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. 2020 Nov;25(11):e1671-e1680.
doi: 10.1634/theoncologist.2020-0356. Epub 2020 Aug 10.

Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer

Yun Guo #  1 , Xian-Ling Guo #  2   3 , Shuang Wang  4 , Xinyu Chen  1 , Jiaochun Shi  5 , Jian Wang  5 , Kai Wang  5 , Samuel J Klempner  6   7 , Weifeng Wang  5 , Min Xiao  8
Affiliations

Genomic Alterations of NTRK, POLE, ERBB2, and Microsatellite Instability Status in Chinese Patients with Colorectal Cancer

Yun Guo et al. Oncologist. 2020 Nov.

Abstract

Background: The increasing molecular characterization of colorectal cancers (CRCs) has spurred the need to look beyond RAS, BRAF, and microsatellite instability (MSI). Genomic alterations, including ERBB2 amplifications and mutations, POLE mutations, MSI, and NTRK1-3 fusions, have emerged as targets for matched therapies. We sought to study a clinically annotated Chinese cohort of CRC subjected to genomic profiling to explore relative target frequencies.

Methods: Tumor and matched whole blood were collected from 609 Chinese patients with CRC. Extracted DNA was analyzed for all classes of genomic alterations across 450 cancer-related genes, including single-nucleotide variations (SNVs), short and long insertions and deletions (indels), copy number variations, and gene rearrangements. Next-generation sequencing-based computational algorithms also determined tumor mutational burden and MSI status.

Results: Alterations in TP53 (76%), APC (72%), and KRAS (46%) were common in Chinese patients with CRC. For the first time, the prevalence of NTRK gene fusion was observed to be around 7% in the MSI-high CRC cohort. Across the cohort, MSI was found in 9%, ERBB2 amplification in 3%, and POLE pathogenic mutation in 1.5% of patients. Such results mostly parallel frequencies observed in Western patients. However, POLE existed at a higher frequency and was associated with large tumor T-cell infiltration.

Conclusion: Comparing to the Western counterparts, POLE mutations were increased in our cohort. The prevalence of NTRK gene fusion was around 7% in the MSI-high CRC cohort. Increased adoption of molecular profiling in Asian patients is essential for the improvement of therapeutic outcomes.

Implications for practice: The increasing use of genomic profiling assays in colorectal cancer (CRC) has allowed for the identification of a higher number of patient subsets benefiting from matched therapies. With an increase in the number of therapies, assays simultaneously evaluating all candidate biomarkers are critical. The results of this study provide an early support for the feasibility and utility of genomic profiling in Chinese patients with CRC.

Keywords: Colorectal cancer; DNA polymerase ε; ERBB2 amplification; Tropomyosin receptor kinase; Tumor mutational burden.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1
Figure 1
TMB's association with MSI, TP53, and KRAS mutations. (A): MSI‐H colorectal cancers (CRCs) were found more commonly at early stage I or stages II and III (81%) versus the MSS CRC subcohort (51%). (B): Microsatellite statuses and TMB are shown for each tumor (n = 609). The MSI‐H subcohort's median TMB (n = 55) is 59.4 mutations per megabase (mut/Mb), which is much higher than the MSS subcohort (n = 554) at 5.4 mut/Mb, with the exclusion of patients with POLE pathogenic mutation. KRAS mutations previously shown, causing elevated TMB in lung cancer, did not result in higher TMBs in CRC. Wild‐type TP53 was associated with a marginally higher TMB, mainly because of the relatively enriched MSI‐H cases in this cohort. Abbreviations: MSI, microsatellite instability; MSI‐H, MSI‐high; MSS, microsatellite stable; MUT, mutant; TMB, tumor mutational burden; WT, wild type.
Figure 2
Figure 2
Landscape of colorectal cancer genomic alterations. A total of 609 patients with colorectal cancer were classified into two groups based on their microsatellite status. The remaining pathologic and genomic information was plotted accordingly. In each subcohort, patients were arranged by their TMB values in ascending order, as follows: individuals with extremely high TMB at the MSS section carrying POLE pathogenic mutations; patients in MSI segment displaying overall elevated mutational burden. The bottom half of the figure shows that MSS colorectal cancer's genomic alteration was TP53, APC, and KRAS, whereas the high frequency mutated genes in the MSI counterpart were ACVR2A, ACVR1B, TGFBR2, CTNNB1, ARID1A, and mismatch repair–related genes (i.e., MSH6, MSH2, and MLH1). Abbreviations: MSI, microsatellite instability; MSI‐H, MSI‐high; MSS, microsatellite stable; mut/Mb, mutations per megabase; TMB, tumor mutational burden.
Figure 3
Figure 3
Frequently deregulated signaling pathways in colorectal cancer (CRC). MSI‐H and MSS CRC samples with confirmed genetic variants in related signal pathways such as WNT, TP53, RAS, and TGF‐β were analyzed separately. Alteration frequencies of activated (red) and inactivated (blue) alterations are expressed as a percentage of all cases in each cohort. Samples with alterations in five pathways—WNT, RTK/RAS, PIK3K, TP53, and TGF‐β—are plotted in the middle panel. Abbreviation: MSI, microsatellite instability; MSI‐H, MSI‐high; MSS, microsatellite stable.
Figure 4
Figure 4
Variants of NTRK and POLE. (A): Genomic profiling of NTRK gene fusion–positive colorectal cancer (CRC). The NTRK‐positive cancer lacks other activating gene variants and is enriched in MSI‐H CRC. (B): The mutations in the DNA polymerase proofreading exonuclease domain encoded by exons 9 to 14 (residues 268–471), causing exceptional high mutational burden, are designated as pathogenic. The remaining mutations in the nonproofreading region appear to be benign. (C): Immunohistochemical analysis of CD3 and PD‐L1 for CRC carrying POLE pathogenic mutation. A highly abundant infiltration of CD3‐positive lymphocytes was observed in all five CRC samples carrying POLE pathogenic mutation. Additionally, a positive staining for PD‐L1 was found in #3634 (TPS, 5%) and #3244 (TPS, 60%). (D): The red and blue bars represent gene amplification events occurring in MSI‐H and MSS CRC, respectively. The event of gene amplification occurred much less frequently in the MSI‐H (5 events in 55 patients) than in the MSS (668 events in 554 patients) cohort. Abbreviations: MSI, microsatellite instability; MSI‐H, MSI‐high; MSS, microsatellite stable; TMB, tumor mutational burden; TPS, tumor proportion score.
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