The existence of a relationship between cancer and heredity has been recognized for years, but only recently has emerging knowledge in this area enabled physicians to detect and treat cancer earlier in affected individuals and to prevent its occurrence in others

Diasio, Robert B.

Mueller, John M.

VCU Scholars Compass

Genetics and Cancer JOHN M. MUELLER, M.D. AND ROBERT B. DIASIO, M.D., Division of Medical Oncology The existence of a relationship between cancer and heredity has been recognized for years, but only recently has emerging knowledge in this area enabled physicians to detect and treat cancer earlier in af-fected individuals and to prevent its occurrence in others. The genetics of human cancer can be divided into three categories: first, cancers inherited by direct gene transmission; second, familial disorders not characterized by malignant disease themselves but which predispose to an increased likelihood of devel-oping cancer; third, cancers of one or more types occurring with an increased incidence within a family but with a mode of genetic transmission that may not be clear. A relatively small proportion of cancers are in-herited as a result of direct single gene transmission . One example is retinoblastoma, a highly malignant tumor of the eye which presents in early childhood, and which occurs in two different forms. The less common familial form of the disease is usually trans-mitted as a highly penetrant dominant trait, with af-fected individuals often having bilateral involvement and a somewhat earlier age of onset. The more com-mon form is characteristically sporadic, with affected individuals having unilateral disease and a later age of onset.' As more affected persons will now reach adulthood and reproduce because of improved treat-ment, clarification of the mode of inheritance is mandatory to allow proper genetic counseling. Multiple endocrine adenomatosis type II or Sipple syndrome consists of the association of medul-lary carcinoma of the thyroid, pheochromocytoma, and parathyroid hyperplasia. This disorder appears to be inherited as an autosomal dominant but with incomplete penetrance. As with many inherited can-Correspondence and reprint requests to Dr. R obert B. Diasio, Box 725, Medical College of Virginia, Richmond, Virginia 23298. 154 cers, there is an increased incidence of bilateral organ involvement. Clinically, the patient may present with evidence of carcinoma in only one system; for ex-ample, medullary carcinoma of the thyroid may be present without a palpable thyroid nodule. However, appropriate testing may show occult disease in the other organs. An elevated serum calcitonin level may suggest an occult cancer in predisposed individuals2; therefore, diagnosis of any of the features of this unusual syndrome should lead to careful exclusion of the others, as well as to a search among close relatives for additional, possibly presymptomatic, cases. Familial polyposis coli is an autosomal domi-nant disorder in which adenomatous polyps may be so numerous that they actually carpet the entire colon and rectum; Gardner syndrome is a distinct variant that includes associated sebaceous cysts and osteo-mas of bone. Early recognition of these disorders is critical since virtually I 00% of affected persons will develop carcinoma of the colon by age 50 unless a prophylactic colectomy is performed.3 A number of oncologists now recommend total colectomy as soon as the disorder is discovered in childhood unless it is possible to follow the affected child with regular sig-moidoscopies and barium enemas. The management of these families can be extremely d ifficult since it is essential both to stress the importance of regular examination and to avoid contributing to an obses-sive cancer phobia. Neurofibromatosis is an a utosomal dominant disorder characterized by cafe au lait spots and mul-tiple neurofibromas. The neurofibromas show a sar-comatous degeneration in about I 0% of patients, and there is an increased risk of gliomas of the brain or optic nerve, meningiomas, acoustic neuromas, and pheochromocytomas. Xeroderma pigmentosa is a rare disorder mani-fested by sun sensitivity and the development of freckles on sun-exposed areas which then become dry and scaly. Basa l cell and squamous cell carcinomas of MCV QUARTERLY 13(4): 154-1 56, 1977 MUELLER AND DIASIO: GENETICS AND CANCER 155 the skin later develop, and even if they are arrested, affected individuals have an increased risk of mela- Neoplasms with Possible Familial Occurrence noma. 1 Xeroderma pigmentosa is transmitted as an autosomal recessive trait. The defect has been shown to be a specific deficiency in one of the several en-zymes normally required to repair ultraviolet radia-tion damage to the DNA of epidermal cells.4 When the precipitating causes of the problem are appreci-ated, the physician can teach affected individuals to protect themselves from the carcinogenic effects of ultraviolet radiation without undue disruption of a normal lifestyle.5 Immune deficiency disorders are associated with an increased incidence of cancer, particularly lym-phoma. The prime examples are the recessively inher-ited syndromes such as X-linked agammaglobuli-nemia, ataxia telangiectasia, and Wiskott-Aldrich syndrome. Individually, each of these recessive syn-dromes is rare, and in the aggregate, affected homo-zygotes (or hemizygotes if the trait is X-linked) con-stitute only a small proportion of all patients who develop cancer. However, there is increasing evidence that heterozygous carriers of at least some of these recessive genes may also be predisposed to cancer. Carriers of rare recessive genes are, of course, much more numerous in the general population than are affected homozygotes; in fact, the rarer the recessive trait, the greater the relative frequency of hetero-zygous carriers in the population in comparison with affected homozygotes. Therefore, a small effect of cancer risk in heterozygotes could have much greater public health significance than would a major effect in homozygotes. Swift6 has provided convincing evi-dence that heterozygous carriers of the genes for ataxia telangiectasia and Fanconi anemia have a three- to fourfold increased risk of developing cancer; he has estimated that at least 3% of all cancers arise in individuals who are heterozygous for one or the other of these two genes alone. At present, no laboratory test is available to identify carriers. Detecting an increased familial risk of cancer and following the involved family members for evi-dence of developing neoplasia is an important activ-ity for practicing physicians. The cancers may be always of the same organ, that is, a site-specific tumor may occur in familial aggregations, or they may be of multiple varied organs. The Table lists the site-spe-cific malignant neoplasms with possible familial oc-currence.7 There is considerable heterogeneity in the ge-netics of certain cancers, especially breast cancer. Breast Colon Stomach Prostate Endometrium Hodgkin disease Waldenstrom disease Multiple myeloma Leukemia Lymphoma Hepatocellular tumors Testicular tumors Neuroblastoma Wilmstumor Burkitt lymphoma Bronchogenic carcinoma Ovarian carcinoma Studies8 - 10 have helped elucidate some of the risk factors. It is important to know whether the disease has occurred in two or more female first-degree re-latives, whether the disease was pre- or post-meno-pausal in onset, and whether it was bilateral. In the premenopausal age group, the relative risk of breast cancer among family members of an affected individual is approximately three times that of con-trols, whereas in the postmenopausal age group, the risk is only slightly greater than that of controls. Relatives of women with bilateral disease have a five-fold risk compared to controls. The relatives of women with premenopausal and bilateral disease have a relative risk of developing breast cancer that is almost nine times greater than that of controls, while the relatives of patients with postmenopausal bilat-eral disease have a risk that is four times greater. The risk to other family members also depends upon the relationship of prior affected persons to the proband. For example, if prior disease involved a proband's mother, the proband's sisters will have a 30% in-cidence of cancer in the 20-to 29-year age group, a risk 47 times greater than that of the general popu-lation . Clearly, these facts imply a genetic factor in breast cancer which appears most consistent with polygenic inheritance of a predisposition. Physician recognition of and response to this inherited pre-disposition is important particularly in the high-risk situation. In one such family, for example, bilateral reduction mammoplasty with implantation of a sub-cutaneous prosthesis was recommended for a 19-year-old girl whose two sisters, mother, and maternal grandmother had had early onset of breast cancer. 11 The concept of "cancer families" has been broadened to include kindreds displaying familial oc-currence of diverse neoplasms even of dissimilar cell types. 12 The cancer family has the following charac-teristics: I) an increased occurrence of adenocarci-noma primarily of colon and endometrium; 2) in-156 MUELLER AND DIASIO: GENETICS AND CANCER creased frequency of multiple primary malignant neoplasms; 3) early age of onset of cancer relative to the usual age of onset of that cancer in the general population; 4) vertical transmission of cancer consis-tent with an autosomal dominant inheritance pattern. One such family has been described in Virginia. 13 Environmental factors may also influence ex-pression of the disease when there is a familial ten-dency to cancer. Studies by Tokuhata have confirmed an increased incidence of cancer of the lung in rela-tives of patients with lung cancer, and his data sug-gest that the combined risk of cigarette smoking and the familial host factor increase the liability of devel-oping lung cancer in a synergistic rather than additive manner. 1• The interrelationships between heredity and en-vironment in the occurrence of cancer are complex and in many cases not completely characterized, but certain facts are clear. Specific cancers can be inher-ited directly . Certain diseases that predispose to can-cer are inherited, and specific cancers or specific ten-dencies to develop a variety of cancers are inherited in families. Examples of each of these have been discussed. The long-range challenge to physicians is to recognize these situations and to study them thor-oughly to further our understanding of the causes of cancer. More immediately, however, the alert physi-cian who takes a detailed family history can recognize the increased risk of a particular malignancy and, by careful examination, testing, advice, and follow-up, can provide early treatment or even prevent the de-velopment of a potentially fatal malignancy. 11 REFERENCES I. HESTON WE: The genetic aspects of human cancer. Adv Can-cer Res 23:1-21 , 1976. 2. KEISER HR, BEAVEN MA, DOPPMAN J, ET AL: Sipple's syn-drome: medullary thyroid carcinoma, pheochromocytoma and parathyroid disease. Studies in a large family Ann Intern Med 78:561-579, 1973. 3. LYNCH HT, LYNCHJ, GUIRGIS H: Heredity and colon cancer, in Lynch HT (ed): Cancer Genetics, Springfield, Charles C Thomas, 1976, pp 326-354. 4. EPSTEIN JH, FUKUYAMA K, REED WB, ET AL: Defect in DNA synthesis in skin of patients with xeroderma pigmentosum dem-onstrated in vivo. Science 168:1477-1478, 1970. 5. LYNCH HT, ANDERSON DE, KRUSH AJ, ET AL: Cancer, hered-ity and genetic counseling: xeroderma pigmentosum. Cancer 20:1796-1801, 1967. 6. SWIFT M: Malignant neoplasms in heterozygous carriers of genes for certain autosomal recessive syndromes, in Mulvihill 11 , Miller RW, Fraumeni JR (eds): Genetics of Human Cancer. New York, Raven Press, 1977, pp. 209-215. 7. LYNCH HT, GUIRGIS HA, LYNCH PM, ET AL: Familial cancer syndromes: a survey. Cancer 39:1867-1881 , 1977. 8. ANDERSON DE: Some characteristics of familial breast cancer. Cancer 28: 1500-1504, 1971. 9. ANDERSON DE: A genetic study of human breast cancer. J Natl Cancer Inst 48:1029-1034, 1972. 10. ANDERSON DE: Genetic study of breast cancer: Identification of a high risk group. Cancer 34:1090-1097, 1974. 11. LYNCH HT, LYNCHJ, LYNCH P: Management and control of familial cancer, in Mulvihill JJ, Miller RW, Fraumeni JR (eds): Genetics of Human Cancer. New York, Raven Press, 1977, pp 235-256. 12. LYNCH HT, KRUSH AJ, THOMAS RJ, ET AL: Cancer family syndrome, in Lynch HT (ed): Cancer Genetics. Springfield, Charles C Thomas, I 976, pp 355-388. 13. CANNON MM, LEAVELL BS: Multiple cancer types in one family. Cancer 19:538-540, 1966. 14. TOKUHATA GK: Cancer of the lung: host and environmental interaction, in Lynch HT (ed): Cancer Genetics. Springfield, Charles C Thomas, 1976, pp 213-232. 

Genetics and Cancer

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