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CANCER IS A GENETIC DISEASE

Cancer has been recognized as a specific pathological entity since the nineteenth century, and there have been multiple proposed mechanistic explanations for this disease process. Theodor Boveri determined that cancer was a cellular process caused by a scrambling of the chromosomes, and in 1902, he proposed that physical insults such as radiation, chemical agents, or even microbial pathogens might be responsible for this. Over the past 120 years, most of Boveri’s proposed triggers have been linked to cancer. Although abnormalities in chromosomes are frequently found in cancers, the degree of aneuploidy is quite diverse among tumors, and a few cancers are nearly diploid (but may be highly mutated). However, every cancer has genetic aberrations of some sort, and all investigators involved in cancer research agree that cancer is fundamentally a genetic disease. Most cancers are not a result of inherited germline mutations (or epimutations), but all cancers are driven by aberrant gene expression. The variety of ways through which cancers develop and the heterogeneity of genetic alterations in tumors have served to fascinate and perplex those who study the disease.

It is important to distinguish germline alterations (those inherited from the parents and identical in all cells of an organism) from somatic mutations (those mutations found in cancer cells but not in the germline). Germline mutations and somatic mutations are both important in cancer but for different reasons. Germline mutations are sometimes involved in creating increased risk for cancer, through a variety of mechanisms. Some cancer-associated germline mutations are in genes that normally regulate cellular proliferation; when inactivated, the progeny grow without one layer of control. Other germline mutations may occur in systems that monitor or repair deoxyribonucleic acid (DNA) damage and, when inactivated, permit an accelerated accumulation of mutations. Somatic mutations occur in a wide variety of genes and alter the biology of the affected cells, as discussed later. The combination of somatic mutations determines the nature of cancer cell growth and the ability to metastasize and determines the responses to therapies. Virtually all of the cancer-associated germline mutations can be found as somatic mutations in cancers; however, the reverse is not the case.

GENETIC TERMINOLOGY

Dominant, Recessive, Dominant Negatives, and Haploinsufficiency

In traditional genetics, hereditary diseases are usually classified as autosomal dominant (only one mutant allele is sufficient), autosomal recessive (two mutant alleles are required), and sex-linked (truly recessive, but the allele is on the X chromosome, so it appears dominant in men). Based upon the study of hereditary and sporadic retinoblastomas, in 1971 Knudson proposed that the involvement of genes in cancer required “two hits” for the tumor to develop, i.e., that both alleles of the culprit gene needed to be affected. This novel concept accommodated the observation that familial cancer syndromes (like familial retinoblastoma or familial adenomatous polyposis [FAP]) can be inherited in an autosomal dominant fashion ...

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