M. Ponz de Leon

Genetic Predisposition and Environmental Factors in Gastric Carcinoma

The biology of gastric carcinoma remains poorly understood and rather mysterious, often eludeing not only any rational explanation but also common sense. Thus, a decline in the incidence of gastric cancer has been reported in most countries over the last 5–6 decades; however, no satisfactory explanation for this trend has been provided; moreover, the fall in incidence concerns mainly antral carcinomas but not cancer of the cardia (whose frequency is increasing), and is more marked for the “intestinal” histologic type. Second, incidence and mortality rates show a large geographic variation, which ranges from values as low as 3 to more than 100 new cases/100000 per year; this might not be surprising, since it has been observed for many other malignancies — the characteristic of gastric cancer is that a wide variation in mortality can be detected even within small countries such as Belgium, where rather curiously the disease is much more frequent among the Flemish than the Walloon population. Third, it has been suggested that fresh fruit and vegetables exert a protective effect against the development of these tumors; however, there is evidence indicating that the disease is more frequent in rural areas, where we should reasonably expect a larger consumption of green vegetables and several fruits. Finally, recent investigations favor a pathogenetic link between Helicobacter pylori infection and gastric carcinogenesis; however, despite the interest of these observations, one should not forget that owing to the diffusion of this infection most individuals positive for Helicobacter pylori will never develop gastric cancer.

Hereditary and Familial Ovarian Cancer

Ovarian cancer is a common and frequently lethal condition, especially in well-developed and industrialized countries. The disease shows several analogies with breast carcinoma, and both neoplasms represent examples of probable, or possible, interaction between environmental and genetic factors in tumor promotion and progression. Thus, hormonal and reproductive factors are thought to be of some pathogenetic relevance in breast as well as in ovarian carcinoma, and a “risk profile” can tentatively be traced for both neoplasms. Many of these factors are closely related to modern habits and lifestyle; interestingly, some of these factors (i.e., oral contraceptives) might actually be protective against ovarian cancer development.

Cancer-Prone Hereditary Diseases Associated with Abnormalities of DNA Repair

In 1968, Cleaver [1] was able to establish a direct correlation between defective DNA repair and carcinogenesis. The author showed that normal skin fibroblasts could repair ultraviolet radiation-induced DNA damage by inserting new bases into DNA, while in fibroblasts from patients with xeroderma pigmentosum DNA repair occurred at a much reduced level, or it was completely absent. Since patients with xeroderma pigmentosum are particularly susceptible to skin cancer occurrence when exposed to sunlight, it was speculated that the inability to repair DNA in the skin cells as efficiently as normal individuals might be somehow related to cancer development. In the following years, besides xeroderma pigmentosum, other diseases were identified in which a particular predisposition to cancer could be associated with alterations in processing the damaged DNA. The most widely investigated of these clinical conditions include ataxia telangiectasia, Bloom’s syndrome, Cockayne’s syndrome, and Fanconi’s anemia, all inherited diseases characterized by an autosomal recessive type of transmission.

Hereditary and Familial Colorectal Cancer

Colorectal cancer is a major cause of death in Western countries and one of the neoplasms in which the contribution of heritable factors has been investigated in more detail, in terms of both genetic epidemiology and molecular biology.

Genetic Factors in Lung Cancer

Lung cancer is the commonest malignancy in the male sex and a major public health problem in the world. These tumors provide the most appropriate example of what is usually associated with the concept of neoplasia: pain, suffering, distress, and rapid death. This dismal outlook should not obscure the progress achieved in the basic knowledge of lung tumor biology and the consequent hope of a gradual improvement in prevention and clinical management.

Genetic Factors in Precancerous Lesions and Cancer of the Esophagus

Esophageal carcinoma is a highly malignant disease in which the various therapeutic approaches so far have been discouraging. It follows that prognosis remains extremely poor, with 5-year overall survival in the order of 5% or less.

Biomarkers of increased susceptibility to cancer.

Tumor markers can be defined, in general terms, as biological indicators of the presence of cancer. These markers can be found in the tumor itself — and revealed using biochemical, immunologic, or histochemical techniques — or, more often, can be detected in excessive quantities in the blood of patients with cancer. Carcinoembryonic antigen, α-fetoprotein, acid phosphatase, and polyamines are well-known examples of tumor markers frequently used in clinical practice. Moreover, in recent years several other compounds (CA-19-9, CA-125, and many others) of potential interest have been investigated [1, 2]. Though sometimes of value in evaluating the extent of the disease and in monitoring the response to treatment, tumor markers are of little or no value in the early detection of cancer and in the definition of the risk profile of unaffected individuals.

Hereditary Melanoma and Dysplastic Nevus Syndrome

The rapid and continuing increase of incidence of malignant melanoma, especially in developed countries, renders this disease one of the major challenges for oncologists in the future. Melanoma is also of extreme interest in genetic epidemiology; in the introductory chapter, this was defined, in its essence, as the study of the interaction between genes and environmental factors in the etiology and pathogenesis of a given disease. About 10% of all malignant melanomas (MM) have a genetic component; moreover, there is no doubt that environmental factors (sunlight exposure) are also of major importance in their development. We are probably not far from the reality in hypothesizing that a more detailed investigation on the interaction between hereditary predisposition to melanoma (which has now been linked to specific chromosomal loci) and some environmental agents (which can induce highly selective genetic changes) might represent the key passage to the comprehension of this disease.

Multiple Endocrine Neoplasia

Multiple endocrine tumors have been recognized from the beginning of this century, when a case of pituitary gland adenoma with concomitant parathyroid hyperplasia was reported [1]. After other reports of individual cases, the familial basis of this clinical entity was documented [2], and this led to the definition of the three main patterns of the disease. Multiple endocrine neoplasia type 1 (MEN-1, or Wermer syndrome) is characterized by a combination of pancreatic islet, pituitary, and parathyroid tumors; in MEN-2A (or Sipple syndrome), there is an association of thyroid (medullary carcinoma, MTC), adrenal medullary, and parathyroid tumors; MEN-2B (also called MEN-3 or multiple mucosal neuroma syndrome), in addition to the features of MEN-2A, shows an unusual phenotype, which includes eye and oral ganglioneuromas, a marfanoid habitus, and facial and skeletal involvement [3]. Finally, some authors described as MEN-4 (MEN of mixed type) the clinical condition featured by some overlap between MEN-1 and MEN-2 [4]. An outline of organs involved, the main type of tumors, and the symptoms occurring in various MEN syndromes are shown in Table 1.

Hereditary tumors of the nervous system.

Little is known about the relation between environmental factors and tumors of the nervous system; thus, the most common carcinogens or tumor promoters (tobacco smoking, alcohol, dietary pattern) have never been associated with the development of these neoplasms. In contrast, we know much more about the role of genetic factors on their pathogenesis, since besides the aspecific aggregation of cases in families, several types of tumors of the nervous system recognize a mendelian pattern of inheritance.