Microsatellite stable (MSS) deficient mismatch repair (dMMR) tumor and mutational signature with targeted NGS

Slide

  • https://rpubs.com/JKang/MMRdMSS

Contents

  • Case
  • Review of microsatellite stable (MSS) deficient mismatch repair (dMMR) tumor
  • Review of mutational signature with targeted NGS

Case

  • 62/F
  • Liver mass

HE/MSH6

Past history

  • Liver stone, segmentectomy
  • Endometrial cancer
  • Meningioma
  • Chronic lymphocytic leukaemia/small lymphocytic lymphoma

NGS

Gene HGVSc HGVSp AF(%)
MSH6 c.3132C>A p.Tyr1044Ter 61.8
BRAF c.1405G>C p.Gly469Arg 14.7
KRAS c.182A>T p.Gln61Leu 9.7
MAP2K4 c.946C>T p.Gln316Ter 5.5
STK11 c.255_256delinsCT p.Leu85_Arg86delinsPheTer 44.7
BCOR c.4540C>T p.Arg1514Ter 17.1

NGS

  • Microsatellite stable
  • Tumor mutation burden (mutations/Mb): 21.7

Difference among MMRd (Helderman et al. 2023)

  • PMS2-MLH1 complex (hMutL\(\alpha\))
    • Essential for the repair of SNVs and INDELs
  • MSH2-MSH6 complex (hMutS\(\alpha\))
    • Mainly involved in the repair of SNVs
    • Redundant for INDEL repair, MSH2-MSH3 complex (hMutS\(\beta\))

Difference among Lynch syndrome (Valle 2023)

MMRd mutational signatures (Fang et al. 2021)

Mutation context

Mutational signature (Rosenthal et al. 2016)

Mutational signature from targeted NGS (Lee et al. 2023)

  • Courtesy of Lee, Donghyuk at Department of Stastics, Pusan National University

Mutational signature from targeted NGS

Mutational signature from targeted NGS

References

Fang, Hu, Xiaoqiang Zhu, Haocheng Yang, Jieun Oh, Jayne A. Barbour, and Jason W. H. Wong. 2021. “Deficiency of Replication-Independent DNA Mismatch Repair Drives a 5-Methylcytosine Deamination Mutational Signature in Cancer.” Science Advances 7 (45): eabg4398. https://doi.org/10.1126/sciadv.abg4398.
Helderman, Noah c, Anne-Sophie Van Der Werf-’T Lam, Diantha Terlouw, Sanne W. Bajwa-ten Broeke, Mar Rodríguez-Girondo, Demi van Egmond, Alexandra M. J. Langers, et al. 2023. “Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome.” Gastroenterology 165 (1): 271–274.e2. https://doi.org/10.1053/j.gastro.2023.03.198.
Lee, Donghyuk, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, et al. 2023. “SATS: A Mutational Signature Analyzer of Targeted Sequenced Tumors.” medRxiv. https://doi.org/10.1101/2023.05.18.23290188.
Rosenthal, Rachel, Nicholas McGranahan, Javier Herrero, Barry S. Taylor, and Charles Swanton. 2016. “deconstructSigs: Delineating Mutational Processes in Single Tumors Distinguishes DNA Repair Deficiencies and Patterns of Carcinoma Evolution.” Genome Biology 17 (1): 31. https://doi.org/10.1186/s13059-016-0893-4.
Valle, Laura. 2023. “Lynch Syndrome: A Single Hereditary Cancer Syndrome or Multiple Syndromes Defined by Different Mismatch Repair Genes?” Gastroenterology 165 (1): 20–23. https://doi.org/10.1053/j.gastro.2023.04.027.