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Molecular Genetics and Hereditary Colorectal Cancer: Resolution of the Diagnostic Dilemma of Hereditary Nonpolyposis Colorectal Cancer, Lynch Syndrome, Familial Colorectal Cancer Type X, and Multiple Polyposis Syndromes

Henry T. Lynch, MD, Zoran Gatalica, MD, DSc, and Joseph Knezetic, PhD

From the Department of Preventative Medicine and Public Health (H.T.L.), and Department of Pathology (Z.G., J.K.), Creighton University School of Medicine

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

Address reprint requests to Henry T. Lynch, MD, Director, Creighton Hereditary Cancer Center, Creighton University School of Medicine, 2500 California Plaza, HLSB Rm. 202, Omaha, NE, ZIP; e-mail: htlynch{at}creighton.edu

Overview: Of the 1,023,152 incident cases of colorectal cancer occurring annually worldwide, 2% to 5% (20,460 to 51,160 cases) represent the Lynch syndrome (LS) and fewer than 1% (10,130) cases constitute familial adenomatous polyposis, and approximately 20% (204,630 cases) represent familial colorectal cancer (CRC), defined by two or more first-degree relatives with CRC. The challenge revolves around the role of molecular genetics in certain genetic cancer syndromes where germline mutations may provide levels of cancer-risk certainty. In the case of LS, CRC as well as selected syndromic extracolonic cancers can be screened effectively using molecular tools and managed in the interest of improved familial cancer control. This manuscript will feature LS, its responsible molecular genetic features, inclusive of DNA microsatellite instability, immunohistochemistry, and mismatch repair proteins’ expressions and genes’ mutations. Syndromes that constitute the differential diagnosis of LS (i.e., familial adenomatous polyposis [FAP], hamartomatous polyposis syndromes, and the recently described familial CRC) in the presence of Amsterdam Criteria but lack the molecular genetic evidence for LS (often referred to as familial CRC type X) must be considered in its differential diagnosis.

The past few decades have significantly changed the landscape of LS, particularly when considering the remarkably high level of certainty afforded by mismatch repair genes’ mutation discoveries. However, the clinician’s knowledge of each hereditary CRC syndrome’s natural history is necessary so that appropriate molecular genetic testing can be performed.