Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels Journal Article


Authors: Stadler, Z. K.; Battaglin, F.; Middha, S.; Hechtman, J. F.; Tran, C.; Cercek, A.; Yaeger, R.; Segal, N. H.; Varghese, A. M.; Reidy-Lagunes, D. L.; Kemeny, N. E.; Salo-Mullen, E. E.; Ashraf, A.; Weiser, M. R.; Garcia-Aguilar, J.; Robson, M. E.; Offit, K.; Arcila, M. E.; Berger, M. F.; Shia, J.; Solit, D. B.; Saltz, L. B.
Article Title: Reliable detection of mismatch repair deficiency in colorectal cancers using mutational load in next-generation sequencing panels
Abstract: Purpose: Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. Methods: We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. Results: Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). Conclusion: A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping. © 2016 by American Society of Clinical Oncology.
Journal Title: Journal of Clinical Oncology
Volume: 34
Issue: 18
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2016-06-20
Start Page: 2141
End Page: 2147
Language: English
DOI: 10.1200/jco.2015.65.1067
PROVIDER: scopus
PUBMED: 27022117
PMCID: PMC4962706
DOI/URL:
Notes: Article -- Export Date: 1 July 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Kenneth Offit
    494 Offit
  2. Leonard B Saltz
    555 Saltz
  3. Mark E Robson
    358 Robson
  4. David Solit
    420 Solit
  5. Neil Howard Segal
    94 Segal
  6. Zsofia Kinga Stadler
    139 Stadler
  7. Diane Lauren Reidy
    139 Reidy
  8. Jinru Shia
    445 Shia
  9. Martin R Weiser
    330 Weiser
  10. Rona Denit Yaeger
    61 Yaeger
  11. Michael Forman Berger
    373 Berger
  12. Maria Eugenia Arcila
    328 Arcila
  13. Nancy Kemeny
    334 Kemeny
  14. Christine Ann Tran
    3 Tran
  15. Asad   Ashraf
    6 Ashraf
  16. Sumit   Middha
    51 Middha