Originally published as JCO Early Release 10.1200/JCO.2006.06.9781 on January 16 2007

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Clinicopathologic and Pedigree Differences in Amsterdam I–Positive Hereditary Nonpolyposis Colorectal Cancer Families According to Tumor Microsatellite Instability Status

Laura Valle, Jose Perea, Pablo Carbonell, Victoria Fernandez, Ana M. Dotor, Javier Benitez, Miguel Urioste

From the Familial Cancer Unit and the Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Centre; Tumor Bank Unit, Molecular Pathology Program, Spanish National Cancer Centre, Madrid; Surgery Department, Hospital de Segovia, Segovia; Molecular Genetics Unit, Centro de Bioquímica y Genética Clínica, Hospital Virgen de la Arrixaca, Murcia, Spain

Address reprint requests to Laura Valle, PhD, Familial Cancer Unit, Spanish National Cancer Centre, Melchor Fernández Almagro, 3, E-28029, Madrid, Spain; e-mail: lvalle{at}cnio.es

Purpose: To establish the clinicopathologic and familial differences within Amsterdam I–positive families, showing either tumor microsatellite instability (MSI) or microsatellite stability (MSS) in order to confirm or deny the existence of hereditary nonpolyposis colorectal cancer (HNPCC) without defects in the mismatch repair system.

Patients and Methods: Sixty-four Amsterdam I–positive families were included in the study for which full, three-generation, family medical histories and colorectal paraffin-embedded tumors were obtained. Both personal and clinicopathologic information of patients were collected. In all cases, both the MSI status and the mismatch repair (MMR) protein expression were analyzed. MMR genetic testing was performed on the MSI families.

Results: Of the Amsterdam I–positive families, 59.4% were tumor MSI, and 40.6% were tumor MSS. When comparing both groups, the statistical differences were observed in the age of onset (MSI, 41 years; MSS, 53 years); in the colorectal tumor location, more frequently proximal in MSI cases; in fewer mucinous tumors in MSS; and loss of MMR protein expression in the MSI tumors. Regarding the individual and familial cancer history, we observed a predominance of individuals with multiple primary tumors in MSI pedigrees, as well as differences in the type of tumors developed within the family.

Conclusion: Our findings support the suspicion of another hereditary colorectal syndrome different from HNPCC and characterized by MSS, the normal MMR immunohistochemical expression, the presence of only colorectal tumors, and the absence of individuals with multiple primary tumors. All these circumstances suggest the existence of a non-MMR gene being responsible for this new syndrome.

published online ahead of print at www.jco.org on January 16, 2007.

L.V. and J.P. contributed equally to this article.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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