Comparison of universal screening in major lynch-associated tumors: a systematic review of literature.

Lynch syndrome (LS) is associated with an increased lifetime risk of several cancers including colorectal (CRC), endometrial (EC), ovarian (OC), urinary (UT) and sebaceous tumors (ST). The benefit for universal screening in CRC and EC is well known. However, this benefit in other major lynch-associated tumors is unclear. We performed a systematic review of all published articles in the MEDLINE database between 2005 to 2017 to identify studies performing universal screening for LS in unselected CRC, EC, OC, UT and ST. All cases with MSI-H (instability in two or more markers) or missing one or more proteins on IHC testing were considered screening positive. Cases with MLH1 promoter hypermethylation or BRAF mutation positive were considered to have somatic mutations. A total of 3788 articles were identified in MEDLINE yielding 129 study arms from 113 studies. The overall pooled yield of universal LS screening and germline mismatch gene mutation was significantly different across the major LS-associated tumors (Mann Whitney test, p < 0.001). The pooled screening yield was highest in ST [52.5% (355/676), 95% CI 48.74-56.26%] followed by EC [22.65% (1142/5041), 95% CI 21.54-23.86%], CRC [11.9% (5649/47,545), 95% CI 11.61-12.19%], OC [11.29% (320/2833), 95% CI 10.13-12.47%] and UT [11.2% (31/276), 95% CI 7.48-14.92%]. ST also had the highest pooled germline positivity for mismatch repair gene mutation [18.8%, 33/176, 95%CI 13.03-24.57], followed by EC [2.6% (97/3765), 95% CI 2.09-3.11], CRC [1.8% (682/37,220), 95% CI 1.66-1.94%], UT [1.8%(3/164), 95% CI - 0.24-3.83%] and OC [0.83%(25/2983), 95% CI 0.48-1.12%]. LS screening in EC yielded significantly higher somatic mutations compared to CRC [pooled percentage 16.94% [(538/3176), 95%CI 15.60-18.20%] vs. 5.23% [(1639/26,152), 95% CI 4.93-5.47%], Mann Whitney test, p < 0.0001. Universal LS testing should be routinely performed in OC, UT and STs in addition to CRC and EC. Our findings also support consideration for IHC and somatic mutation testing before germline testing in EC due to higher prevalence of somatic mutations as well as germline testing in all patients with ST. Our results have implications for future design of LS screening programs and further studies are needed to assess the cost effectiveness and burden on genetic counselling services with expanded universal testing for LS.

Worldwide variation in lynch syndrome screening: case for universal screening in low colorectal cancer prevalence areas.

To perform a systematic assessment of universal Lynch syndrome (LS) screening yield in colorectal cancer (CRC) patients around the world. Universal screening for LS is recommended in all CRC patients. However, the variation in yield of LS screening in the setting of significant global variation in CRC prevalence is unknown. A systematic review of articles in the MEDLINE database was performed to identify studies performing universal screening for LS. All cases with microsatellite instability (MSI-H) or missing one or more proteins on immunohistochemistry (IHC) were considered screening positive. The overall pooled yield of universal LS screening in 97 study arms from 89 identified studies was 11.9% (5649/47545) and the overall pooled percentage of confirmed LS patients was 1.8% (682/37220). LS screening positivity varied significantly based on geographic region (Kruskal Wallis test, p < 0.001) and reported 5-year CRC prevalence in the country (Fisher's exact, p < 0.001). Significant inverse correlation was found between LS screening positivity and 5-year CRC prevalence (Pearson correlation, r = - 0.56, p < 0.001). The overall yield of LS screening was 15.00% (382/2553) and rate of confirmed LS was 7.7% (113/1475) in LS screening done in patients ≤ 50 years (16 studies). There is significant geographic variation in LS screening positivity with higher yield in countries with lower prevalence of CRC. Our results highlight the importance of universal LS screening in younger patients and low CRC prevalence countries.