Hereditary cancer syndromes

Abstract

Introduction: Persons carrying mutations for hereditary cancer syndromes are at high risk for the development of tumors at an early age, as well as the synchronous or metachronous development of multiple tumors of the corresponding tumor spectrum. The genetic causes of many hereditary cancer syndromes have already been identified. About 5% of all cancers are part of a hereditary cancer syndrome.

Methods: Selective literature review, including evidence-based guidelines and recommendations.

Results: Clinical criteria are currently available according to which many hereditary cancer syndromes can be diagnosed or suspected and which point the way to further molecular genetic analysis. A physician can easily determine whether these criteria are met by directed questioning about the patient's personal and family medical history. The identification of the causative germ line mutation in the family allows confirmation of the diagnosis in the affected individual and opens up the option of predictive testing in healthy relatives.

Discussion: Mutation carriers for hereditary cancer syndromes need long-term medical surveillance in a specialized center. It is important that these persons should be identified in the primary care setting and then referred for genetic counseling if molecular genetic testing is to be performed in a targeted, rational manner.

Keywords: cancer syndromes; genetic counseling; molecular genetic diagnostics; monogenic diseases; surveillance.

Figure 1

Schematic diagram of cancer etiology. Sporadic tumors develop from originally "normal" body cells due to an increased incidence of somatic mutations during the cell divisions. Mutation carriers for a hereditary cancer syndrome already have a mutation in every body cell (germline mutation), the pathway to the cancer cell is thereby shortened. For cancer to develop, however, here too further somatic mutations have to occur during the cell mitoses. The diagram shortens this protracted multi-step process to only a few cell generations. Modified from: Cavenee WK and White RL: Anhäufung genetischer Defekte bei Krebs. In: Spektrum der Wissenschaft 5/1995, 41

Figure 2

Family with suspected autosomal-dominant hereditary breast and ovarian cancer. Roman numerals indicate the generations (I-III), arabic numerals the persons (–7) in the generations. Squares symbolize male persons, circles female persons. Taking into account the incomplete penetrance of the disease and age, the risk of being a mutation carrier for hereditary breast and ovarian cancer (heterozygotic risk/H-R) was calculated for each family member using the Cyrillic 2.1 computer program. On the assumption that it is a hereditary form of breast and ovarian cancer, persons II:2 and II:4 are obligate mutation carriers for the disease, since their daughters (III:4 and III:7) are affected by the disease.

Figure 3

Example of evidence of a mutation in the MSH2 gene in molecular genetic diagnostics (direct sequencing in lymphocyte DNA). The upper diagram shows the unchanged sequence; the lower diagram shows a base exchange (C > T) in the form of a germline mutation in a gene copy.