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. 2022 Sep 27;4(3):zcac026.
doi: 10.1093/narcan/zcac026. eCollection 2022 Sep.

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer

Wendell Jones  1 , David Tait  2 , Chad Livasy  3 , Mahrukh Ganapathi  2 , Ram Ganapathi  2
Affiliations

PLK3 amplification and tumor immune microenvironment of metastatic tumors are linked to adjuvant treatment outcomes in uterine serous cancer

Wendell Jones et al. NAR Cancer. .

Abstract

Uterine serous carcinoma (USC), an aggressive variant of endometrial cancer representing approximately 10% of endometrial cancer diagnoses, accounts for ∼39% of endometrial cancer-related deaths. We examined the role of genomic alterations in advanced-stage USC associated with outcome using paired primary-metastatic tumors (n = 29) treated with adjuvant platinum and taxane chemotherapy. Comparative genomic analysis of paired primary-metastatic patient tumors included whole exome sequencing and targeted gene expression. Both PLK3 amplification and the tumor immune microenvironment (TIME) in metastatic tumors were linked to time-to-recurrence (TTR) risk without any such association observed with primary tumors. TP53 loss was significantly more frequent in metastatic tumors of platinum-resistant versus platinum-sensitive patients and was also associated with increased recurrence and mortality risk. Increased levels of chr1 breakpoints in USC metastatic versus primary tumors co-occur with PLK3 amplification. PLK3 and the TIME are potential targets for improving outcomes in USC adjuvant therapy.

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Figures

Graphical Abstract
Graphical Abstract
PLK3 amplifications, TP53 loss, and immune status of the metastatic (and not the primary) tumor are highly informative for outcomes in metastatic uterine serous cancer. The metastatic uterine cancer illustration is used with permission © 2017 Terese Winslow LLC, U.S. Govt. has certain rights. Also, the Immune Response figure is from the US NIAID.
Figure 1.
Figure 1.
A comparison of the percent of the genome under sCNA by patient for the uterine serous cancer metastatic-primary pairs where the metastatic alteration percent is on the Y-axis and the primary alteration percent is on the X-axis.
Figure 2.
Figure 2.
(A, B) Differences in average number of breakpoints between PtS and PtR patients by chromosome (bands show one standard error in each direction) for primary and metastatic tumors. Only metastatic tumors had significant (P = 0.045) differences in breakpoints for chromosome 1.
Figure 3.
Figure 3.
(A, B) Genomic region with estimated CN changes in PLK3 metastatic tumors relative to immune signature and treatment outcomes for patients having both measurements. (B) Breakpoint locations and estimated CN status for all patients around gene PLK3. The numbers next to lines correspond to study patient IDs. Each line represents a genomic region between breakpoints where the CN is estimated to be uniform for that patient. The estimated CN is indicated by the height of the line except for lines in the gray region where all patients in gray for the respective subregion spanned by the line are assumed to have copy neutral diploid status.
Figure 4.
Figure 4.
Estimated sCNA changes for TP53 and their association with PtS/PtR patients and immune status in their metastatic tumors for patients having both measurements. The numbers shown correspond to patient IDs.
Figure 5.
Figure 5.
Kaplan–Meier plot of PLK3 Copy-neutral/PLK3 Gain relative to Favorable/Unfavorable Immune status for TTR in the metastatic tumor.
See this image and copyright information in PMC

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