Confronted With Cancer

Is there cancer in your family’s medical pedigree? And if so, how are you going to find it? From death certificates? Obituaries? Perhaps they will help, but death certificates were established as public health documents, not for the enlightenment of genealogists, so don’t get your hopes too high! It may take some real detective work, but it’s certainly worth the try. So let’s get out your family pedigree chart and see how we succeed. Let’s begin with the most recent generations.

We know that cancer is a problem today in all the developed countries around the world. Thanks to the National Health Institute (NIH) and the American Cancer Society (ACS) we can study the statistics, see the trends, and decide where to focus our efforts. If you know of any cancers in the youngest generation, enter them now. If there was a cancer death, be sure to record the date, of course, but also keep a record of any “incidental” cancer cases -- those which might have contributed to death or just be an incidental finding. As one out of every four deaths in the United States is from cancer, the odds are pretty strong that it won’t be long before you’ve noted some cases. If you do, be sure to note the estimated date of ONSET, or at least when it was first suspected or diagnosed.

Your best source of information will probably be from any living relatives. It’s a good idea to make a checklist, at least of the most common malignant diseases, or how they might present, such as a lump in the breast, rectal bleeding, a productive cough or perhaps urinary tract problems. And don’t forget skin lesions, which are often obvious but might be overlooked, and any disease which might have necessitated numerous blood transfusions. The list may refresh someone’s memory about a relative’s symptoms. Be sure to inquire whether the relative smoked or drank and, of course, their geographical locations and their occupations.

What should you look for? In males, 55% of invasive cancer cases are of the prostate, lungs, and the colo-rectal areas. Prostate cancer accounts for 30% of new cancer cases in men. The three most common cancers in women are breast, lung, and colorectal cancer. These figures, however, do not include some other extremely common tumors: carcinoma in situ (non-invasive cancer) of the uterine cervix and over a million basal and squamous cell carcinomas of the skin. It’s also important to remember that a family history of breast or ovarian cancer is just as important on the paternal as on the maternal side.

Lung cancer has been the leading cause of cancer deaths in women since 1987, when it surpassed breast cancer. If you are a male, your lifetime probability of developing cancer is 43 percent. In men under age 40, leukemia is the most common fatal cancer; in older males it is cancer of the lung and bronchus, followed by colorectal cancer.

It may surprise you to learn that in children, cancer is the second leading cause of death between ages 1-14 in the U.S., with accidents causing the most fatalities. The diseases affecting children are much different than those in adults; lymphocytic and other leukemias are the most common, followed by tumors of the nervous system, lymphomas, soft-tissue lesions and tumors of the kidneys.

Cancer in a Changing World
The figures you read about adult cancer can be very misleading, however, because cancer statistics change with each generation, reflecting longevity, occupations, life styles, local environments, and even susceptibility to other illness. Let’s start with longevity. We take it for granted that most persons will live to age 70 or above today, with females having a little edge over the males. But let’s look back a bit and see how long your ancestors could have expected to live: (Ref. Table 1)

Table 1.

Years of Life Expectancy, U.S.A.

The 1850 figures are for Massachusetts only. 99% of the measured population was white and the remaining 1% includes all other races.

Pretty remarkable, isn’t it?. Back in 1900, most people weren’t living long enough to develop most of the cancers. And that’s still the case in many of the undeveloped nations. When Project HOPE visited Indonesia in 1961, about the only cancers were oral cancer from chewing betel nuts and choriocarcinoma, which a very rare uterine tumor. Twenty-five years later, people were still dying of malaria but cancer was beginning to appear, because their average life span had lengthened. The same thing happened earlier in the United States. Nutrition and public health improved and the longevity increased remarkably, except around 1918, when the deadly epidemic of influenza took its toll.

Cancer arrived hand-in-hand with the industrial revolution. Although we are interested in the genetic aspects, we should never underestimate the influence of environment. Cancers have inscribed their own documentation of human history. (Ref. Table 2)

Table 2.

Occupational, Recreational, and Nutritional Diseases

All you had to do was smoke while you were working to increase your chances of dying from lung cancer -- or bladder cancer. This is by no means a complete list of carcinogens, but perhaps it suggests there is genetic influence, as well.

So far, it appears that creating a medical genogram for cancer isn’t likely to be too productive except for looking at the last couple of generations, when cancer became more popular. We aren’t likely to discover many inheritance patterns for malignant diseases by climbing up our family tree. But there’s an important way a pedigree study can be of significant value to current and future generations of your family. If you have not already done so, you can verify your ethnicity. “Oh, I know my ethnic background,” you insist.

Perhaps you do, because folks weren’t too mobile back when to travel you either had to walk or ride a horse or mule. Early New Englanders tended to marry whomever they encountered in the next haystack But if you start counting, it may make you wonder a bit. Four grandparents, but eight great-grandparents, and then your forebears really begin to multiply: 16, 32, 64, 128, 256.... probability of a multi-ethnic pedigree is high. Are you sure they’re all accounted for?

Importance of Ethnicity to Cancer Genetics
When we examine various types of cancer in the United States, predispostion based upon ethnicity various considerably from one disease to another, but unfortunately for African Americans, they have the highest incidence and mortality rates for cancer. Theincidence rate is fully 60% higher than in Hispanics and Asian/Pacific Islanders and double that for American Indians. The overall cancer mortality rate for African Americans is 33% higher than in Asian/Pacific Islanders, American Indians and Hispanics. But there are exceptions, as breast and lung cancer death rates are higher in whites than in African Americans. And certain cancers are more common in Ashkenazi Jews.

These figures and those for other cancers need very careful interpretation, of course, because there are numerous non-genetic factors which contribute greatly to the discrepancies. Major considerations include poverty, unavailability of health care for both screening and treatment, language barriers, occupatins, diet and many more.

Cancer Management
Because cancer management, which involves prevention, screening and treatment, requires such a large proportion of the effort and funding spent on health care in the industrialized world, our knowledge of cancer genetics has grown rapidly. All this research has begun to educate us about mutations predisposing us to cancer, the various types of heritability, preventive strategies, the importance of early diagnosis and the use of the most appropriate therapy. Most of our knowledge is linked to specific tumors and does not necessary apply to other types of cancer. Much of the published work relates to the “common” cancers which attract the most funding for research.

Genetic Predisposition to Cancer
Summaries of our progress in understanding the genetic basis of cancer have been published by Hyon Ju Kim and by M. Tevfik Dorak. Both refer to the “two hit” concept of Dr. Albert Knudson, in which a dominantly inherited susceptibility to cancer consists of the first hit, which is a germ line mutation, but requires a second hit to somatic cells. According to this hypothesis, sporadic cancer also requires two hits, but both would be to somatic cells, so that a person carrying hereditary germ line mutations would only require one more hit and thus be at risk to develop a specific type of cancer.

In most cancers, the mode of inheritance is complex, and cancer has been described as being a multigenic, multifactorial, and multistep phenomenon. To this I would add one more description, multiconfusion. Multigenic refers to the variety of genes involved -- oncogenes, tumor suppressor genes and MHC genes. Multifactorial describes various factors that are involved with cancer development; these include chemicals, hormones, viruses, diet, radiation, etc. The multisteps in development of a cancer would be transformation and promotion leading to overt cancer. Multiconfusion is, of course, one of the end results.

Many tumors just appear in a sporadic fashion, with no apparent inherited genetic abnormalities. In about 5-10% of cancers there are mutations involving the germ line and the cancer is familial in nature.

Long before the Human Genome Project, physicians knew that our immune system had an important influence on our susceptibility to cancer. When there are immune deficiencies, there is increased cancer risk, especially for lymphoid tumors. They had also identified tumor-specific T-lymphocytes which could kill cells, or were cytotoxic (CTL), and tumor-infiltrating lymphocytes (TIL). When tumor suppressor genes (MHC genes) become impaired, or there is “loss of MHC expression,” cancer can develop. Scientists had proposed the immune surveillance theory, in which malignant changes can take place in normal cells but the immune system removes these cells from the system.

Dominant Genetic Imbalances in Cancer
Cancers occur when cell division goes wild. The controls that usually control cell reproduction, such as growth factors, cell surface receptors, enzymes, proteins, signaling molecules, growth inhibiting factors, and others, no longer function in an orderly manner. There are over 50 genes in the human genome, proto-oncogenes, which are very similar to cancer-producing retroviruses, or viral oncogenes. And they are inherited in a dominant manner. What makes these proto-oncogenes go bezerk and act like oncogenes?

A number of events can cause trigger this behavior and turn them into what we might call psychogenes. The mechanisms are all complex, but just listing them shows the diversity of the causes of cancer. (Table 3)

Table 3

1. Amplification -- takes place in breast cancer, neuroblastomas
2. Insertional mutagenesis -- as caused by a virus in Burkitt’s lymphoma.
3. Chromosomal translocations -- genes moving around on their chromosomes
4. Mutations in genetic codings -- changes genetic activity, described as missense, nonsense or frameshift types.
5. Demethylation or hypomethylation -- occurs in chronic lymphoid leukemia.
6. Cyclins, genes involved in the control of cell cycling, can become oncogenes when they have mutated
7. Loss or inactivation of tumor suppressors

BLADDER CANCER
Cancer of the urinary bladder is most common in industrialized countries; rates in Asia and South America are only 30 percent of those in the United States. Mortality rates are 2-3 times higher in men than in women. There is a definite risk to people working with chemicals known as arylamines, and cigarette smoking increase the risk for bladder cancer by 2-5 times. The disease primarily affects older individuals. The highest rates are in white male and female non-Hispanics, but no specific genetic links have been reported to date.

BREAST CANCER
Breast cancer is far more prevalent in females, and for this reason, most of the scientific literature and research is based upon diagnosing and treating women. But it also can occur in males, often with aggressive behavior and very serious consequences. Also, it would be more correct to speak of breast “cancers” in women, because there are different varieties and their clinical courses can very dissimilar. Breast cancers are second only to non-melanoma skin cancers in women, with an estimated 211,240 new cases predicted for 2005.

They will also cause 40,410 female deaths and 470 male deaths in the US (Amer. Cancer Soc.). A woman’s risk of developing breast cancer conferred by a first-degree relative is 2.1. The younger the relative was when diagnosed, the higher the risk to her first degree relative, especially if it occurred before age 50. The number of affected relatives and the closeness of biological family relationship are also significant in determining the risk. Linkage analysis studies of families have proved there is an autosomal dominant type of breast cancer that occurs in 5-10 percent of cases. Some highly penetrant genes are present in cancer-prone families.

NON-GENETIC FACTORS
As is true with many cancers, the breast lesions result from a combination of genetic and so-called “environmental” factors, and in this case, some of the environmental factors play very significant roles. At particular risk are women with a history of pre-menopausal breast cancer in the mother or a sister, a previous personal history of breast cancer or benign poliferative breast disease. Very likely under genetic influence are the high risks for cancer present in women having an early onset of menstruation (especially if before age 12) or those experiencing a late menopause (age 55 or older). Prolonged use of birth control pills and failure to deliver a baby by age 30 seem to be related, and post-menopausal use of estrogens may increase risk slightly. Other possible related causes, still being studied, are obesity and high alcohol consumption.

GENETIC FINDINGS
Much of the research on breast cancer has focused on mutations either in the BRCA1 or BRCA2 genes. The BRCA1 gene is on chromosome 17, the BRCA2 gene on chromosome 13. There are a couple of hundred variant alleles for BRCA2, and twice as many for BRCA1, but only some of them are related to breast cancer. Inheritance of any of these cancer-susceptiblity genes confers a lifetime risk of breast cancer of 50 to 85 percent, plus a significant risk of ovarian cancer.

Although the BRCA1 and BRCA2 mutations contribute to but a small percentage of all the cases of breast cancer, about 10 percent of breast cancer in women under age 40 and 75 percent of familial cases occur in women carrying these mutations. For this reason, some women having these genes have undergone bilateral prophylactic mastectomies. This difficult decision is controversial, because of the personal effects of the surgery, the fact that all carriers do not develop breast cancer and that it is possible to treat breast cancer successfully if detected early. It appears that a better argument has been made for prophylactic bilateral salpingo-oophorectomy in these patients (see discussion of ovarian cancer).

High-risk variants are more common in certain populations. They are found in 2.5 percent of Ashkenazi Jews and cause over a quarter of the breast cancers before age 40 in that ethnic group. In the general population, though, these high-risk variants areuncommon, being found in less than 0.5 percent and being associated with 5 to 10 percent of all breast cancer. The ATM gene on chromosome 11 is also under suspicion and being studied.

The characteristics of the breast cancer differ in these two types of mutations. In the BRCA1 cases, the tumors are “high grade” with many mitoses (indicating active cell division). The tumors have smooth margins and are infiltrated with lymphoytes. BRCA2 tumors can also be “high grade,” and don’t tend to form tubules. There are also special stains and tests that help distinguish the two, but now it is also possible to use high-density microarray technology.

Dr. N. Rahmen, at the Institute of Cancer Research in Surrey, United Kingdom, recently reported that the checkpoint kinase gene, CHEK2, is also associated with a high risk of breast cancer in both females and males. This gene acts in the same pathways as BRCA1 and BRCA2. Also, a new methodology has been used to detect the BRCA1 and BRCA2 mutations. It is allele-specific gene expression (AGE) analysis and it uses decay in the cells’ own RNA surveillance mechanism to pick out carriers of these mutations.

USING GENES FOR PROGNOSIS
Of particular interest are studies being done to recognize the degree of risk presented by a breast tumor so that the most appropriate treatment can be used to control the disease. Traditional methods have been the uses of “frozen sections” of a tumor during surgery so that the pathologist can grade the tumor, and similar microscopic examinations of slides containing sections of suspicious regional lymph nodes. These provide valuable information to the surgeon which helps in making decisions about the extent of surgery necessary. The preserved tissues are later evaluated much more thoroughly in a systematic manner before deciding upon the need for chemotherapy or hormonal therapy. These adjuvant treatment methods reduce the risk of distant metastases by about one-third, but a high percentage of patients receiving this treatment would have survived without it.

Investigators in The Netherlands used DNA microarray analysis on breast tumors of 117 young patients and state they have come up with a gene expression profile that can be used to predict the behavior of the cancer.

The investigators used genes regulating cell duplication, invasion, metastasis and small blood vessel formation to indentify patients with poor prognosis and who would benefit most from the adjuvant treatment with hormonal or chemotherapy. Finnish researchers have also reported finding another means of identifying breast tumors having poor prognosis -- they found elevated cyclooxygenase-2 (Cox-2) increases associated with poor survival. So far we could find no reported break-throughs which might lead to gene-specific tailored methods of therapy, but keep looking, because it isn’t because nobody’s looking for one!

Because so many of breast cancer patients develop tumor resistance to current treatments, scientists are searching for new gene-targeted therapies that are both tumor-specific and well tolerated by the patient. Herceptin is one of the new agents which can be combined with other methods and seems particularly effective in patients with human epidermal-growth-factor receptor (HER2) gene amplification or high overexpression of HER2. Pathologists can detect HER2 protein in samples of breast tissue so that Herceptin can be used in appropriate cases. Other similar agents will eventually improve survival rates and the quality of life of cancer patients.

FINDING IF YOU ARE AT RISK
If you have worries about having inherited genes that might put you at risk for cancer, you should first consult your physician and/or a genetic counselor. If someone in the family has breast cancer, she should have genetic testing so that her genetic pattern is recorded. Also, it would be advisable to bank some DNA for future studies when needed. But even if a relative doesn’t have one or more of the high-risk variants of the BRCA1 or BRCA2 genes, if there is a strong family history of cancer, the risk is still statistically high in close relatives and careful surveillance is important. It is very probable that all of the genes associated with breast cancer have not yet been found.

CERVICAL CANCER
Thanks to Dr.George Papanicolaou, most cancers of the uterine cervix are now discovered in a very early stage in the United States, before they have become invasive. Risk factors for cervical cancer include early sexual activity, multiple sexual partners,cigarette smoking and infection with human papilloma virus 16.

There are strong ethnic patterns which suggest a genetic susceptibility, but more research is needed in this area. The highest incidence is in Vietnamese women (43/100,000), and the lowest in Japanese women (5.8/100,000).

Incidence rates exceeding 15/100,000 are found in Alaska Native, Korean and Hispanic women in the United States.

COLORECTAL CANCER
colon and the rectum, which comprise the lower portion of the gastrointestinal tract, are host to a variety of tumors which add up to the fourth most common cancers and are second in causing cancer deaths in the United States. There are marked ethnic differences in susceptibility. The highest ethnic rates in males in the U.S. are in the Alaskan Native population, followed in decreasing order by Japanese, African-Americans and whites, Chinese, Hawaiians and Hispanics, Filipinos, Koreans and Vietnamese. In females colo-rectal cancer is also most common in Alaskan Natives, followed by African-Americans, Japanese, whites, Chinese, Hawaiians, Vietnamese, Hispanics, Koreans and Filipinos. In each ethnic group the incidence rates for men is higher than that for women, but the ratio is highest among Japanese and Filipinos. Colon cancer is generally more common than rectal cancer in all of the ethnic groups, with about 95,000 cases of colon cancer diagnosed annually in comparison with 35,000 cases of rectal cancer. Colorectal cancer begins to appear after age 40 and peaks between ages 60 and 75, causing about 55,000 deaths each year. There are even statistics showing the incidence of colon cancer by ZIP code in parts of New York State. (www.health.state.ny.us/nysdoh)

ENVIRONMENTAL EFFECTS
Environmental effects are very important in the development of colo-rectal cancer and they no doubt are reflected to a great extent in the variable ethnicity. Diets high in animal fat and sugar have been implicated, plus a sedentary life style, alcoholic intake and the use of tobacco. For a long time it was believed that high-fiber diets protected against the development of colonic cancer, but this has been questioned. There is evidence that diets high in calcium vitamin D plus leafy vegetables such as Brussel sprouts, broccoli, cabbage and turnip greens reduce the risk of colonic cancer. Three inflammatory diseases predispose to the develop of cancer -- ulcerative colitis, Crohn’s disease and chronic diverticulitis of the colon.

MULTIPLE POLYPOSIS OF COLON
A hereditary condition which almost invariably leads to colo-rectal cancer by age 40 is familial adenomatosis polyposis, which also goes under the names of adenomatous polyposis of the colon, multiple polyposis coli, or familial multiple polyposis. And if that doesn’t make it confusing enough, there are at least nine disorder subdivisions, including Gardner syndrome and Turcot syndrome. The APC gene, located on chromosome 5, is atypical in these neoplasms. Familial adenomatous polyposis is inherited as an autosomal dominant trait.

GENES CONTRIBUTING TO SUSCEPTIBILITY
FAP genes Mutations in these genes result in the FAP syndrome, in which hundreds or even thousands of polyps develop in the mucosal linings of the colon and rectum. Each one has the potential of becoming malignant, and by age 40, cancer develops in nearly every case. This process is associated with the previously mentioned APC gene.

HNPCC genes Four of the HNPCC genes cause the HNPCC syndrome, which occurs in various forms and can include cancers in the breast, ovaries, small bowel, stomach and uterus. They are hMSH2 on chromosome 2, hMLH1 on chromosome 3, hPMS1 on chromosome 2 and hPMS2 on chromosome 7. Persons with HNPCC often develop colon cancer before age 50 and may have a family history of colorectal cancer.

Other genes Ninety percent of colorectal cancer is caused by other genes, some of which have combined effects but which are weaker than those of the FAP and HNPCC genes. Some of these genes are involved with the inflammatory bowel diseases which can later be associated with cancer. There are ethnic predispositions for these diseases, as they are most common among whites and especially persons with Ashkenazi Jewish heritage. In 1997, researchers at Johns Hopkins reported the APCI1307K mutation on the same gene that carries FAP; this mutation is not a direct cause of colon cancer but makes the gene susceptible to other changes which do cause the cancer. According to their findings, the types of colorectal cancer in Ashkenazi Jews occur as follows:

Persons 50 years or older; no known risks factor for colorectal cancer

Fecal occult blood screening every year

AND

Flexible sigmoidoscopy every 5 years

OR

Double contrast barium enema every 5-10 years

or

Colonoscopy every 10 years

Persons with Close Relatives who have had Colorectal Cancer or Polyps

Same as above but starting by age 40

Persons with History of Adenomatous Polyps

Colonoscopy 3 years after removal of a polyp, unless shorter interval is recommended. The interval would be based upon the type, size and number of polyps found. (Note: For a benign polyp to become malignant usually takes 10 years.)

Persons with History of Colorectal Cancer

Colonic surgery for colorectal cancer should have a colonoscopy within 1 year after surgery. If this is normal, is should be repeated again in 3 years; if normal, repeat every 5 years thereafter.

Comments: The annual occult blood screening test, in which 3 stool samples are submitted, is the most cost-efficient method of screening. Colonoscopy is by far the best of the above methods for finding colorectal polyps or early cancer. Sigmoidoscopy can only examine the distal, or lower portion of the colon, and cannot locate polyps or other lesions farther up in the colon. Colonoscopy has been found statistically better than barium enemas for finding colonic cancer. Because sigmoidoscopy can be done without general anesthesia, it is much more readily available and far less expensive, making it the choice of most insurance programs. These options should be discussed with your own physician.

TREATMENT AND SURVIVAL: GENETIC AIDS
The primary treatment of colorectal cancer is surgical, depending upon the site, the degree of local invasion and the spread to regional lymph nodes or other parts of the body. These factors are expressed in stages, e.g., Duke’s stage A, B or C. Adjuvant chemotherapy improves survival among patients with Duke’s Stage C (also known as stage III) and is sometimes considered for patients with Duke’s Stage B (or stage II). Investigators at a number of medical schools have now identified genetic and molecular alterations which can be used to predict survival after chemotherapy. This information should aid in the development and use of more effective means of supplementing the surgical procedures.

ENDOMETRIAL CANCER
The ethnic occurrence of endometrial cancer in the U.S. has a pattern similar to that of breast cancer, with the highest age-adjusted incidence in Hawaiians, Whites, Japanese and Afican Americans. Lowest rates are in Korean, Vietnamese and American Indian women. Obesity is a risk factor. The postmenopausal use of exogenous estrogens is also a risk factor, but the risk is considerably reduced when they are taken with progesterone.

ESOPHAGEAL CANCER
Cancer of the esophagus is more common in Asia, Africa and Latin American than in the United States. It is primarily a disease of men, and it occurs in different forms. Most cancers of the esophagus were once of the squamous cell variety (similar to the cells of your skin). Recently there has been an increase of a glandular cell type, called adenocarcinomas, especially involving Caucasian males. The squamous type has its highest incidence in African Americans (15/100,000) and the lowest rate in Filipinos (2.9/100,000). Rates are also low in Chinese and Japanese men.

Environmental factors include smoking tobacco and heavy alcohol consumption, plus possible nutritional deficiencies in developing countries. There is no convincing evidence of genetic predisposition.

KIDNEY CANCER
Kidneys are complex organs and have the capability of developing various types of benign and malignant tumors. Children can develop a Wilm’s tumor, also known as nephroblastoma, embryoma or adenomyosarcoma. It is a mixture of stromal cells, spindle cells and epithelial cells. The most common pediatric tumor of kidneys, it makes up 5-6 percent of pediatric cancer in the U.S., affecting 8.1 million white children. It can be unilateral or bilateral.

Wilm’s tumor can be accompanied by a number of other inherited syndromes. It is sometimes linked to paternal exposure to lead or hydrocarbons. However, its genetic basis is well documented. The WT-1 gene involves chromosome 11p1310 exons, 4mRNA’s and 1 protein, apparently a classic tumor suppressor. The genes targeted are unknown, but the predisposition is inherited as a dominant negative oncogene. Other Wilm’s genes include WT-2 gene and Familial WT. About 85 percent of cases can be cured, although this is a high incidence of secondary tumors in irradiated areas.

Adult renal cancer includes that from renal cells in the body of the kidney and from the lining cells of the renal pelvis, which funnels the urine into the bladder via the ureter. Men are affected about twice as often as women. The highest rates are in American Indian men in New Mexico. Rates in Afican Americans, Hispanics and Caucasians range from 10-13/100,000 for men and about 6,100,000 in women. Lowest rates are found in Asian populations. The only established risk is from cigarette smoking.

A research team found a genetic link to clear cell carcinoma of the kidney in 1994; this variety causes about 85 percent of the adult renal cancer, amounting to about 23,500 cases per year. The mutant is a tumor suppressor gene located on the short arm of chromosome 3. The protein produced by this gene normally restrains growth. Both copies of this gene have to be damaged (two-hit model) for cancer to develop. This same gene plays a major role in an inherited cancer syndrome, von Hippel-Lindau disease. Persons with this disease can develop multiple tumors, including cancers of the kidney, eye, brain, spinal cord and adrenal glands.

LIVER CANCER
Cancers of the liver and intrahepatic bile ducts are most common in regions of Africa and Asia, accounting for only 1.5 percent of cancer cases in the United States. Because they are not diagnosed early, the five-year survival rates are less than 10 percent. The highest incidence rate is in Vietnamese men (41.8 per 100,000), and their are high rates in Chinese and other Asian-American populations. There is association with viral B hepatitis.

LUNG AND BRONCHUS CANCER
Lung cancer (which includes cancer arising in the bronchial tree) is the second most common cancer among men and women in the United States and the leading cause of death. Ethnic rates vary widely, from a high of 117/100,000 in African American males to a low of 14/100,000 in American Indian males. Rates for male Vietnamese, Caucasians, Alaska natives and Hawaiians are high, from 71-89/100,000. Among women, the highest rate is 51/100,000 in Alaska Natives, the low 15 /100,000 in Japanese. Smoking puts all groups at significant risk, and is blamed for 90 of all lung cancers. Asbestos exposure is another known cause, as is radon exposure.

Genetic research is being done on lung cancers -- researchers are finding the genetic patterns are likely to be complex. There are four common types of lung cancer: squamous cell, adenocarcinoma, large cell and small cell. Even with adenocarcinomas, tumors which appear histologically similar respond quite differently to treatment. Dr. David Botstein and researchers at Stanford University have been using RNA from samples of normal lungs and lung tumors to identify suspicious genes. They were able to identify 3 subtypes of adenocarcinomas in which the patients had differing survival patterns and are continuing the studies in the hope of finding ways of targeting lung cancers with the most appropriate treatment. At the Medical College of Wisconsin, Dr. Steven Ahrendt and his colleagues are using bronchial washings to collect cancer cells for DNA studies. They report finding numerous different mutations in these cells, but more studies will be needed to obtain data that would aid in making an early diagnosis for a specific type of cancer.

Polymorphisms in the p53 gene, found in nearly 30 percent of African Americans in an Anderson Cancer Center study reported by D. I. Amos, were associated with an increased risk for lung cancer. The mechanisms for how these polymorphisms work are still under investigation.

Bronchial epithelium undergoes a number of changes when it becomes malignant. Most obvious are the abnormalities in the epithelial cells, which become dysplastic, with irregular shapes and enlarged, deeply staining nuclei. These cells begin to proliferate at an abnormally rapid rate. There is also atypical proliferation of tiny vascular channels, known as angiogenesis, and there are significant changes in proteins on the cell surfaces. One family of proteins, the epidermal growth factor receptors (EGFR), become “overexpressed” in nearly all squamous cell carcinomas and in most of the large cell and adenocarcinomas. Only the small cell tumors fail to express EGFR.

Overexpression of EGFR is a consistent finding in the bronchial lining cells of high-risk smokers. Research is currently being conducted to see how EGFR information might contribute to chemoprevention or targeted lung cancer treatment.

LYMPHOMAS
Lymphomas are generally divided into Hodgkin’s and non-Hodgkin’s types; the more common non-Hodgkin’s lymphoma (NHL) will be discussed here, but its worth noting that together these lymphomas are the fifth most common type of cancer diagnosed in the U.S.A. The risk of developing NHL is increased by:

Exposure to human T-lymphotrophic virus type I
Exposure to Epstein-Barr (EBV) virus
Infection of the gastrointestinal tract with Helicobacter pylori
Infection with human immunodeficiency virus (HIV)
Malarial infection

Other resources are supported by sponsored by various pharmaceutical and genomics companies:

Amgen Trials Resource Center
www.AmgenTrials.com
Amgen: 1-866-572-6346

Cancer Clinical Trials Hotline
Aventic Pharmaceuticals: 1-800-RxTrial

Cancer Survival Toolbox
www.cansearch.org/programs/toolbox.html

Clinical Trials Resource Center
www.nccra.org

Pharmacia Corp., Pfizer, National Colorectal Cancer Research Alliance
1-800-724-4100

Cycle of Hope
www.cycleofhope.org
Bristol-Myers-Squibb Co.: 1-800-717-HOPE

Novartis Oncology Clinical Trials Information
Novartis: 1-800-340-6843

Strength for Caring
www.StrengthforCaring.com
Ortho Biotech Products, L.P.: 1-888-ICARE80

Lilly
1-877-CT-Lilly
www.lillytrials.com

The National Cancer Institute has booklets, brochures, etc. for patients, health professionals and the public on cancer, including various types, coping with cancer, diagnostic testing and clinical trials for methods of treatment. http//cancer.gov/publications

Cancer Information Service: 1-800-4-CANCER
National Cancer Institute
31 Center Drive MSC 2580
Bethesda MD 20892-2580