Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53 co-alteration in pancreatic cancer

Datta, Jashodeep; Bianchi, Anna; Silva, Iago De Castro; Deshpande, Nilesh; Cao, Long Long; Mehra, Siddharth; Singh, Samara; Rafie, Christine I.; Sun, Xiaodian; Chen, Xi; Dai, Xizi; Colaprico, Antonio; Sharma, Prateek; Dosch, Austin R.; Pillai, Asha; Hosein, Peter J.; Nagathihalli, Nagaraj S.; Komanduri, Krishna V.; Wilson, Julie M.; Ban, Yuguang; Merchant, Nipun B.

doi:10.1038/s41388-022-02368-w

Cited by 25 publications

(13 citation statements)

References 64 publications

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“…In this cohort, we did not have an adequate sample size to analyze the clinical outcome from wild-type KRAS with GATA6 amplification. It was previously shown that both KRAS and TP53 mutations are independently associated with poor prognosis [39], and our cohort with TP53 mutation co-harbored KRAS mutation at the same time. Therefore, it will be interesting to see the interaction between GATA6 amplification with KRAS activation.…”

Section: Discussionsupporting

confidence: 60%

GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

Yang

Habowski

Deschênes

et al. 2023

Preprint

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Background: Molecular profiling of pancreatic adenocarcinoma (PDAC) demonstrates that genomic and transcriptomic features are associated with prognosis and chemosensitivity. We evaluated treatment outcomes by genetic alterations in TP53 and GATA6 to determine the prognostic and predictive impact of comutations, among patients with pancreatic cancer in New York largest healthcare system. Methods: Retrospective analysis was performed of patients at Northwell Health diagnosed with PDAC between 2014 to 2022. Surgical status was used to segregate patients into two groups: resected and unresected. TP53 genotype and GATA6 amplification status were compared for overall survival (OS) as measured from time of diagnosis. Additionally, patient survival by chemotherapy regimen administered was evaluated. The Kaplan Meier method was used to determine overall survival (OS) and the Wilcoxon test was used to compare survival curves. Previously established and published patient-derived organoids were used to investigate GATA6 expression, genetic status, and chemotherapy drug sensitivity. Results: Tumor mutation status was available for 128 patients. TP53 mutations were found in 104 patients (81.3%), GATA6 amplifications were found in 18 patients (14.0%), and 16 (12.5%) patients had mutations in both genes. Patients with TP53 mutations had worse OS compared to the wild type TP53 population (n = 22) (median OS 22.4 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.0 to 82.0, HR 2.03, p = 0.038). Among patients with a TP53 mutation, a survival advantage was observed in those who had a GATA6 amplification (n=16) compared to those who did not (n=86) (median OS 25.5 months vs. 19.4 months, HR 1.82, p = 0.027). Among patients with unresected PDAC who were TP53 mutant, the presence of GATA6 amplification (n=11) was associated with a substantial survival advantage compared to GATA6 wildtype (n=52) (median OS 25.5 months, vs. 10.1 months, HR 0.35, p = 0.004). In the TP53 mutation group, among 33 patients who received gemcitabine and nab-paclitaxel as the first line palliative chemotherapy, patients with GATA6 amplification (n = 8) had significantly improved survival compared to those without GATA6 amplification (n = 25) (mean OS 23.1 months vs 9.4 months, HR 0.52, p = 0.017). However, pancreatic cancer organoids with TP53 mutation (n=34) did not exhibit increased drug sensitivity to GnP with GATA6 amplification. Conclusions: Genetic mutations in TP53 were associated with shorter OS than wild type TP53. We found that GATA6 amplification appeared to attenuate poor prognosis observed in TP53 mutant patients regardless of type of standard chemotherapy received.

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Section: Discussionsupporting

confidence: 60%

GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

Yang

Habowski

Deschênes

et al. 2023

Preprint

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“…By contrast, TP53/KRAS co-mutated non-small cell lung cancer patients benefited from PD-L1 blockage in comparison to docetaxel, while KRAS -mutant patients without additional TP53 mutation did not [ 60 ]. A distinct immunoregulatory program was uncovered in TP53 / KRAS co-mutated pancreatic ductal adenocarcinoma [ 61 ]. In models of TP53mut triple-negative breast cancer restoration of TP53 activity sensitized for blockade of the PD-L1/PD1 axis [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis

et al. 2023

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TP53 is the most frequently mutated gene in human cancer. While no TP53-targeting drugs have been approved in the USA or Europe so far, preclinical and clinical studies are underway to investigate targeting of specific or all TP53 mutations, for example, by restoration of the functionality of mutated TP53 (TP53mut) or protecting wildtype TP53 (TP53wt) from negative regulation. We performed a comprehensive mRNA expression analysis in 24 cancer types of TCGA to extract (i) a consensus expression signature shared across TP53 mutation types and cancer types, (ii) differential gene expression patterns between tumors harboring different TP53 mutation types such as loss of function, gain of function or dominant-negative mutations, and (iii) cancer-type-specific patterns of gene expression and immune infiltration. Analysis of mutational hotspots revealed both similarities across cancer types and cancer type-specific hotspots. Underlying ubiquitous and cancer type-specific mutational processes with the associated mutational signatures contributed to explaining this observation. Virtually no genes were differentially expressed between tumors harboring different TP53 mutation types, while hundreds of genes were over- and underexpressed in TP53mut compared to TP53wt tumors. A consensus list included 178 genes that were overexpressed and 32 genes that were underexpressed in the TP53mut tumors of at least 16 of the investigated 24 cancer types. In an association analysis of immune infiltration with TP53 mutations in 32 cancer subtypes, decreased immune infiltration was observed in six subtypes, increased infiltration in two subtypes, a mixed pattern of decreased and increased immune cell populations in four subtypes, while immune infiltration was not associated with TP53 status in 20 subtypes. The analysis of a large cohort of human tumors complements results from experimental studies and supports the view that TP53 mutations should be further evaluated as predictive markers for immunotherapy and targeted therapies.

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“…3,20 This lack of concordance might be attributable to our substantially larger cohort size and/or the inherent heterogeneity of patients enrolled in this pragmatic “real world” study capturing data with wide geographic and clinicodemographic variability, which present novel insights into the genotype-immunophenotype chasm in YOPC. 47 Multiple pathways enriched in YOPC tumors converged upon regulation of the tumor immune microenvironment with various predicted effects. For instance, cytokine signaling, cancer pathways, and angiogenic signaling may restrict tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer

Ogobuiro

Baca

Ribeiro

et al. 2023

Preprint

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Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients. Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age- and molecularly-defined cohorts. Significance was determined as FDR-corrected P-values (Q)<0.05. Results: YOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-,RNF43-,CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%; Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+ T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients with KRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months; P=0.008) but notKRAS-mutant tumors (P=0.084). Conclusion: In this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

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Distinct mechanisms of innate and adaptive immune regulation underlie poor oncologic outcomes associated with KRAS-TP53 co-alteration in pancreatic cancer

Cited by 25 publications

References 64 publications

GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

Homogenous TP53mut-associated tumor biology across mutation and cancer types revealed by transcriptome analysis

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer

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