Cancer Genetics

Edited by: Eugene Russo Photo: Robert Neroni Photo: Michael Price PERFECT FHIT: Kay Huebner and Carlo Croce of the Kimmel Cancer Center discovered a correlation between the deletion of the FHIT gene and the onset of lung cancer. G. Sozzi, M. L. Veronese, M. Negrini, R. Baffa, M.G. Cotticelli, H. Inoue, S. Tornielli, S. Pilotti, L. De Gregorio, U. Pastorino, M. A. Pierotti, M. Ohta, K. Huebner, C. Croce, "The FHIT gene at 3p14.2 is abnormal in lung cancer," Cell, 85:17-26, 1996. (Cited in more than 85 publications as of February 1998) Comments by Carlo Croce, Kimmel Cancer Center, Jefferson Medical College, Philadelphia Mortality rates for lung cancer victims have not improved significantly in the last 20 years. Recently, scientists have looked to the molecular pathogenesis of the disease in an attempt to improve diagnosis and treatment. The most popular subjects of investigation have been the tumor suppressor gene p53, the retinoblasma (Rb) gene (a gene responsible for malignant tumors of the retina), and the short arm of chromosome 3, a region frequently involved in deletions in human tumors. The FHIT (fragile histidine triad) gene, located on the short arm of chromosome 3 at 3p14.2, has been of particular interest. A research team led by Kay Huebner, a professor of microbiology at the Kimmel Cancer Center at Jefferson Medical College in Philadelphia, and Carlo Croce, director of Jefferson's Kimmel Cancer Center, has been studying the role of the FHIT gene in tumorigenesis for the past 2½ years. Huebner and Croce's team, working with researchers from Kyushu University in Japan, first reported the identification of the gene in February 1996 (M. Ohta et al., Cell, 84:587-97, 1996). In conjunction with researchers from Milan, Italy; New York; and San Antonio, Texas, Huebner and Croce's team then confirmed that the lack of FHIT function is directly related to tumor growth; they demonstrated that the replacement of FHIT in cancer cells suppresses tumorigenicity (Z. Siprashvili et al., Proceedings of the National Academy of Sciences, 94:13771-6, 1997). A subsequent paper detailed the sequencing of a region of the FHIT gene known as FRA3B, a so-called fragile region believed to make the gene especially susceptible to breakage and malfunction (H. Inoue et al., Proceedings of the National Academy of Sciences, 96:14584-9, 1997). This April 1996 Cell paper was the first to elucidate the role of FHIT in lung carcinogenesis. Huebner and Croce's team found abnormalities of the FHIT gene in nearly all small cell lung cancers (SCLC) and in most of the non-small cell lung cancers (NSCLC) studied. They analyzed 59 SCLC and NSCLC tumors by reverse transcription of FHIT messenger RNA followed by polymerase chain reaction (PCR) amplification. Both SCLC and NSCLC tumors showed abnormalities in RNA transcripts of FHIT-they lacked two or more FHIT exons, expressed regions of the mRNA. Seventy-six percent of the tumors exhibited the loss of FHIT alleles. "These genes appear to be deleted . . . with great frequency in some of the most common human tumors," notes Croce. "In fact, FHIT is mutated . . . predominantly by deletion, even more frequently than p53 in some of the most common human cancers." Because FHIT is deleted early and often in the pathogenesis of lung and other cancers, it's an ideal target for the application of new drugs and therapies. "If we start to understand the normal signaling pathway, we might develop a way to kill cells which are FHIT-negative," maintains Croce. Widespread interest in such therapies is one reason that the paper has been cited so frequently, he speculates.

Cancer Genetics

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Photo: Robert Neroni	Photo: Michael Price

*PERFECT FHIT:* Kay Huebner and Carlo Croce of the Kimmel Cancer Center discovered a correlation between the deletion of the FHIT gene and the onset of lung cancer.