Patient overlap, cohort-relative scaling, and biological context in cross-cohort evaluation of a mitochondrial proteostasis-associated score in triple-negative breast cancer.

Authors

Xiaoyuan Weng, Yanqi Tang, Caiji Wang, Zhaofeng Huang, Xiyin Huang, Jinsheng Wang

Published in

PloS one. Volume 21. Issue 10. Pages e0355652. Epub Oct 09, 2026.

Abstract

Public transcriptomic cohort evaluation can be distorted by patient reuse, dependence among study sources, and cohort-relative normalization. Objective: To evaluate the association between a fixed 15-gene cohort-relative mitochondrial proteostasis score and source-study-defined pathological complete response (pCR) across four accession-defined cohorts from three principal study sources.
The fixed score comprised 15 genes with equal positive weights, a specified expected direction, and a platform-coverage rule. After patient-level deduplication and duplicate-aliquot collapse, 285 patients with strict triple-negative breast cancer, including 104 with pCR, were analyzed. Cohort-specific odds ratios (ORs) per one-standard-deviation score increase were pooled by restricted maximum-likelihood random-effects meta-analysis with modified Hartung-Knapp inference. Sensitivity analyses summarized three study sources, used Paule-Mandel heterogeneity estimation, and applied one fixed single-sample RankScore implementation.
The primary four-cohort estimate was OR 0.958 (95% CI, 0.639-1.437; P = 0.760; tau^2 = 0). The three-source REML estimate was OR 0.971 (95% CI, 0.492-1.914; P = 0.868; tau^2 = 0.0201). The RankScore sensitivity was imprecise (OR 0.613 per 0.10 RankScore; 95% CI, 0.148-2.542; P = 0.354). The overlap assessment identified 57 strict-TNBC patients duplicated between GSE20194 and GSE25055; treating them as an additional accession effect increased nominal n from 285 to 342 without adding independent participants. Contextual NeoTRIP, single-cell, and I-SPY2 analyses were included to characterize biological and treatment context.
Across four accession-defined cohorts from three principal study sources, the evaluated score implementations did not show a reproducible association with pCR. Source-level estimates remained imprecise. Patient overlap, reference dependence, and limited independent study sources are key considerations in cross-cohort biomarker evaluation.

PMID:
42853826
Bibliographic data and abstract were imported from PubMed on 10 Oct 2026.

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