Abstract 5773: A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study
Authors: Li Cong , Xu Yun , Liu Fangqi , Xu Ye 
Published: June 2022

Abstract
Background: Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths worldwide. Between 3 and 6% of all CRC cases are attributed to hereditary colorectal cancer (HCRC). It is important to distinguish CRCs that arise hereditarily from those that arise sporadically, because patients with HCRC and their relatives can benefit from intensive clinical management and surveillance. The detection of germline variants using tumor tissue and paired non-cancerous tissue/whole blood cells (WBC) (conventional method) is considered as the gold standard for germline confirmation, but which could introduce high cost and long turnaround time. In this work, we aimed to investigate the feasibility of diagnosing HCRC using only tumor next-generation sequencing data without normal tissue/WBC data.
Methods: One-hundred patients with suspected HCRC were prospectively enrolled according to the clinical diagnosis. Both tumor tissue and paired WBC were collected from each patient. Capture-based targeted sequencing using a panel consisting of 41 cancer-related genes was performed on both tumor tissue and WBC sample. The germline variants were identified using conventional and ColonCore method, respectively. The sensitivity and positive predictive value (PPV) of ColonCore method in identifying germline alterations were calculated, when conventional method was used as a reference.
Results: A total of 636 alterations were identified using ColonCore method, including 606 somatic alterations and 30 germline alterations. Among the somatic alterations detected from this panel, 599 single-nucleotide variants and 7 copy number variants were observed. The most frequently mutated genes were APC, TP53, and KRAS, occurring in 76%, 66%, and 46% of patients, respectively. For ColonCore analysis, 17, 9, 2, and 2 patients harbored germline pathogenic variants in DNA mismatch repair (MMR) genes, APC, MUTYH, and ATM, respectively. Compared to the conventional method, the sensitivity of ColonCore method in the diagnosis of HCRC achieved 88.5% with a PPV of 82.1%. Next, the diagnostic performance of ColonCore method in Lynch syndrome (LS) and familial adenomatous polyposis (FAP) was subsequently investigated. We found its sensitivity in the diagnosis of LS achieved 100% (with a PPV of 98.8%), which was obviously higher than that in the diagnosis of FAP (70.0% with a PPV of 63.6%). Twenty-three patients identified as having a microsatellite instability (MSI)-high tumor using ColonCore method were also identified as having an MMR-deficient (dMMR) tumor using immunohistochemistry staining analysis.
Conclusions: Our study suggests that ColorCore method is a one-stop approach for detecting germline/somatic alterations and MSI/dMMR status for suspected HCRC. Furthermore, ColorCore method is a feasible and valid tool to diagnose HCRC, especially LS.
Citation Format: Cong Li, Yun Xu, Fangqi Liu, Ye Xu. A one-stop approach in diagnosing hereditary colorectal cancer: A prospective, proof-of-principle, single-center study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5773.