TY - JOUR
T1 - Comparison of universal screening in major lynch-associated tumors
T2 - a systematic review of literature
AU - Kunnackal John, George
AU - Das Villgran, Vipin
AU - Caufield-Noll, Christine
AU - Giardiello, Francis M.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Lynch syndrome
KW - Universal screening
UR - http://www.scopus.com/inward/record.url?scp=85099224958&partnerID=8YFLogxK
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U2 - 10.1007/s10689-020-00226-w
DO - 10.1007/s10689-020-00226-w
M3 - Article
C2 - 33426601
AN - SCOPUS:85099224958
SN - 1389-9600
VL - 21
SP - 57
EP - 67
JO - Familial Cancer
JF - Familial Cancer
IS - 1
ER -