The impact of screening on the clinical course of lynch syndrome

• Main Author: Stuckless, Susan N.
• Format: Thesis
• Language: English
• Published: Memorial University of Newfoundland 2012
• Subjects: Lynch; Newfoundland
• Online Access: https://research.library.mun.ca/11487/; https://research.library.mun.ca/11487/1/Stuckless_SusanN2.pdf

Background & Aims: Lynch syndrome (LS) is an autosomal dominant disorder and is caused by mutations in one of the DNA mismatch repair (MMR) genes, in particular, MLH1, MSH2, MSH6 and PMS2. Lynch syndrome mutation carriers are at a high risk of developing colorectal cancer (CRC) and gynecological cancers, and as such, targeted screening programs have been developed. The primary objective of this thesis was to determine the phenotypic expression of three different MSH2 mutations causing LS in Newfoundland and to examine the impact of screening in this group of MSH2 mutation earners. -- Methods: Age to onset of first CRC, first extracolonic cancers and death were compared for those with an intron 5 splice site mutation, an exon 8 deletion and an exon 4-16 deletion. To determine the impact of colonoscopic screening in male and female MSH2 mutation carriers, CRC incidence and survival in the screened group was compared to that expected, derived from the non-screened group. To correct for survivor bias controls were matched for age at entry into screening and also for gender. Compliance with screening recommendations of colonoscopy every 1-2 years was also addressed. Gynecological cancer incidence and overall survival was compared in females who received gynecological screening and in matched controls. Controls were randomly selected from non-screened mutation carriers who were alive and disease-free at the age the case entered the screening program. One matched control was selected for each case. -- Results: For all three mutations males had a higher age-related risk of CRC and death compared to females. For the intron 5 splice site mutation carriers, the number of transitional cell cancers of the urinary tract was significantly lower and time to first ovarian cancer was significantly higher than in the carriers of the genomic deletions. Median age to CRC was 58 years in males who received colonoscopic screening whereas expected was 47 years (P<.0001), and median survival in screened males was 66 years ...