Originally published as JCO Early Release 10.1200/JCO.2008.17.5950 on September 22 2008

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Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer

Heather Hampel, Wendy L. Frankel, Edward Martin, Mark Arnold, Karamjit Khanduja, Philip Kuebler, Mark Clendenning, Kaisa Sotamaa, Thomas Prior, Judith A. Westman, Jenny Panescu, Dan Fix, Janet Lockman, Jennifer LaJeunesse, Ilene Comeras, Albert de la Chapelle

From the Human Cancer Genetics Program, Comprehensive Cancer Center, and Departments of Molecular Virology, Immunology, Medical Genetics, Pathology, Surgery, and Internal Medicine, Ohio State University; Mount Carmel Health System; and the Ohio Health Riverside Methodist Hospital, Columbus, OH

Corresponding author: Albert de la Chapelle, MD, PhD, Human Cancer Genetics Program, 646 Medical Research Facility, 804 Biomedical Research Tower, 460 W 12th Ave, Columbus, OH 43210; e-mail: albert.delachapelle{at}osumc.edu

Purpose Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.

Patients and Methods MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed.

Results Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations.

Conclusion One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.

published online ahead of print at www.jco.org on September 22, 2008.

Supported by Grants No. CA67941 and CA16058 from the National Institutes of Health. This publication was also prepared under a grant from the State of Ohio Biomedical Research and Technology Transfer Commission.

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

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