Current status of the molecular genetics of human prostatic adenocarcinomas

Molecular genetic mechanisms involved in the progression of prostate cancer are not well understood due to extensive tumor heterogeneity and lack of suitable models. New methods such as fluorescence in-situ hybridization (FISH), comparative genomic hybridization (CGH) and microsatellite analysis have documented losses or gains on various chromosomes. Altered chromosomal regions have been associated with the activation of oncogenes and the inactivation of tumor suppressor genes or defects in mismatch repair (MMR) genes. It is suggested that increased genomic instability is associated with decreased androgen-responsive and progressive behavior of human prostate tumors, but it remains unclear whether this genomic instability is causing the progression of cancer or is the consequence of cancer. Extended studies on hereditary prostate cancer have identified 7 prostate cancer susceptibility loci on several chromosomes, but no specific gene has been confined for a large proportion of susceptibility. In this review we summarize the ongoing molecular genetic events associated with the sporadic and hereditary prostate cancer development and progression.     

Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer

Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation.     

Defective DNA strand break repair after DNA damage in prostate cancer cells: implications for genetic instability and prostate cancer progression

Together with cell cycle checkpoint control, DNA repair plays a pivotal role in protecting the genome from endogenous and exogenous DNA damage. Although increased genetic instability has been associated with prostate cancer progression, the relative role of DNA double-strand break repair in malignant versus normal prostate epithelial cells is not known. In this study, we determined the RNA and protein expression of a series of DNA double-strand break repair genes in both normal (PrEC-epithelial and PrSC-stromal) and malignant (LNCaP, DU-145, and PC-3) prostate cultures. Expression of genes downstream of ATM after ionizing radiation-induced DNA damage reflected the p53 status of the cell lines. In the malignant prostate cell lines, mRNA and protein levels of the Rad51, Xrcc3, Rad52, and Rad54 genes involved in homologous recombination were elevated approximately 2- to 5-fold in comparison to normal PrEC cells. The XRCC1, DNA polymerase-beta and -delta proteins were also elevated. There were no consistent differences in gene expression relating to the nonhomologous end-joining pathway. Despite increased expression of DNA repair genes, malignant prostate cancer cells had defective repair of DNA breaks, alkali-labile sites, and oxidative base damage. Furthermore, after ionizing radiation and mitomycin C treatment, chromosomal aberration assays confirmed that malignant prostate cells had defective DNA repair. This discordance between expression and function of DNA repair genes in malignant prostate cancer cells supports the hypothesis that prostate tumor progression may reflect aberrant DNA repair. Our findings support the development of novel treatment strategies designed to reinstate normal DNA repair in prostate cancer cells.     

Genetic variation in DNA repair genes and prostate cancer risk: results from a population-based study

Objective  

DNA repair pathways are crucial to prevent accumulation of DNA damage and maintain genomic stability. Alterations of this pathway have been reported in many cancers. An increase in oxidative DNA damage or decrease in DNA repair capacity with aging or due to germline genetic variation may affect prostate cancer risk.     

Clonal heterogeneity influences drug responsiveness in renal cancer assessed by ex vivo drug testing of multiple patient-derived cancer cells

Renal cell cancer (RCC) has become a prototype example of the extensive intratumor heterogeneity and clonal evolution of human cancers. However, there is little direct evidence on how the genetic heterogeneity impacts on drug response profiles of the cancer cells. Our goal was to determine how genomic clonal evolution impacts drug responses. Finding from our study could help to define the challenge that clonal evolution poses on cancer therapy. We established multiple patient-derived cells (PDCs) from different tumor regions of four RCC patients, verified their clonal relationship to each other and to the uncultured tumor tissue by genome sequencing. Furthermore, comprehensive drug-sensitivity testing with 460 oncological drugs was performed on all PDC clones. The PDCs retained many cancer-specific copy number alterations and mutations in driver genes such as VHL, PBRM1, PIK3C2A, KMD5C and TSC2 genes. The drug testing highlighted vulnerability in the PDCs toward approved RCC drugs, such as the mTOR-inhibitor temsirolimus, but also novel sensitivities were uncovered. The individual PDC clones from different tumor regions in a patient showed distinct drug–response profiles, suggesting that genomic heterogeneity contributes to the variability in drug responses. Studies of multiple PDCs from a patient with cancer are informative for elucidating cancer heterogeneity and for the determination on how the genomic evolution is manifested in cancer drug responsiveness. This approach could facilitate tailoring of drugs and drug combinations to individual patients.     

Plasma genetic and genomic abnormalities predict treatment response and clinical outcome in advanced prostate cancer

Liquid biopsies, examinations of tumor components in body fluids, have shown promise for predicting clinical outcomes. To evaluate tumor-associated genomic and genetic variations in plasma cell-free DNA (cfDNA) and their associations with treatment response and overall survival, we applied whole genome and targeted sequencing to examine the plasma cfDNAs derived from 20 patients with advanced prostate cancer. Sequencing-based genomic abnormality analysis revealed locus-specific gains or losses that were common in prostate cancer, such as 8q gains, AR amplifications, PTEN losses and TMPRSS2-ERG fusions. To estimate tumor burden in cfDNA, we developed a Plasma Genomic Abnormality (PGA) score by summing the most significant copy number variations. Cox regression analysis showed that PGA scores were significantly associated with overall survival (p < 0.04). After androgen deprivation therapy or chemotherapy, targeted sequencing showed significant mutational profile changes in genes involved in androgen biosynthesis, AR activation, DNA repair, and chemotherapy resistance. These changes may reflect the dynamic evolution of heterozygous tumor populations in response to these treatments. These results strongly support the feasibility of using non-invasive liquid biopsies as potential tools to study biological mechanisms underlying therapy-specific resistance and to predict disease progression in advanced prostate cancer.     

Maintenance of genomic integrity after DNA double strand breaks in the human prostate and seminal vesicle epithelium: The best and the worst

Prostate cancer is one of the most frequent cancer types in men, and its incidence is steadily increasing. On the other hand, primary seminal vesicle carcinomas are extremely rare with less than 60 cases reported worldwide. Therefore the difference in cancer incidence has been estimated to be more than a 100,000-fold. This is astonishing, as both tissues share similar epithelial structure and hormonal cues. Clearly, the two epithelia differ substantially in the maintenance of genomic integrity, possibly due to inherent differences in their DNA damage burden and DNA damage signaling. The DNA damage response evoked by DNA double strand breaks may be relevant, as their faulty repair has been implicated in the formation of common genomic rearrangements such as TMPRSS2-ERG fusions during prostate carcinogenesis. Here, we review DNA damaging processes of both tissues with an emphasis on inflammation and androgen signaling. We discuss how benign prostate and seminal vesicle epithelia respond to acute DNA damage, focusing on the canonical DNA double strand break-induced ATM-pathway, p53 and DNA damage induced checkpoints. We propose that the prostate might be more prone to the accumulation of genetic aberrations during epithelial regeneration than seminal vesicles due to a weaker ability to enforce DNA damage checkpoints.     

Polymorphisms in the XRCC1 gene modify survival of bladder cancer patients treated with chemotherapy

Survival of bladder cancer patients depends on several factors including disease stage and grade at diagnosis, age, health status of the patient and the applied treatment. Several studies investigated the role of DNA repair genetic variants in cancer susceptibility, but only few studies investigated their role in survival and response to chemotherapy for bladder cancer. We genotyped 28 single nucleotide polymorphisms (SNP) in DNA repair genes in 456 bladder cancer patients, reconstructed haplotypes and calculated a score for combinations of the SNPs. We estimated Hazard Ratios (adjHR) for time to death. Among patients treated with chemotherapy, variant alleles of five SNPs in the XRCC1 gene conferred better survival (rs915927 adjHR 0.55 (95%CI 0.32–0.94); rs76507 adjHR 0.48 (95%CI 0.27–0.84); rs2854501 adjHR 0.25 (95%CI 0.12–0.52); rs2854509 adjHR 0.21 (95%CI 0.09–0.46); rs3213255 adjHR 0.46 (95%CI 0.26–0.80). In this group of patients, an increasing number of variant alleles in a XRCC1 gene score were associated with a better survival (26% decrease of risk of death for each additional variant allele in XRCC1). By functional analyses we demonstrated that the previous XRCC1 SNPs confer lower DNA repair capacity. This may support the hypothesis that survival in these patients may be modulated by the different DNA repair capacity determined by genetic variants. Chemotherapy treated cancer patients bearing an increasing number of “risky” alleles in XRCC1 gene had a better survival, suggesting that a proficient DNA repair may result in resistance to therapy and shorter survival. This finding may have clinical implications for the choice of therapy.     

Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G₁, G₁/S, G₂, and G₂/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.     

Polymorphisms of the DNA Mismatch Repair Gene <Emphasis Type="BoldItalic">HMSH2</Emphasis> in Breast Cancer Occurence and Progression

Summary The response of the cell to DNA damage and its ability to maintain genomic stability by DNA repair are crucial in preventing cancer initiation and progression. Therefore, polymorphism of DNA repair genes may affect the process of carcinogenesis. The importance of genetic variability of the components of mismatch repair (MMR) genes is well documented in colorectal cancer, but little is known about its role in breast cancer. hMSH2 is one of the crucial proteins of MMR. We performed a case-control study to test the association between two polymorphisms in the hMSH2 gene: an A → G transition at 127 position producing an Asn → Ser substitution at codon 127 (the Asn127Ser polymorphism) and a G → A transition at 1032 position resulting in a Gly → Asp change at codon 322 (the Gly322Asp polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 age-matched women (controls) by restriction fragment length polymorphism and allele-specific PCR. We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom-Richardson grading. A strong association between breast cancer occurrence and the Gly/Gly phenotype of the Gly322Asp polymorphism (odds ratio 8.39; 95% confidence interval 1.44–48.8) was found. Therefore, MMR may play a role in the breast carcinogenesis and the Gly322Asp polymorphism of the hMSH2 gene may be considered as a potential marker in breast cancer.     

The interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies

P53 suppresses tumorigenesis through multiple cellular functions/mechanisms, including genomic stability surveillance. Recently, it has also be reported for its role in cancer immune response modulation. Deficiency in DNA repair pathways lead to the accumulation of genomic alterations and tumor mutation burden and in consequence resulting in the activation of immune response. We investigated the interaction of p53 and DNA repair gene mutations and their impact on tumor mutation burden and immune response in human malignancies by mining cBioPortal data of a range of human cancers. We found that in the majority of human cancers, p53 mutations are equally distributed between DNA repair gene mutation positive and negative cases and in a number of human cancers, p53 and DNA repair gene mutations have a tendency of co-occurrence. Only in colorectal cancer, there is a tendency of ‘mutual exclusivity’ of mutations in p53 and DNA repair genes. In most tumors, p53 and DNA repair gene mutations have synergistic/additive effect in increasing tumor mutation burden, but not in colorectal cancer where they are mutually exclusive. The impact of p53 and DNA repair gene mutations and their interaction on tumor microenvironment immune cells are complex and tumor type specific and not always correlated with tumor mutation burden. In colorectal cancers, these two types of mutations resulted in similar immune cell subpopulation changes and in tumors where the mutations have a tendency of co-occurrence, p53 showed dominant roles on immune response, although they can also counter-act each other for their effect on certain immune cell subtypes.     

A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer

DNA repair is central to genomic integrity. Reduced expression of several nucleotide excision repair genes has been demonstrated to be associated with increased risk of lung cancer. Because methylation of gene promoters is one of the major regulatory mechanisms of gene expression and most nucleotide excision repair gene promoters have not been fully characterized, we hypothesized that genetic variants of the genes that are responsible for regulating genomic methylation are associated with increased risk of lung cancer. Recently, we identified a C-->T transition at a novel promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and found that this polymorphic transition significantly increases the promoter activity. In this hospital-based case-control study of 319 patients with incident lung cancer and 340 healthy controls frequency matched on age (+/-5 years), sex, ethnicity, and smoking status, we genotyped subjects for this DNMT3B promoter polymorphism to determine the association between this genetic variant and risk of lung cancer. Compared with CC homozygotes, CT heterozygotes had a >2-fold increased risk of lung cancer [adjusted odds ratio (OR), 2.13; 95% confidence interval (CI), 1.47-3.08] and TT homozygotes an OR of 1.42 (95% CI, 0.91-2.21). The combined variant genotype (CT + TT) was associated with a nearly 2-fold increased risk (adjusted OR, 1.88; 95% CI, 1.32-2.66). These results suggest that this novel variant of DNMT3B is associated with increased risk of lung cancer and may contribute to identifying individuals genetically susceptible to tobacco-induced cancers. Additional studies on the underlying molecular mechanism of this polymorphism are warranted.     

PARP抑制剂治疗去势抵抗性前列腺癌的研究进展北大核心

近年来随着基因组测序研究的进展使恶性肿瘤的精准治疗不断深入。针对合并特定的DNA损伤修复基因(DNA repair genes,DRGs)突变,包括同源重组介导修复(homologous recombin-mediated repair,HRR)基因突变的前列腺癌症患者,多聚腺苷酸二磷酸核糖聚合酶抑制剂(Poly ADP-ribose polymerase inhibitor,PARPi)可通过抑制DNA的修复介导存在该类基因突变的肿瘤细胞死亡。自2014年PARP抑制剂被首先批准用于晚期卵巢癌以来,针对DNA损伤修复基因突变和PARPi的研究不断进行,如今PARPi在前列腺癌患者尤其是转移性去势抵抗性前列腺癌(mCRPC)的治疗中表现不俗。本文就PARPi在mCRPC患者中的应用作一综述,对已发表和正在进行的临床试验结果进行讨论,为前列腺癌患者的个性化治疗提供更好的临床证据。     

Relevance of DNA damage repair in the management of prostate cancer

Recent insights into the genomic aberrations that underlie and drive prostate cancer have redoubled efforts to molecularly stratify treatments based on predictive markers. Approximately 23% of patients with metastatic castration-resistant prostate cancer exhibit somatic or germline aberrations in genes implicated in DNA repair, such as BRCA2, BRCA1, ATM, CHEK2, and PALB2, as well as mismatch repair genes. At least 10% of men with advanced disease have germline mutations in DNA-repair genes (DRG). The enrichment of DRG defects in metastatic disease compared with localized, primary tumors suggests a possible role in carcinogenesis, disease progression, and potentially accounts for a more aggressive phenotype. Germline BRCA2-mutant prostate cancer is more likely to present with advanced disease, higher Gleason score, and exhibit poorer survival than noncarriers. Very little is currently known about the clinicopathological features of prostate cancer associated with rarer DRG variants. It is currently unknown whether germline carriers of DRG mutations would benefit from additional screening strategies or more intensive treatment of localized prostate cancer. Defective DNA repair may have profound therapeutic implications for advanced disease, conferring tumor-specific vulnerability to poly(ADP-ribose) polymerase inhibitors, platinum chemotherapy, or immunotherapy that can be exploited for clinical benefit. Pertinent issues regarding cancer risk, screening recommendations and risk reduction strategies for carriers of poorly characterized DRG variants remains to be defined. We review the prevalence and potential clinical implications of DNA damage repair defects in prostate cancer. The broader promise and challenge of implementing this knowledge into clinical practice is also discussed.     

Whole genome sequencing of melanomas in adolescent and young adults reveals distinct mutation landscapes and the potential role of germline variants in disease susceptibility

Cutaneous melanoma accounts for at least >10% of all cancers in adolescents and young adults (AYA, 15–30 years of age) in Western countries. To date, little is known about the correlations between germline variants and somatic mutations and mutation signatures in AYA melanoma patients that might explain why they have developed a cancer predominantly affecting those over 65 years of age. We performed genomic analysis of 50 AYA melanoma patients (onset 10–30 years, median 20); 25 underwent whole genome sequencing (WGS) of both tumor and germline DNA, exome data were retrieved from 12 TCGA AYA cases, and targeted DNA sequencing was conducted on 13 cases. The AYA cases were compared with WGS data from 121 adult cutaneous melanomas. Similar to mature adult cutaneous melanomas, AYA melanomas showed a high mutation burden and mutation signatures of ultraviolet radiation (UVR) damage. The frequencies of somatic mutations in BRAF (96%) and PTEN (36%) in the AYA WGS cohort were double the rates observed in adult melanomas (Q < 6.0 × 10⁻⁶ and 0.028, respectively). Furthermore, AYA melanomas contained a higher proportion of non-UVR-related mutation signatures than mature adult melanomas as a proportion of total mutation burden (p = 2.0 × 10⁻⁴). Interestingly, these non-UVR mutation signatures relate to APOBEC or mismatch repair pathways, and germline variants in related genes were observed in some of these cases. We conclude that AYA melanomas harbor some of the same molecular aberrations and mutagenic insults occurring in older adults, but in different proportions. Germline variants that may have conferred disease susceptibility correlated with somatic mutation signatures in a subset of AYA melanomas.     

Next-generation sequencing of prostate cancer: genomic and pathway alterations,potential actionability patterns,and relative rate of use of clinical-grade testing

Despite being one of the most common cancers, treatment options for prostate cancer are limited. Novel approaches for advanced disease are needed. We evaluated the relative rate of use of clinical-grade next generation sequencing (NGS) in prostate cancer, as well as genomic alterations identified and their potential actionability. Of 4864 patients from multiple institutions for whom NGS was ordered by physicians, only 67 (1.4%) had prostate cancer, representing 1/10 the ordering rate for lung cancer. Prostate cancers harbored 148 unique alterations affecting 63 distinct genes. No two patients had an identical molecular portfolio. The median number of characterized genomic alterations per patient was 3 (range, 1 to 9). Fifty-six of 67 patients (84%) had ≥ 1 potentially actionable alteration. TMPRSS2 fusions affected 28.4% of patients. Genomic aberrations were most frequently detected in TP53 (55.2% of patients), PTEN (29.9%), MYC (17.9%), PIK3CA (13.4%), APC (9.0%), BRCA2 (9.0%), CCND1 (9.0%), and RB1 genes (9.0%). The PI3K (52.2% of patients), WNT (13.5%), DNA repair (17.9%), cell cycle (19.4%), and MAPK (14.9%) machinery were commonly impacted. A minority of patients harbored BRAF, NTRK, ERBB2, or mismatch repair gene abnormalities, which are highly druggable in some cancers. Only ~ 10% of prostate cancer trials (clinicaltrials.gov, year 2017) applied a (non-hormone) biomarker before intervention. In conclusion, though use of clinical-grade NGS is relatively low and only a minority of trials deploy DNA-based biomarkers, many prostate cancer-associated molecular alterations may be pharmacologically tractable with genomcially targeted therapy or, in the case of mismatch repair anomalies, with checkpoint inhibitor immunotherapy.     

Polymorphisms in DNA repair genes and associations with cancer risk.

Common polymorphisms in DNA repair genes may alter protein function and an individual's capacity to repair damaged DNA; deficits in repair capacity may lead to genetic instability and carcinogenesis. To establish our overall understanding of possible in vivo relationships between DNA repair polymorphisms and the development of cancer, we performed a literature review of epidemiological studies that assessed associations between such polymorphisms and risk of cancer. Thirty studies of polymorphisms in OGG1, XRCC1, ERCC1, XPC, XPD, XPF, BRCA2, and XRCC3 were identified in the April 30, 2002 MEDLINE database (National Center for Biotechnology Information. PubMed Database: http://www.ncbi.nlm.nih.gov/entrez). These studies focused on adult glioma, bladder cancer, breast cancer, esophageal cancer, lung cancer, prostate cancer, skin cancer (melanoma and nonmelanoma), squamous cell carcinoma of the head and neck, and stomach cancer. We found that a small proportion of the published studies were large and population-based. Nonetheless, published data were consistent with associations between: (a) the OGG1 S326C variant and increased risk of various types of cancer; (b) the XRCC1 R194W variant and reduced risk of various types of cancer; and (c) the BRCA2 N372H variant and increased risk of breast cancer. Suggestive results were seen for polymorphisms in other genes; however, small sample sizes may have contributed to false-positive or false-negative findings. We conclude that large, well-designed studies of common polymorphisms in DNA repair genes are needed. Such studies may benefit from analysis of multiple genes or polymorphisms and from the consideration of relevant exposures that may influence the likelihood of cancer in the presence of reduced DNA repair capacity.     

Genomic alterations in tumor tissue and ctDNA from Chinese pancreatic cancer patients

Though the genomic feature of pancreatic cancer has been comprehensively studied in western patients, the genetic feature of Chinese patients is poorly clarified. In this study, a total of 225 pancreatic cancer patients were enrolled, mainly pancreatic ductal adenocarcinoma (PDAC, 97.33%). 140 patients (62.22%) provided sufficient tumor tissues for genomic analysis, and the rest (37.78%) were provided serum instead. Utilizing target next-generation sequencing (NGS), we analyzed genomic alterations of 618 selected genes. Corresponding data in the TCGA database were also analyzed here. In total, 26 (11.61%) patients had pathogenic or likely pathogenic germline variants, mainly (84.62%) involved genes in the DNA damage repair (DDR) pathway. The mean and median counts of somatic alterations per sample were 6.28 and 5, respectively. The most frequently mutated genes in our cohort were KRAS, TP53, CDKN2A, SMAD4, FBXW7 and ARID1A, revealing a significantly different prevalence of genes including KRAS, CDKN2A, ARID1A, NOTCH1, ARID1B than the corresponding data in the TCGA database. 39.11% of patients were identified with actionable alteration and the ratio was not significantly different between tissue and serum samples. 22.67% of patients harbored DDR gene alterations, which were associated with a higher tumor mutation burden. We also found that all the DDR alterations were not correlated with the overall survival and immune and stroma score, but the changes in NK cells and follicular T cells were identified in samples with DDR changes according to TCGA database. In summary, we identified a distinct genomic feature of Chinese pancreatic cancer patients by comparing with the data in TCGA database, and suggested the role for genetic testing using tissue or ctDNA samples in decision-making process. DDR alterations were associated with a higher tumor mutation burden and the significantly higher counts of NK cells in DDR altered samples may raise the attention in future related drugs development.