RT Journal Article
SR Electronic
T1 Comparison of the clinical prediction model PREMM<sub>1,2,6</sub> and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 272
OP 279
DO 10.1136/gutjnl-2011-301265
VO 62
IS 2
A1 Fay Kastrinos
A1 Ewout W Steyerberg
A1 Judith Balmaña
A1 Rowena Mercado
A1 Steven Gallinger
A1 Robert Haile
A1 Graham Casey
A1 John L Hopper
A1 Loic LeMarchand
A1 Noralane M Lindor
A1 Polly A Newcomb
A1 Stephen N Thibodeau
A1 Sapna Syngal
A1 the Colon Cancer Family Registry
YR 2013
UL http://gut.bmj.com/content/62/2/272.abstract
AB Background Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM1,2,6 model predicts the likelihood of a MMR gene mutation based on personal and family cancer history. Objective To compare strategies using PREMM1,2,6 and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers. Design Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2, MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM1,2,6 predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM1,2,6, (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM1,2,6+IHC+MSI. Results Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM1,2,6 discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM1,2,6 was slightly greater than PREMM1,2,6+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM1,2,6+IHC did not improve discrimination. Conclusion PREMM1,2,6 and IHC showed excellent performance in distinguishing mutation carriers from non-carriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM1,2,6 scores where genetic evaluation does not disclose a MMR mutation.