Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer

Fay Kastrinos, Ewout W. Steyerberg, Judith Balmaña, Rowena Mercado, Steven Gallinger, Robert Haile, Graham Casey, John L. Hopper, Loic LeMarchand, Noralane Morey Lindor, Polly A. Newcomb, Stephen N Thibodeau, Sapna Syngal

Research output: Contribution to journalArticle

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Abstract

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) PREMM 1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM 1,2,6+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+PREMM 1,2,6 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 noncarriers 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 PREMM 1,2,6 scores where genetic evaluation does not disclose a MMR mutation.

Original languageEnglish (US)
Pages (from-to)272-279
Number of pages8
JournalGut
Volume62
Issue number2
DOIs
StatePublished - Feb 2013

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Hereditary Nonpolyposis Colorectal Neoplasms
Microsatellite Instability
Colorectal Neoplasms
Immunohistochemistry
DNA Mismatch Repair
Mutation
Area Under Curve
Neoplasms
Logistic Models
Aptitude
Germ-Line Mutation
ROC Curve
Colonic Neoplasms
Genes
Registries

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Kastrinos, F., Steyerberg, E. W., Balmaña, J., Mercado, R., Gallinger, S., Haile, R., ... Syngal, S. (2013). Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer. Gut, 62(2), 272-279. https://doi.org/10.1136/gutjnl-2011-301265

Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer. / Kastrinos, Fay; Steyerberg, Ewout W.; Balmaña, Judith; Mercado, Rowena; Gallinger, Steven; Haile, Robert; Casey, Graham; Hopper, John L.; LeMarchand, Loic; Lindor, Noralane Morey; Newcomb, Polly A.; Thibodeau, Stephen N; Syngal, Sapna.

In: Gut, Vol. 62, No. 2, 02.2013, p. 272-279.

Research output: Contribution to journalArticle

Kastrinos, F, Steyerberg, EW, Balmaña, J, Mercado, R, Gallinger, S, Haile, R, Casey, G, Hopper, JL, LeMarchand, L, Lindor, NM, Newcomb, PA, Thibodeau, SN & Syngal, S 2013, 'Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer', Gut, vol. 62, no. 2, pp. 272-279. https://doi.org/10.1136/gutjnl-2011-301265
Kastrinos, Fay ; Steyerberg, Ewout W. ; Balmaña, Judith ; Mercado, Rowena ; Gallinger, Steven ; Haile, Robert ; Casey, Graham ; Hopper, John L. ; LeMarchand, Loic ; Lindor, Noralane Morey ; Newcomb, Polly A. ; Thibodeau, Stephen N ; Syngal, Sapna. / Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer. In: Gut. 2013 ; Vol. 62, No. 2. pp. 272-279.
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abstract = "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) PREMM 1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM 1,2,6+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+PREMM 1,2,6 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 noncarriers 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 PREMM 1,2,6 scores where genetic evaluation does not disclose a MMR mutation.",
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T1 - Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer

AU - Kastrinos, Fay

AU - Steyerberg, Ewout W.

AU - Balmaña, Judith

AU - Mercado, Rowena

AU - Gallinger, Steven

AU - Haile, Robert

AU - Casey, Graham

AU - Hopper, John L.

AU - LeMarchand, Loic

AU - Lindor, Noralane Morey

AU - Newcomb, Polly A.

AU - Thibodeau, Stephen N

AU - Syngal, Sapna

PY - 2013/2

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N2 - 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) PREMM 1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM 1,2,6+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+PREMM 1,2,6 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 noncarriers 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 PREMM 1,2,6 scores where genetic evaluation does not disclose a MMR mutation.

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) PREMM 1,2,6+MSI, (6) PREMM1,2,6+IHC, (7) PREMM 1,2,6+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+PREMM 1,2,6 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 noncarriers 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 PREMM 1,2,6 scores where genetic evaluation does not disclose a MMR mutation.

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