SMARCA4 突变恶性肿瘤患者的性别和共突变依赖性预后
Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies.
作者信息
Pan Minggui, Jiang Chen, Zhang Zheyang, Achacoso Ninah, Solorzano-Pinto Aleyda V, Tse Pam, Chung Elaine, Suga Jennifer Marie, Thomas Sachdev, Habel Laurel A
机构信息
Department of Oncology and Hematology, Kaiser Permanente, Santa Clara, CA 94051, USA.
Division of Research, Kaiser Permanente, Oakland, CA 94612, USA.
出版信息
Cancers (Basel). 2023 May 9;15(10):2665. doi: 10.3390/cancers15102665.
BACKGROUND
Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear.
METHODS
This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and , , , , and co-mutations.
RESULTS
Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were (mutp53, 59.2%), (mutKRAS, 28.8%), (mutCDKN2A, 31.2%), (mutSTK11, 12.8%), and (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92-3.18]) with a median OS of 3.0 versus 43.3 months ( < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76-73.4]) with a median OS of 2.75 months versus un-estimable ( = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04-4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87-7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06-1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12-22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16-148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89-26.61}) were associated with worse OS.
CONCLUSION
In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4.
背景
性别和共同突变是否会影响SMARCA4突变（mutSMARCA4）恶性肿瘤患者的预后尚不清楚。
方法
该队列包括来自北加利福尼亚凯撒医疗集团的患者，他们在2020年8月至2022年10月期间进行了下一代测序（NGS）。我们使用Cox回归模型来研究性别与总生存期（OS）之间的关联，并对人口统计学、体能状态、查尔森合并症指数、治疗接受情况、肿瘤突变负荷（TMB）以及其他共同突变进行了调整。
结果
在9221例进行了NGS检测的病例中，125例（1.4%）存在mutSMARCA4。最常见的伴有mutSMARCA4的恶性肿瘤是非小细胞肺癌（NSCLC，35.2%）、食管和胃腺癌（12.8%）以及原发灶不明的癌症（11.2%）。最常见的共同突变是p53突变（mutp53，59.2%）、KRAS突变（mutKRAS，28.8%）、CDKN2A突变（mutCDKN2A，31.2%）、STK11突变（mutSTK11，12.8%）和Keap1突变（mutKeap1，8.8%）。在整个mutSMARCA4队列中，男性患者的OS明显比女性患者差（HR = 1.71，[95% CI 0.92 - 3.18]），中位OS分别为3.0个月和43.3个月（P < 0.001）；在NSCLC亚组中也是如此（HR = 14.2，[95% CI 2.76 - 73.4]），中位OS分别为2.75个月和无法估计（P = 0.02）。在所有mutSMARCA4患者中，p53突变型与野生型p53相比（HR = 2.12，[95% CI 1.04 - 4.29]）以及STK11突变型与野生型STK11相比（HR = 2.59，[95% CI 0.87 - 7.73]）与较差的OS相关。在NSCLC亚组中，p53突变型与野生型p53相比（HR = 0.35，[0.06 - 1.97]）以及KRAS突变型与野生型KRAS相比（HR = 0.04，[0.003 - 0.45]）与较好的OS相关，而CDKN2A突变型与野生型CDKN2A相比（HR = 5.04，[1.12 - 22.32]）、STK11突变型与野生型STK11相比（HR = 13.10，[95% CI 1.16 - 148.26]）以及Keap1突变型与野生型Keap1相比（HR = 5.06，[95% CI 0.89 - 26.61]）与较差的OS相关。
结论
在我们的mutSMARCA4患者队列中，男性的预后明显比女性差，而mutTP53、mutKRAS、mutCDKN2A、mutSTK11和mutKeap1在所有患者和NSCLC亚组中与预后的关联存在差异。我们的结果若得到证实，可能提示在肿瘤携带mutSMARCA4的患者中，这种性别和共同突变依赖性预后差异背后潜在的未被识别的机制。
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