Experts comment on EBioMedicine Shen Baiyong/Fang Hai/Wang Chaofu/Zhang Henghui's team published the results of the first Chinese pancreatic cancer cohort driven copy number variation-driven molecular typing study

Pancreatic cancer (PAAD) is one of the deadliest cancers, causing approximately 80,000 new deaths each year in China alone
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The current histological risk stratification fails to find the right treatment for the right patient
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There has also been limited progress in stratification based on mutant genes
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The high mortality of pancreatic cancer (PAAD) indicates that patients have a poor prognosis and lack of effective systemic treatments.
At present, there is still a lack of molecular typing studies that guide the prognosis and treatment of pancreatic cancer patients
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Therefore, it is necessary to explore the molecular classification of PAAD patients and construct a prognostic model to distinguish the risk of recurrence, so as to help patients with pancreatic cancer find suitable treatments and predict prognosis
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On November 25, 2021, the team of Shen Baiyong/Fang Hai/Wang Chaofu of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wuxi Zhenhe Biotechnology Co.
, Ltd.
(hereinafter referred to as "Zhenhe Technology") Zhang Henghui’s team published online on EBioMedicine titled The research paper "Identification of copy number variation-driven molecular subtypes informative for prognosis and treatment in pancreatic adenocarcinoma of a Chinese cohort" reveals the molecular subtypes of pancreatic cancer patients in a large Chinese cohort for the first time, emphasizing routine molecular subtypes The importance of typing detection to help manage pancreatic cancer patients, the molecular subtype and prognosis model constructed in this study can be transformed and applied to improve the diagnosis, treatment and management of pancreatic cancer patients
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This study attempts to comprehensively describe the gene mutation profile of pancreatic cancer patients in the Chinese cohort, determine molecular subtypes and establish prognostic models to help select the most appropriate treatment options
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First of all, this study did not find that high mutation frequency genes and homologous recombination repair (HRR) gene point mutations have prognostic value, which may be related to the limited number of mutated genes that may not provide prognostic information for complex cancers such as pancreatic cancer
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Secondly, this study used a combination of unsupervised clustering and CNV score stratification to divide PAAD patients into four molecular subtypes, including repair defects, active proliferation, repair intact, and repair enhancement.
Among them, repair defect type and proliferation active type Patients with DNA damage are more suitable for DNA damage treatment, and immunotherapy is strongly recommended for patients with intact repair type and enhanced repair type
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In addition, four molecular subtypes were verified using the TCGA-PAAD cohort
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Finally, we constructed a prognostic model that stratifies patients according to the risk of recurrence, which helps to identify patients at high risk of recurrence early
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In addition, the results of the study confirmed that there are differences in the tumor microenvironment between PAAD patients with high-risk or low-risk prognosis scores.
In the TCGA cohort, low-risk patients have more beneficial tumor microenvironments than high-risk patients
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The study describes a comprehensive resource involving the genetic variation of 608 PAAD patients.
This is the largest cohort study in China's history, and it is all collected in one center
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The genetic changes outlined include somatic mutations, copy number variation (CNV) and many others.
They provide evidence that, instead of using somatic mutations, only CNV information on DNA repair and receptor tyrosine kinase-related genes can be used to treat patients.
Divided into prognostic information subtypes
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They further showed that prognostic models based on these genes can predict patients with low or high risk of recurrence
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This study emphasizes the importance of molecular classification to guide the treatment of PAAD patients: repair-deficient and proliferatively active patients are more suitable for DNA damage treatment, while immunotherapy is strongly recommended for repair intact and repair-enhanced patients
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Shen Baiyong, chief physician of Pancreatic Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, researcher Fang Hai of the National Center for Translational Medicine (Shanghai), chief physician Wang Chaofu of the Department of Pathology, and researcher Zhang Henghui of Zhenhe Technology are the co-corresponding authors of this article
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Deputy Chief Physician Zhan Qian of Pancreatic Surgery, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Attending Physician Wen Chenlei, and Dr.
Zhao Yi from Zhenhe Technology are the co-first authors of this article
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Expert CommentPancreatic Cancer: Targeted Therapy Is Expected to Be Realized On December 16, 2021, Professor Li Min from the University of Oklahoma Health Science Center and Chairman of the American Society of Pancreatic Diseases published the title "Pancreatic Cancer: Targeted Therapy Holds the Promise" in the same journal "Review
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Pancreatic cancer is one of the deadliest cancers.
The five-year survival rate of patients is less than 10%.
The demand for treatment of this devastating disease has not yet been met
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The molecular classification of pancreatic cancer can help us understand the heterogeneity between and within tumors, and ultimately achieve precise treatment
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Dysregulation of genome integrity and transcriptome recombination play an important role in tumorigenesis
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Homologous recombination (HR), as a member of the DNA damage repair (DDR) pathway, is essential for maintaining genome integrity
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The deletion of germline or system HR genes (such as ATM, BRCA1, BRCA2) can lead to HR defects, also known as BRCA-like (BRCAness), which ultimately leads to accumulation of DNA damage and tumor formation
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Transcriptome profiling studies have improved our understanding of the molecular subtypes of pancreatic cancer, but the copy number variation of the HR pathway in pancreatic cancer remains unclear
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Recently, Zhan Qian, deputy chief physician of Pancreatic Surgery, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, and attending physician Wen Chenlei, published important work on EBioMedicine to evaluate pancreatic cancer patients' genome mutations, especially HR pathway copy number mutations, and The relationship between prognosis
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Studies have found that gene amplification of HR and RTK-related signaling indicates a poor prognosis
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Using unsupervised clustering method, PAAD patients were divided into two cohorts (CNV-G1, CNV-G2) for repairing defects in homologous recombination and repairing complete homologous recombination
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The author further analyzed the differentially expressed genes of the two queues and established a CNV scoring algorithm to more accurately divide patients into four subtypes, including repair defect type (CNV-G1+CNV low score) and proliferative active type (CNV-G1).
+CNV high score), repair complete type (CNV-G2+CNV low score), repair enhanced type (CNV-G2+CNV high score)
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Repair defective subtypes have the best prognosis and may respond strongly to PARP inhibitors, while repair enhanced and repaired intact types show higher tumor mutation burden (TMB), and immunotherapy is strongly recommended
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The significance of this study lies in the in-depth analysis of the CNV panorama and the role of HR gene CNV in the heterogeneity of pancreatic cancer between tumors and within tumors
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There is ample evidence that this model can be used as an alternative biomarker for predicting the efficacy of PARP inhibitors
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Moreover, the newly constructed molecular subtypes may help patients with pancreatic cancer formulate individualized treatment plans
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Based on the POLO study, the U.
S.
Food and Drug Administration (FDA) has approved the PARP inhibitor olaparib as the first-line treatment for patients with metastatic pancreatic cancer carrying germline BRCA mutations (gBRCA), which can provide personalized medicine for pancreatic cancer patients.
Especially patients with specific mutations such as harmful gBRCA mutations
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It is worth noting that olaparib response heterogeneity is widespread in gBRCA mutant patients, suggesting that other germline mutations may also cause heterogeneity
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Chromosomal imbalance can cause genome instability
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Four subtypes of chromosome rearrangement have been identified, local rearrangement, dispersion, stability, and instability.
Among them, the incidence of chromosomal instability subtypes in pancreatic cancer is 14%
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Most "stable" tumors exhibit an imbalance in the number of chromosomes, also known as aneuploidy, which is related to reduced immune infiltration and suppression of immune surveillance
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Unstable subtypes are characterized by instability of the genome, suggesting a defect in the DDR pathway
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Interestingly, most unstable tumors exhibit harmful BRCA mutations and respond better to PARP inhibitors than stable ones
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This classification also partially explains that chromosomal imbalance will increase the heterogeneity between tumors caused by HR defects
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In addition, pre-existing intratumoral heterogeneity may lead to treatment resistance
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Basal-like and classic pancreatic cancer cells can coexist in the same tumor sample
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Through the analysis of the evolutionary trajectory of mutation KRAS copy number changes, it is confirmed that KRAS imbalance is a key event that drives genome doubling and instability, which may lead to pancreatic cancer or cause the classic type to become basal-like
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The plasticity between subtypes leads to spatial heterogeneity, which emphasizes the need to further study the evolutionary trajectory of specific copy number changes in cell lineages
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Although this study did not detect an increase in TMB in repair-deficient patients, emerging data shows that HR deficiency can improve the response of immunotherapy
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For example, patients with BRCA2 mutations show better immunotherapy benefits
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The lack of ATM can restore innate immune monitoring and improve the efficacy of immunotherapy
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It is worth noting that among the HR genes, the ATM mutation rate is the highest (3.
45% in this study), which is consistent with the 4% data previously reported for sporadic pancreatic cancer
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Absence of ATM will increase the risk of intraductal papillary myxoma (IPMN) in patients with pancreatic cancer
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These conclusions provide a basis for the study of HR-deficient pancreatic cancer patients
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There have been some phase I/II clinical trials evaluating the efficacy of PARP inhibitors combined with immunotherapy (NCT03404960, NCT03637491)
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All in all, this study further confirms that pancreatic cancer patients with HR deficiency are more likely to benefit from PARP inhibitors
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Combining genomic mutations and mathematical algorithms, a novel prognostic model was constructed to screen pancreatic cancer patients who are more likely to benefit from PARP inhibitors and immunotherapy
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This CNV model combined with some of the most advanced technologies such as liquid biopsy and single-cell sequencing may change the rules of individualized treatment and ultimately translate into the clinical benefits of this devastating malignant tumor
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Welfare Postdoctoral recruitment notice for the Pancreas Center of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine https://