PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer

Mihara, Y.; Hirasaki, M.; Horita, Y.; Fujino, T.; Fukushima, H.; Kamakurab, Y.; Uranishi, K.; Hirano, Y.; Ryozawa, S.; Yasuda, M.; Makino, Y.; Shibasaki, S.; Hamaguchi, T.

doi:10.1101/2022.11.28.518259

bioRxiv · 10.1101/2022.11.28.518259

PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer

Mihara, Y.·Hirasaki, M.·Horita, Y.·Fujino, T.·Fukushima, H.·Kamakurab, Y.·Uranishi, K.·Hirano, Y.·Ryozawa, S.·Yasuda, M.·Makino, Y.·Shibasaki, S.·Hamaguchi, T.

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Abstract

BackgroundFluoropyrimidine-based adjuvant chemotherapy is globally recommended for postoperative stage III colon cancer and high-risk stage II patients. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, a recurrence-prevention biomarker of adjuvant chemotherapy for colorectal cancer is necessary for providing such treatments to appropriate patients. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between the single-nucleotide variants of autophagy-related genes and recurrence rates to identify the recurrence-prevention biomarkers of adjuvant chemotherapy in colorectal cancer. MethodsWe analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer patient relapse rates. ResultsWe detected 560 single-nucleotide variants or insertions/deletions in the target region. The results of Fishers exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single- nucleotide variants (c.1018G>A [p < 0.005] or c.1562A>C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. ConclusionsThe two single-nucleotide variants of this mitophagy-related gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

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Mihara, Y., Hirasaki, M., Horita, Y., Fujino, T., Fukushima, H., Kamakurab, Y., Uranishi, K., Hirano, Y., Ryozawa, S., Yasuda, M., Makino, Y., Shibasaki, S., Hamaguchi, T.. 2022-11-30. PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer. https://doi.org/10.1101/2022.11.28.518259

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