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JAMA Oncol. 2018 Jun 1;4(6):806-813. doi: 10.1001/jamaoncol.2018.0104.

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer.

Author information

1
Department of Internal Medicine and the Comprehensive Cancer Center, Ohio State University, Columbus.
2
Department of Laboratory Medicine, University of Washington, Seattle.
3
Department of Pathology, Ohio State University Wexner Medical Center, Columbus.
4
Department of Obstetrics and Gynecology, Ohio State University Wexner Medical Center, Columbus.
5
Department of Internal Medicine, West Virginia University Cancer Institute, Morgantown, West Virginia.
6
Department of Cancer Biology and Genetics, Ohio State University, Columbus.

Abstract

Importance:

Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol.

Objective:

To determine whether up-front tumor sequencing (TS) could replace the current multiple sequential test approach for universal tumor screening for LS.

Design, Setting, and Participants:

Tumor DNA from 419 consecutive CRC cases undergoing standard universal tumor screening and germline genetic testing when indicated as part of the multicenter, population-based Ohio Colorectal Cancer Prevention Initiative from October 2015 through February 2016 (the prospective cohort) and 46 patients with CRC known to have LS due to a germline mutation in a mismatch repair gene from January 2013 through September 2015 (the validation cohort) underwent blinded TS.

Main Outcomes and Measures:

Sensitivity of TS compared with microsatellite instability (MSI) testing and immunohistochemical (IHC) staining for the detection of LS.

Results:

In the 465 patients, mean age at diagnosis was 59.9 years (range, 20-96 years), and 241 (51.8%) were female. Tumor sequencing identified all 46 known LS cases from the validation cohort and an additional 12 LS cases from the 419-member prospective cohort. Testing with MSI or IHC, followed by BRAF p.V600E testing missed 5 and 6 cases of LS, respectively. Tumor sequencing alone had better sensitivity (100%; 95% CI, 93.8%-100%) than IHC plus BRAF (89.7%; 95% CI, 78.8%-96.1%; P = .04) and MSI plus BRAF (91.4%; 95% CI, 81.0%-97.1%; P = .07). Tumor sequencing had equal specificity (95.3%; 95% CI, 92.6%-97.2%) to IHC plus BRAF (94.6%; 95% CI, 91.9%-96.6%; P > .99) and MSI plus BRAF (94.8%; 95% CI, 92.2%-96.8%; P = .88). Tumor sequencing identified 284 cases with KRAS, NRAS, or BRAF mutations that could affect therapy for stage IV CRC, avoiding another test. Finally, TS identified 8 patients with germline DPYD mutations that confer toxicity to fluorouracil chemotherapy, which could also be useful for treatment selection.

Conclusions and Relevance:

Up-front TS in CRC is simpler and has superior sensitivity to current multitest approaches to LS screening, while simultaneously providing critical information for treatment selection.

PMID:
29596542
PMCID:
PMC5885168
[Available on 2019-03-29]
DOI:
10.1001/jamaoncol.2018.0104

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