The growing understanding of the molecular basis of carcinogenesis has revolutionized the field of cancer genetics.The discovery of genes that, when somatically altered, are involved in tumor development and in the progression of a variety of cancers has led to entirely new avenues of research to identify molecular targets for therapeutic interventions and management of cancer patients.<sup>27 Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation San Diego: Academic Press (1999). 

Cliccare qui per andare alla sezione Riferimenti</sup> The process of gene discovery has been greatly enhanced by the study of families with hereditary cancer to identify and characterize the molecular basis of susceptibility to cancer.<sup>14 Genetic Predisposition to Cancer Oxford, UK: Chapman and Hall Medical (1996). 

Cliccare qui per andare alla sezione Riferimenti</sup> This research strategy has resulted in the identification of dozens of cancer genes associated with a variety of hereditary cancer syndromes.<sup>34 Mulvihill J.J.   Catalog of Human Cancer Genes Baltimore: Johns Hopkins Press (1999). 

Cliccare qui per andare alla sezione Riferimenti</sup>Table 1 summarizes some of the better known syndromes for which genetic testing may improve cancer risk management of patients and their families.

The results of subsequent studies that link mutational and molecular data with clinical phenotypes among patients and families have been even more intriguing. For example, mutation in the APC gene was found to be the genetic basis for the autosomal dominant colorectal cancer syndrome, familial adenomatous polyposis (FAP). It was subsequently discovered that Gardner's syndrome (in which additional extracolonic manifestations occur, such as osteomas and desmoid tumors) was caused by mutations in the same gene and could be clinically categorized with FAP on molecular grounds.<sup>35 Nakamura Y., Nishisho I., Kinzler K.W. , e al. Mutations of the adenomatous polyposis coli gene in familial polyposis coli patients and sporadic colorectal tumors Princess Takamatsu Symp 1991 ;  22 : 285

Cliccare qui per andare alla sezione Riferimenti</sup> On the other hand, in some patients Turcot's syndrome, once thought to be an autosomal recessive condition featuring colon tumors and brain tumors, <sup>52 Turcot J., Despres J.-P., St Pierre P. Malignant tumors of the central nervous system associated with familial polyposis of the colon: Report of two cases Dis Colon Rectum 1959 ;  2 : 465  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> has been found to result from mutations in the APC gene (which cause FAP), but in other patients Turcot's syndrome is caused by mismatch repair genes associated with autosomal dominant hereditary nonpolyposis colorectal cancer (HNPCC) syndrome.<sup>20 Hamilton S.R., Liu B., Parsons R.E. , e al. The molecular basis of “Turcot syndrome.” N Engl J Med 1995 ;  332 : 839  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> Thus, molecular genetic testing can enhance clinical diagnoses. It has also been learned that, depending on the location of a mutation within a gene, there may be variation in phenotype severity. The location of the mutation in the APC gene may cause attenuated polyposis or dense polyposis.<sup>47 Soravia C., Berk T., Madlensky L. , e al. Genotype-phenotype correlation in attenuated adenomatous polyposis coli Am J Hum Genet 1998 ;  62 : 1290  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 48 Spirio L., Olschwang S., Groden J. , e al. Alleles of the APC gene: An attenuated form of familial polyposis Cell 1993 ;  75 : 951  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> A gene can give rise to different syndromes altogether. For example, multiple endocrine neoplasia type 2A and type 2B, familial medullary thyroid cancer, and Hirschsprung's disease are all caused by mutations involving different regions of the RET gene.<sup>9 Carlson K.M., Dou S., Chi D. , e al. Single missense mutations in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B Proc Natl Acad Sci U S A 1994 ;  91 : 1579  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 13 Edery P., Lyonnet S., Mulligan G. , e al. Mutations of the RET protooncogene in Hirschsprung disease Nature 1994 ;  367 : 378  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 22 Hofstra R.M., Landsvater R.M., Ceccherini I. , e al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma Nature 1994 ;  367 : 375  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 33 Mulligan L.M., Kwok J.B.J., Healey C.S. , e al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A Nature 1993 ;  363 : 458  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti, 44 Romeo G., Ronchetto P., Luo Y. , e al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung disease Nature 1994 ;  367 : 377  [cross-ref]

Cliccare qui per andare alla sezione Riferimenti</sup> The ability of molecular genetic testing to distinguish among various forms of inherited cancer will prove valuable as genetic knowledge and technology are incorporated into clinical practice.