Higher Incidence of Early-Onset Colorectal Cancer in Southeastern Appalachian Kentucky Due to Genetic and Epigenetic Characteristics

Abstract

Introduction: The aim of this project is to evaluate the genetic and epigenetic factor (smoking) associated with colorectal cancer (CRC) in Southeastern (SE) Appalachian Kentucky. The highest CRC incidence in the United States is in SE KY. The age adjusted CRC incidence rate in KY is 61.3% for males and 44% for females, but in SE KY, the rates are higher (Males: 67.3%; Females: 47.8%). Methods: 41 CRC patients' data were collected retrospectively from 2012-15 from the ARH hospital in Hazard, KY. We performed germ line genetic testing for Lynch syndrome at Myriad Genetic Lab for 18 of the 41 CRC patients. The other 23 patients had tumor screening for Lynch syndrome using immunohistochemical staining of the four mismatch repair proteins at Mayo Lab. We further analyzed data according to age, sex, smoking habits, location of tumor (right-sided or left-sided), family history of CRC, age of diagnosis, and type of MMR gene mutation. Results: 51.2% of patients were male. 30.6% were smokers. 10 of the 41 CRC patients were diagnosed under age 50 (22.7%) compared to 10% expected frequency of CRC cases under age 50. 35.63% of smokers with CRC were diagnosed under age 50. 55% of Lynch (+) CRC patients were smokers. Of the 9 Lynch patients, 4 were left-sided, 4 were right-sided, and 1 had two synchronous left and right tumors. Of the 10 Lynch CRC negative patients, 7 were right-sided, 3 were left-sided. 55.7% of Lynch CRC patients were under 50 years. Of the 9 Lynch (+) test patients, 5 had a MSH2 exon 1-6 deletion mutation, 2 had MLH1 mutations, 1 had a MSH6 mutation, and 1 had a PMS2 mutation. IHC stains were all negative on 23 patients. Of the 29 patients who had detailed family history of CRC, 14.5% had one FDR with CRC, 18% with two FDRs, 16.4% with 3 FDRs, 1.8% with four FDRS, and 1.8% with five FDRs. Conclusion: The incidence of CRC under age 50 is higher in SE Appalachian KY. There seems to be a high correlation between smoking and CRC under age 50 and between Lynch syndrome and CRC under age 50. Our Lynch patients had colon cancer located equally in both proximal and distal colon, indicating increasing incidence of left-sided Lynch syndrome. The MSHS2 exon 1-6 deletion, also known as the American Founder Mutation which has been previously linked to families from SE KY, seems to be the predominate mutation seen in Lynch syndrome patients from this region. Genetic factors, positive family history and smoking may be responsible for the higher incidence of CRC in younger patients in our region.