Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

Golan, Talia; O’Kane, Grainne M.; Denroche, Robert E.; Raitses‐Gurevich, Maria; Grant, Robert C.; Holter, Spring; Wang, Yifan; Zhang, Amy; Jang, Gun Ho; Stossel, Chani; Atias, Dikla; Halperin, Sharon; Berger, Raanan; Glick, Yulia; Park, J. Patrick; Cuggia, Adeline; Williamson, Laura; Wong, Hui‐Li; Schaeffer, David F.; Renouf, Daniel J.; Borgida, Ayelet; Dodd, Anna; Wilson, Julie M.; Fischer, Sandra E.; Notta, Faiyaz; Knox, Jennifer J.; Zogopoulos, George; Gallinger, Steven

doi:10.1053/j.gastro.2021.01.220

Cited by 101 publications

(112 citation statements)

References 50 publications

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“…That said, it is also true that alterations affecting the homologous recombination machinery have been already associated with high-TMB in other tumors [58,59]. However, PDAC harboring BRCA-genes mutations represent one of the very few PDAC molecular sub-groups with already established effective therapeutic strategies, which includes platinum-based chemotherapy and PARP-inhibitors [60][61][62]. Thus, in such cases, in the presence of high-TMB, the potential role of immunotherapy may be considered at a later stage for non-responders or in the case of disease progression.…”

Section: Discussionmentioning

confidence: 99%

Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Lawlor

Mattiolo

Mafficini

et al. 2021

Cancers

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Tumor mutational burden (TMB) is a numeric index that expresses the number of mutations per megabase (muts/Mb) harbored by tumor cells in a neoplasm. TMB can be determined using different approaches based on next-generation sequencing. In the case of high values, it indicates a potential response to immunotherapy. In this systematic review, we assessed the potential predictive role of high-TMB in pancreatic ductal adenocarcinoma (PDAC), as well as the histo-molecular features of high-TMB PDAC. High-TMB appeared as a rare but not-negligible molecular feature in PDAC, being present in about 1.1% of cases. This genetic condition was closely associated with mucinous/colloid and medullary histology (p < 0.01). PDAC with high-TMB frequently harbored other actionable alterations, with microsatellite instability/defective mismatch repair as the most common. Immunotherapy has shown promising results in high-TMB PDAC, but the sample size of high-TMB PDAC treated so far is quite small. This study highlights interesting peculiarities of PDAC harboring high-TMB and may represent a reliable starting point for the assessment of TMB in the clinical management of patients affected by pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Lawlor

Mattiolo

Mafficini

et al. 2021

Cancers

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“…11,12,18,25,28,29 Moreover, recent largescale whole-exome sequencing (WES) and wholegenome sequencing (WGS) analyses suggest that HRD likely extends beyond point mutations in core genes, implying other molecular mechanisms, which are yet to be elucidated. 7,21,24,[33][34][35][36] Here, we present a systematic review of the current literature on HRD in PDAC and perform a prevalence metaanalysis of the better-characterized HRD genes with known or potential clinical utility. Particular focus was given to germline variants, both in sporadic and familial cases, to assess the contribution of HRD genes to cancer susceptibility and potential intervention.…”

Section: Introductionmentioning

confidence: 99%

Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis

Casolino

Paiella²,

Azzolina

et al. 2021

JCO

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PURPOSE To analyze the prevalence of homologous recombination deficiency (HRD) in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS We conducted a systematic review and meta-analysis of the prevalence of HRD in PDAC from PubMed, Scopus, and Cochrane Library databases, and online cancer genomic data sets. The main outcome was pooled prevalence of somatic and germline mutations in the better characterized HRD genes ( BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, RAD51, and the FANC genes). The secondary outcomes were prevalence of germline mutations overall, and in sporadic and familial cases; prevalence of germline BRCA1/2 mutations in Ashkenazi Jewish (AJ); and prevalence of HRD based on other definitions (ie, alterations in other genes, genomic scars, and mutational signatures). Random-effects modeling with the Freeman-Tukey transformation was used for the analyses. PROSPERO registration number: (CRD42020190813). RESULTS Sixty studies with 21,842 participants were included in the systematic review and 57 in the meta-analysis. Prevalence of germline and somatic mutations was BRCA1: 0.9%, BRCA2: 3.5%, PALB2: 0.2%, ATM: 2.2%, CHEK2: 0.3%, FANC: 0.5%, RAD51: 0.0%, and ATR: 0.1%. Prevalence of germline mutations was BRCA1: 0.9% (2.4% in AJ), BRCA2: 3.8% (8.2% in AJ), PALB2: 0.2%, ATM: 2%, CHEK2: 0.3%, and FANC: 0.4%. No significant differences between sporadic and familial cases were identified. HRD prevalence ranged between 14.5%-16.5% through targeted next-generation sequencing and 24%-44% through whole-genome or whole-exome sequencing allowing complementary genomic analysis, including genomic scars and other signatures (surrogate markers of HRD). CONCLUSION Surrogate readouts of HRD identify a greater proportion of patients with HRD than analyses limited to gene-level approaches. There is a clear need to harmonize HRD definitions and to validate the optimal biomarker for treatment selection. Universal HRD screening including integrated somatic and germline analysis should be offered to all patients with PDAC.

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“…To study the composition and function of subTMEs, we assembled a workflow for large-scale patient-matched integration of histopathology, clinical datasets, multidimensional analytical techniques, and subTME-specific model systems. Our first step was to construct subTME-specific multiOMIC profiles from 32 of the 143 patients in our Stage I&II cohort ( Figure 2A ) with typical tumor morphology, sufficient material, sufficient stromal content (> 50%), matched high-quality whole genome sequencing (WGS), and no homologous recombination-repair deficiency (Golan et al, 2021) or other rare genomic events. We used laser capture microdissection (LCM) to separately extract different subTMEs and the tumor cells residing within ( Figure S2A ).…”

Section: Resultsmentioning

confidence: 99%

Spatially confined sub-tumor microenvironments orchestrate pancreatic cancer pathobiology

Grünwald

Devisme

Andrieux

et al. 2021

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) remains resistant to most treatments and demonstrates a complex pathobiology. Here, we deconvolute regional heterogeneity in the human PDAC tumor microenvironment (TME), a long-standing obstacle, to define precise stromal contributions to PDAC progression. Large scale integration of histology-guided multiOMICs with clinical data sets and functional in vitro models uncovers two microenvironmental programs in PDAC that were anchored in fibroblast differentiation states. These sub-tumor microenvironments (subTMEs) co-occurred intratumorally and were spatially confined, producing patient-specific cellular and molecular heterogeneity associated with shortened patient survival. Each subTME was uniquely structured to support discrete aspects of tumor biology: reactive regions rich in activated fibroblast communities were immune-hot and promoted aggressive tumor progression while deserted regions enriched in extracellular matrix supported tumor differentiation yet were markedly chemoprotective. In conclusion, PDAC regional heterogeneity derives from biologically distinct reactive and protective TME elements with a defined, active role in PDAC progression.

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Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma

Cited by 101 publications

References 50 publications

Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Pancreatic Cancer: Systematic Review and Still-Open Questions

Homologous Recombination Deficiency in Pancreatic Cancer: A Systematic Review and Prevalence Meta-Analysis

Spatially confined sub-tumor microenvironments orchestrate pancreatic cancer pathobiology

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