Therapeutic Advances in Medical Oncology (Jun 2021)

Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study

  • Mengyuan Yang,
  • Dan Li,
  • Wu Jiang,
  • Lizhen Zhu,
  • Haixing Ju,
  • Yan Sun,
  • Yuqiang Shan,
  • Chunkang Yang,
  • Jian Dong,
  • Lin Wang,
  • Baoping Wu,
  • Meng Qiu,
  • Xianli Yin,
  • Xicheng Wang,
  • Bin Xiong,
  • Wei Yan,
  • Tao Liu,
  • Chenglin Liu,
  • Xinru Mao,
  • Kefeng Ding,
  • Suzhan Zhang,
  • Shu Zheng,
  • Dong Xu,
  • Peirong Ding,
  • Ying Yuan

DOI
https://doi.org/10.1177/17588359211023290
Journal volume & issue
Vol. 13

Abstract

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Background: This multicenter study aimed to reveal the genetic spectrum of colorectal cancer (CRC) with deficient mismatch repair (dMMR) and build a screening model for Lynch syndrome (LS). Methods: Through the immunohistochemical (IHC) screening of mismatch repair protein results in postoperative CRC patients, 311 dMMR cases, whose germline and somatic variants were detected using the ColonCore panel, were collected. Univariate and multivariate logistic regression analysis was performed on the clinical characteristics of these dMMR individuals, and a clinical nomogram, incorporating statistically significant factors identified using multivariate logistic regression analysis, was constructed to predict the probability of LS. The model was validated externally by an independent cohort. Results: In total, 311 CRC patients with IHC dMMR included 95 identified MMR germline variant (LS) cases and 216 cases without pathogenic or likely pathogenic variants in MMR genes (non-Lynch-associated dMMR). Of the 95 individuals, approximately 51.6%, 28.4%, 14.7%, and 5.3% cases carried germline MLH1 , MSH2 , MSH6 , and PMS2 pathogenic or likely pathogenic variants, respectively. A novel nomogram was then built to predict the probability of LS for CRC patients with dMMR intuitively. The receiver operating characteristic (ROC) curve informed that this nomogram-based screening model could identify LS with a higher specificity and sensitivity with an area under curve (AUC) of 0.87 than current screening criteria based on family history. In the external validation cohort, the AUC of the ROC curve reached 0.804, inferring the screening model’s universal applicability. We recommend that dMMR-CRC patients with a probability of LS greater than 0.435 should receive a further germline sequencing. Conclusion: This novel screening model based on the clinical characteristic differences between LS and non-Lynch-associated dMMR may assist clinicians to preliminarily screen LS and refer susceptible patients to experienced specialists.