Zeitschrift für genetische Syndrome und Gentherapie
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Novel Germline Mutation (Q1260X) in APC Gene Causes Familial Adenomatous Polyposis in a Ukrainian Family

Luciana Russo, Rosa Anna Cifarelli, Beatrice Di Venere, Alessandro Sgambato, Marina Susi, Alberto Fragasso and Oronzo Scarciolla

Colorectal Cancer (CRC) in developed countries is the major causes of cancer death. It may have sporadic or hereditary origin. Familial Adenomatous Polyposis (FAP) is a very frequent hereditary syndromes predisposing to Colorectal Cancer and is characterized by the development of numerous precancerous polyps (from hundreds to thousands) in the second decade of life.

Classical FAP is caused by germline mutations in the APC gene (Adenomatous Polyposis Coli) a tumor suppressor gene. Often the results of the genetic mutation are a truncating protein that lacks functional domains, such losing its function and promoting tumorigenesis.

A subject who presents a monoallelic germline variation in APC gene inherits in a dominant manner the predisposition to polyps, which will turn in CRC, through the occurrence of a somatic alteration in the wild-type copy of gene. Molecular analyses of APC gene confirms diagnosis in FAP patients and allow to detect the specific pathological mutation in order to screen the unaffected members of the same family, identify pre-symptomatic highrisk subjects and insert them in endoscopic surveillance protocols. We analyzed the APC mutational status in a Ukrainian woman with a history of CRC and proctocolectomy. By direct sequencing of the encoding exons of APC gene we found a c.3778 C>T heterozygous substitution which causes the substitution of a Glutamine with a stop codon, resulting in a premature truncation of APC protein (Q1260X). This mutation had never been described before and it may be considered as a “novel mutation”. We extended the analyses to 1st grade related, proving that one of the patient’s son was heterozygous for the same mutation and that to the endoscopic evaluation he showed an early develop of hundreds of polyps. This finding confirmed our speculation about the pathologic effect of Q1260X.