Feasibility of screening for Lynch syndrome among patients with colorectal cancer.
OBJECTIVE
Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.


METHODS
MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed.


RESULTS
Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations.


CONCLUSIONS
One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.
Hampel
Heather
H
Department of MolecularVirology, Ohio State UniversityColumbus, OH, USA.
Frankel
Wendy L
WL
Martin
Edward
E
Arnold
Mark
M
Khanduja
Karamjit
K
Kuebler
Philip
P
Clendenning
Mark
M
Sotamaa
Kaisa
K
Prior
Thomas
T
Westman
Judith A
JA
Panescu
Jenny
J
Fix
Dan
D
Lockman
Janet
J
LaJeunesse
Jennifer
J
Comeras
Ilene
I
de la Chapelle
Albert
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000235:genetics; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000175:diagnosis* / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005240:Feasibility Studies; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008403:Mass Screening / Q000379:methods*; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D009820:Ohio; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes