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对 34129 例结直肠癌中 PTEN 突变谱进行全面特征分析。

Comprehensive characterization of PTEN mutational profile in a series of 34,129 colorectal cancers.

机构信息

Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Kazan Federal University, Russian Federation, 420000, Kazan, Russia.

出版信息

Nat Commun. 2022 Mar 25;13(1):1618. doi: 10.1038/s41467-022-29227-2.

DOI:10.1038/s41467-022-29227-2
PMID:35338148
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8956741/
Abstract

Loss of expression or activity of the tumor suppressor PTEN acts similarly to an activating mutation in the oncogene PIK3CA in elevating intracellular levels of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), inducing signaling by AKT and other pro-tumorigenic signaling proteins. Here, we analyze sequence data for 34,129 colorectal cancer (CRC) patients, capturing 3,434 PTEN mutations. We identify specific patterns of PTEN mutation associated with microsatellite stability/instability (MSS/MSI), tumor mutational burden (TMB), patient age, and tumor location. Within groups separated by MSS/MSI status, this identifies distinct profiles of nucleotide hotspots, and suggests differing profiles of protein-damaging effects of mutations. Moreover, discrete categories of PTEN mutations display non-identical patterns of co-occurrence with mutations in other genes important in CRC pathogenesis, including KRAS, APC, TP53, and PIK3CA. These data provide context for clinical targeting of proteins upstream and downstream of PTEN in distinct CRC cohorts.

摘要

抑癌基因 PTEN 的表达或活性丧失，作用类似于癌基因 PIK3CA 的激活突变，可提高细胞内磷脂酰肌醇（3,4,5）-三磷酸（PIP3）的水平，从而诱导 AKT 和其他促肿瘤发生信号蛋白的信号转导。在这里，我们分析了 34129 名结直肠癌（CRC）患者的序列数据，共捕获了 3434 个 PTEN 突变。我们确定了与微卫星稳定性/不稳定性（MSS/MSI）、肿瘤突变负担（TMB）、患者年龄和肿瘤位置相关的特定 PTEN 突变模式。在 MSS/MSI 状态分组内，这确定了核苷酸热点的不同特征，并提示了突变对蛋白质损伤作用的不同特征。此外，PTEN 突变的不同类别与 CRC 发病机制中其他重要基因（包括 KRAS、APC、TP53 和 PIK3CA）的突变存在不同的共同发生模式。这些数据为在不同 CRC 患者群体中针对 PTEN 上下游蛋白进行临床靶向治疗提供了背景信息。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/11574005c6c4/41467_2022_29227_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/51d32f0b4389/41467_2022_29227_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/b8edcc00ecba/41467_2022_29227_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/13e3330dd8b2/41467_2022_29227_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/20bb85e7be2e/41467_2022_29227_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/78b4e1822383/41467_2022_29227_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/679c5aea55d0/41467_2022_29227_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/2cd67b4531b1/41467_2022_29227_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/11574005c6c4/41467_2022_29227_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/51d32f0b4389/41467_2022_29227_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/b8edcc00ecba/41467_2022_29227_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/13e3330dd8b2/41467_2022_29227_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/20bb85e7be2e/41467_2022_29227_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/78b4e1822383/41467_2022_29227_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/679c5aea55d0/41467_2022_29227_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/2cd67b4531b1/41467_2022_29227_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3e6a/8956741/11574005c6c4/41467_2022_29227_Fig8_HTML.jpg

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