Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome.

• Published in: Human Pathology
• Main Authors: Hemminger, Jessica A, Pearlman, Rachel, Haraldsdottir, Sigurdis, Knight, Deborah, Jonasson, Jon Gunnlaugur, Pritchard, Colin C, Hampel, Heather, Frankel, Wendy L
• Other Authors: 1 Ohio State Univ, Wexner Med Ctr, Dept Pathol, Columbus, OH 43210 USA Show more 2 Ohio State Univ, Wexner Med Ctr, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA Show more 3 Stanford Univ, Med Ctr, Dept Med Oncol, Stanford, CA 94305 USA Show more 4 Landspitali Univ Hosp, IS-101 Reykjavik, Iceland Show more 5 Univ Washington, Dept Lab Med, Seattle, WA 98195 USA
• Format: Article in Journal/Newspaper
• Language: English
• Published: W B SAUNDERS CO-ELSEVIER INC 2018
• Subjects: Biallelic mutations; Double somatic mutations; Lynch syndrome; Lynch-like syndrome; MMR deficiency; Ristilkrabbamein; Vefjafræði; Colorectal Neoplasms; Adenocarcinoma; Lynch; Iceland
• Online Access: http://hdl.handle.net/2336/620711; https://doi.org/10.1016/j.humpath.2018.04.017

To access publisher's full text version of this article click on the hyperlink below Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency. Pelotonia, an annual cycling event in Columbus, Ohio National Cancer Institute, Bethesda, MD