors do not get the chest X-ray needed for the diagnosis until it is too late.

Successful Treatment
Misty, diagnosed with A-T at 8 years of age, was a lively, cheerful active member of her family, church, and school until age 14 when she was hospitalized for severe disease in both her lungs. Before this, she had two to three lower respiratory tract infections per year, manifested by dry non-productive cough and wheezing, which responded to daily nebulized bronchodilators and oral antibiotics.

During this hospitalization she had fever, a high white blood count, diarrhea, cough, dehydration, and signs of lung inflammation on physical examination. The chest X-ray showed air trapping, thickening around the bronchial tubes, and infiltrates in both lungs. While this picture is consistent with pneumonia, no bacteria, fungi, or other pathogens were found in her sputum.

When Misty did not improve with intravenous antibiotics and her blood oxygen dipped to a worrisome point, the doctors began treating her with high doses of intravenous corticosteroids. Over the next two weeks, her cough resolved, as did the lung infiltrates. As the corticosteroids were tapered (but never to zero), her blood oxygen level returned to normal and she resumed her active life. She maintained on 5 mg of prednisone (a corticosteroid) daily, and her parents raised the dose to 10 mg whenever Misty began to show increased cough or shortness of breath.

She had a full quality of life over the next 10 years, going to Church Camp, delivering for McDonald’s in the nearby mall, going on excursions with her friends and family, and doing her chores. She never required oxygen outside of the hospital. During the last 13 months of her life, Misty had episodes of fever and respiratory distress that led to hospitalizations, and she died at age 27.

Cancer
To improve the treatment and survival of A-T patients with cancer, Dr. Swift recruited Dr. Claudio Sandoval, a pediatric oncologist at New York Medical College, to review the clinical data from all A-T patients in the family study. These data showed the survival was significantly better for leukemia and lymphoma patients treated with full chemotherapy according to protocol (Medical and Pediatric Oncology 1998). Previously, many doctors had treated A-T patients with reduced chemotherapy because they believed, incorrectly, that chemotherapy had excessive harmful effects similar to radiation therapy. Now full-dose chemotherapy is the standard of care for A T patients with cancer, with much better outcomes.

Leukemia
A seven-year-old boy with A-T benefited from this study even before it had appeared in print. His mother called Dr. Swift as she was rushing her son to St. Jude’s Cancer Hospital shortly after leukemia was diagnosed. At that precise moment of time, the paper by Drs Sandoval and Swift was ready for publication. We called the oncologist at St. Jude’s, who had worked with Claudio during their training, and faxed him the manuscript. The oncologist followed our recommendations and treated the boy with full-dose effective chemotherapy, which induced a complete remission. Unfortunately, the next several years were marked by relapses and recurring lung problems, so this A-T patient died 5 years from the time of diagnosis. Still, this is a much longer survival than A-T patients achieved before full-dose cancer chemotherapy became standard, which it is now.

Painful Skin Sores
Another distressed mother called because her daughter suffered from painful deep sores on her arms and face that had not responded to any treatment. After recognizing that other A-T patients had similar lesions, Dr. Swift sought help from Dr. Amy Paller at the University of Chicago, a leading pediatric dermatologist. Her review of the pathology showed granulomatous lesions (tissues in A-T chronic lung disease contain similar findings). While this disfiguring painful skin disorder did not respond to steroids applied to the skin, we found that injecting steroids into the lesions or, in extreme cases, taking steroids by mouth did control the problem (Journal of Pediatric Health Care 1991). A T patients no longer need to suffer or die from painful, disfiguring skin lesions.

Radiation and Cancer

People fear ionizing radiation because they know it can harm living things yet they cannot see it. Exposure to ionizing radiation can cause many different types of cancer. Ionizing radiation can come from many sources: radioactive materials, nuclear reactions (bombs, energy generation), and cosmic rays. Medical diagnostic X-rays are based on the fact that ionizing radiation penetrates the body so that bones and injected contrast materials can be seen on film. Radiation often successfully treats cancer because it kills cancer cells readily while sparing surrounding normal tissues. However, in certain circumstances A-T mutations can make non-cancerous cells more sensitive to the effects of radiation.

Clinically, A T patients suffer devastating destruction of normal tissues when treated for leukemia or lymphoma with conventional doses of ionizing radiation. Ionizing radiation in the laboratory kills cultured cells from A T patients much more easily than non-A T cells. Cells from A T carriers are somewhat more sensitive to ionizing radiation in the laboratory than control cells, although not as much as cells from A T patients.

Although radiation can cause many different types of cancer, we know the most about its role in breast cancer. High doses definitely lead to cancer. Exposure of girls and young women carries the highest risk. And doses from repeated exposures – even when separated by months or years -- add up to produce cancer more frequently.

Is the cumulative dose from medical diagnostic X-rays ever sufficient to lead to breast cancer in the general population, or in carriers of an A-T mutation?

Scientists have found this question difficult to answer, because no-one records the dose from any clinical X-ray procedure. None of us knows our cumulative radiation exposure. However, we do know the range of dose exposures for most standard X-ray procedures. These vary widely: a CT scan of the chest exposes the female breast to 5000 times more radiation than a standard chest X-ray.

The few studies with reliable estimates of dose exposure in the diagnostic range have provided some evidence that such exposures can lead to excess breast cancer, particularly if the radiation was given to girls or young women. Further studies, with the best possible methodology, are needed to re-examine this question.

The question is particularly pressing for A-T mutation carriers, since A-T mutations predispose to breast cancer and are known to make cells more sensitive to ionizing radiation. The studies of A-T families published in the New England Journal of Medicine (1991 and 1987) have raised the possibility that substantial medical X-ray or occupational exposure may be associated with excess breast cancer in A T mutation carriers.

We are now re-examining the role of medical diagnostic X-rays in causing cancer in A T mutation carriers and hope that these new data will lead to conclusions that will be accepted by the general medical-scientific community.

In the meantime, we make the following recommendations for all girls and women:

           • Concerns about the risks of X-rays should never interfere with obtaining the best possible               medical care.

           • Since the breasts of infants, girls, and young women are most sensitive to cancer induction by ionizing               radiation, females at these ages should make every effort to avoid any exposure. Knowledgeable               radiologists, for example, will not do an upper GI series for an adolescent girl without incredibly strong               justification.

           • Since the effects of ionizing radiation seem to add up with each exposure, the breasts should be               shielded with lead whenever a substantial X-ray exposure of the chest or abdomen is planned. The               breasts can get substantial doses from an upper GI series, an intravenous pyelogram, or even a               barium enema. In most cases, shielding the breasts properly will not prevent obtaining the required               diagnostic information. Routine chest X-rays are not of any concern, since the dose from such X-rays is               so small.

           • Modern screening mammograms give a comparatively small dose – except for digital               mammography. Since early detection of breast cancer can limit complications and improve               survival, every woman should begin periodic screening at age 50. Younger women or those               concerned that repeated mammograms may increase their breast cancer risk might consider               the alternative of frequent periodic examinations by a doctor or nurse highly skilled and               experienced in breast examination.

RADIATION THERAPY AND A-T CARRIERS

Many A-T mutation carriers, and their physicians, have asked whether they can receive radiation therapy for their newly diagnosed breast cancer.  This concern arises because conventional radiation therapy destroys the non-cancerous tissues of A-T patients, who have two mutated A-T genes.  And, of course, many women who carry an A-T mutation may need radiation to fully control their cancer after surgery.

Good news!  No study has found evidence that A-T carriers suffer excess side-effects from radiation treatment of their breast cancers. 

Even better, one study has found that the survival of A-T carriers was significantly improved if they did have radiation therapy instead of only surgery.  If further studies confirm this observation, A­T mutation carriers everywhere might benefit from adding radiation to their cancer treatment plan.  Just think of how many lives could be saved with this knowledge!