The impact of screening on the clinical course of lynch syndrome

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 compared to expected of 62 years (P=.034). In females, median age to CRC in the colonoscopic screened group was 79 years, whereas in the non-screened group it was 57 years (P=.000), and median survival was 80 years in the screened group compared to expected of 63 years (P=.001). Eight of 41 (20%) males and five of 68 (7%) females who had serial screening colonoscopies developed an interval CRC within 2 years of previous colonoscopy. Endometrial or ovarian cancer occurred in 14 of 54 (26%) women in the gynecological screened group. Median age to diagnosis of gynecological cancer was 54 years in the screened group compared to 56 years in matched controls (P=.50). Stage I or II cancer was diagnosed in 92% of screened patients compared to 71% in the control group (P=.17). Mean survival in the screened group was 79 years compared to 69 years in the matched control group (P=.11), likely associated with concomitant colonoscopic screen mg. -- Conclusions: The incidence of CRC in MSH2 mutation carriers, exposed to the same environment, is not modified by the specific mutation, although there is a suggestion that type of mutation may influence development of some extracolonic cancers. For both males and females, colonoscopic screening was associated with decreased CRC risk, later age of onset, and better survival than expected if non-screened; however, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to one year in MSH2 mutation carriers and improving compliance and quality of colonoscopic examination. Gynecological screening did not result in earlier gynecologic cancer detection and despite screening two young women died from ovarian cancer suggesting that prophylactic hysterectomy with bilateral salpingo-oophorectomy be considered in female mutation carriers who have completed childbearing.

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