Laboratory Screening of Colorectal Cancer Patients in Routine Practice Identifies Probable Lynch Syndrome Patients at a High Frequency, Even Among Older Patients

Abstract

Purpose: Lynch Syndrome (LS) is a clinically important colorectal and extracolonic cancer predisposition syndrome that may be underdiagnosed in the U.S. We analyzed results of a laboratory screening program for LS to determine the prevalence, age distribution and family history characteristics of probable LS (PLS) patients in a community practice setting. Methods: All colorectal cancers (CRCs) diagnosed from March 15 through May 14, 2010 at Caris Life Sciences were tested for DNA mismatch repair (MMR) protein expression by immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2. Clinical characteristics were obtained from pathology records. Defects in MMR expression were determined by absent nuclear staining of neoplastic tissue with appropriate positive controls. Combined losses of MLH1/PMS2 or MSH2/MSH6 were considered to have primary abnormalities in MLH1 or MSH2, respectively. Cancers with MSH2, MSH6, and PMS2 deficiency were considered to have PLS. Cancers with MLH1 deficiency and one of more of the following: age <50, two known first or second degree relatives with CRC, or known personal history of CRC < age 50 or other LS-associated cancer, were considered to have PLS. All other MLH1-deficient cases were considered as likely MLH1 methylation silencing. Results: 447 patients with colorectal adenocarcinoma were identified. 53 were not tested (median age 73, 49% men, 64% left-sided) due to: inadequate tissue (9), declination by clinician (37), or the presence of other conditions (7). Of the 394 tested, 326 (83%) showed intact MMR (median age 67, 57% men, 69% left-sided); 45 (11%) had probable MLH1 methylation (median age 80, 40% men, 11% left-sided); and 23 (5.8%) were PLS patients (8 MLH1, 9 MSH2, 3 MSH6, and 3 PMS2, with median age = 53, 48% men, and 38% left-sided). 13 of 23 (57%) PLS patients were over 50 years old; in fact 4.2% (4/95) of CRC patients 60-69 years old and 2.9% (5/174) of those > 70 years old were PLS. Among 19 PLS patients with available personal and family history data following CRC diagnosis, 14 (74%) met Amsterdam (3) or Revised Bethesda (11) criteria for HNPCC, while 5 (26%) had no clinical features of HNPCC/LS. Conclusion: 1. Laboratory screening of all newly diagnosed CRCs reveals a prevalence of probable LS at the upper limit of previous population estimates (5.8%). 2. LS is more prevalent among CRC patients < age 50; however, more than half of all probable LS was identified in patients over age 50. 3. Approximately one quarter of probable LS patients had no clinical features to suggest LS prior to MMR IHC screening. 4. These results support the important clinical role of routine laboratory screening for LS in the community practice setting.