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.
- Cancer syndromes
- cancer genetics
- colorectal cancer genes
- colorectal cancer screening
- cancer prevention
- cancer epidemiology
- cancer registries
- cancer susceptibility
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Funding This work was supported by the National Cancer Institute (K07 CA151769-02 to FK; R01 CA132829 and K24 CA113433 to SS), National Institutes of Health under RFA # CA95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and PIs. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centres in the CFRs, nor does mention of trade names, commercial products, or organisations imply endorsement by the US Government or the CFR. The study sponsors/funders had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Competing interests All authors have completed the unified competing interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that (1) FK, JB, SG, GC, LL, NL, ST, SS have support from the National Institutes of Health/National Cancer Institute for the submitted work and ES, RM, RH, JH, PN have no support from any organisation for the submitted work; (2) ES, JB, RM, RH, GC, JH, LL, NL, PN, ST have no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; FK has been paid for consultancy outside the submitted work by Marinabio, Inc. SS has been paid for consultancy outside the submitted work by Archimedes Inc., Quest Diagnostics Inc., Interquest Inc. and has stock/stock options outside the submitted work through Marinabio Inc.; SG has been paid for consultancy outside the submitted work by Roche; (3) all authors have no other relationships or activities that might appear to have influenced the submitted work.
Patient consent This article does not contain any personal medical information about any identifiable living individuals. All participants provided informed consent for inclusion in the Colon Cancer Family Registry through each registry centre: University of Hawaii (Honolulu, Hawaii), Fred Hutchinson Cancer Research Center (Seattle, Washington), Mayo Clinic (Rochester, Minnesota), University of Southern California Consortium (Los Angeles, California), Cancer Care Ontario (Toronto, Canada) and University of Melbourne (Melbourne, Australia). This study was reviewed and approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board. A waiver of consent for study participants was obtained because the analyses were performed on de-identified data and did not require patient contact.
Ethics approval Ethics approval was provided by the institutional review board at all institutions in the Colon Cancer Family Registry; the Dana-Farber/Harvard Cancer Center Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.