APC I1307K mutations and forkhead box gene (FOXO1A): another piece of an interesting correlation

Department of Surgical, Oncological and Gastroenterological Sciences, 2nd Surgical Clinic, University of Padua, Italy.
The International journal of biological markers (Impact Factor: 1.36). 12/2011; 27(1):13-9. DOI: 10.5301/JBM.2011.8908
Source: PubMed

ABSTRACT Germline nonsense and frameshift mutations in the adenomatous polyposis coli (APC) gene are found in approximately 90% of individuals affected by familial adenomatous polyposis (FAP) and a genotype-phenotype relationship has been observed. Missense mutations have also been found in a few cases, even if their role in FAP is still unknown. An association between a missense mutation, APC I1307K, and the risk of sporadic colorectal cancer (CRC) has been reported. In order to improve the knowledge about the genetic effect of APC I1307K on the phenotype, we tried a new approach using matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS).
An APC mutation (I1307K) was found in an index case of a non-Jewish woman and her son with attenuated familial adenomatous polyposis (A-FAP) and no family history of cancer. In order to evaluate whether the presence and abundance of the ionic species are related to the presence of cancer or the presence of mutation, comparative analyses of 11 healthy clean-colon subjects, 59 patients with CRC (stage II n=19, stage III n=23, stage IV n=17) without polyps, and 9 FAP patients, carriers of a nonsense mutation in the APC gene, were evaluated.
Comparative analysis of serum protein profiles of the index patient and her healthy son, FAP and sporadic CRC patients, and subjects with preneoplastic lesions showed a characteristic abundance of ionic species at m/z 905, which was not present in healthy controls. Two peptides were identified from MALDI/MS/MS spectra of m/z 905 belonging to the kininogen-1 precursor and the human forkhead box protein 01A (FOXO1A). FOXO1A was present in only two subjects carrying I1307K, but not in other patients.
Our findings seem to suggest a relationship between m/z 905, FOXO1A and the development and growth of colorectal cancer. FOXO1A fragment determination in serum with MALDI/MS might be a promising approach for early detection of colon carcinoma or for the development of targeted therapies.

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    ABSTRACT: BACKGROUND: Currently, no guidelines exist for the treatment of patients with multiple colorectal adenomas (MCRAs) (>10 but <100 synchronous nondiminutive polyps of the large bowel). This retrospective study aimed to investigate the clinical and molecular factors related to different treatments for MCRAs. METHODS: Patients with MCRAs were consecutively enrolled from January 2003 to June 2011. Sequencing of their APC and MutYH genes was performed. The clinical, molecular, and family histories of the patients were collected using the Progeny database. The patient treatments were divided into three groups of increasing clinical weight: endoscopic polypectomy, segmental resection, and total colectomy. A logistic regression analysis of clinicomolecular factors related to different treatment options was performed. RESULTS: The study comprised 80 patients (32 women, 40 %) with a median age of 53 years (range 13-74 years). The median number of polyps was 33 (range 10-90).The cases included 62 diffuse polyposis, 18 segmental polyposis coli and synchronous colorectal carcinomas (CRC; 34 cases, 43%). The pathogenetic mutations were biallelic MutYH (n = 19, 24 %) and APC (n = 4, 5 %). The mean follow-up period was 74 months (median 43 months, range 1-468 months). Endoscopic polypectomy was performed in 25 cases (31 %), segmental resection in 16 cases (20 %), and total colectomy in 39 cases (49 %). The logistics regression analysis, considering all the patients, showed that the number of polyps, the presence of CRC, and mutation were correlated with more intensive treatment. For the patients without CRC, only the number of polyps was correlated with the severity of the treatment (p > 0.0166). "On the ROC (receiver operating characteristic) curve, 25 was the number of polyps that best discriminated between surgical and endoscopic therapy. CONCLUSIONS: The majority of patients with MCRAs undergo surgery. For patients without CRC, only the number of polyps, and not the presence of a disease-causing mutation, is correlated with increased heaviness of treatment. Patients with more than 25 polyps are more likely to undergo a surgical resection.
    Surgical Endoscopy 07/2012; DOI:10.1007/s00464-012-2421-2 · 3.31 Impact Factor


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May 31, 2014