Unique Genomic Landscape Research Articles

Genomic insights into molecular profiling of thymic carcinoma: a narrative review.

Thymic carcinoma is an exceptionally rare cancer, with an annual incidence of just 0.15-0.29 per 100,000 people. Owing to its rarity, only few proven treatments have been developed. Understanding its genetic profile is crucial for the development of targeted therapies. However, limited studies have exclusively examined thymic carcinoma mutations, with most investigation combining thymomas and thymic carcinomas. This paper reviews findings from genetic studies focusing on thymic carcinoma alone and compares them to those of thymoma. We conducted a PubMed search for relevant English studies on thymic carcinoma genomics. Then, key papers utilizing target sequencing or whole-exome sequencing were analyzed. The most frequently mutated genes were TP53, CDKN2A, CDKN2B, CYLD, KIT, TET2, SETD2, BAP1, and ASXL1. TP53 and CDKN2A are correlated with poor prognosis. CYLD, which regulates signaling related with proliferation and interacts with AIRE expression and T cell development, might predict the immunotherapy response. KIT mutations might enable targeted therapy. TET2, SETD2, BAP1, and ASXL1 regulate epigenetics, suggesting disruption of these mechanisms. Higher tumor mutational burden (TMB) and 16q loss distinguish thymic carcinoma from thymoma. Although some copy number aberrations are shared, thymic carcinoma exhibits a mutational profile distinct from that of thymoma. Thymic carcinoma demonstrates a unique genomic landscape, suggesting a molecular pathogenesis distinct from that of thymoma. Our findings revealed prognostic biomarkers such as TP53/CDKN2A and potential therapeutic targets such as KIT. Because thymic carcinoma is extremely rare, sharing molecular profiling data could provide valuable insights into the molecular mechanisms driving the development of these tumors.

OTHR-30. THE CLINICAL AND BIOLOGICAL LANDSCAPE OF CNS CANCERS IN CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY: AN IRRDC COHORT STUDY

Abstract BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is an aggressive cancer predisposition syndrome. As a lack of data contributes to management challenges and inferior outcomes, especially in central nervous system (CNS) cancers, we aimed to determine the clinical spectrum, cancer biology, and impact of genetics on patient survival. METHODS To determine the cancer spectrum, biology, estimated incidence, and impact of genotype on cancer onset and survival, including following surveillance and immunotherapy, we collected cross-sectional, longitudinal, and genomic data on CMMRD patients and their cancers registered to an international consortium. RESULTS We report 201 patients enrolled between 2007-2022 (median follow-up: 7.2 years). Overall, 194 (97%) patients developed 339 cancers. Cumulative cancer and CNS tumor incidence were 93% and 82% by age 20, respectively. Median time between cancers was 2 years. Although neoplasms developed in 15 organs and included early-onset adult cancers, CNS tumors had the earliest median age of diagnosis (9.7 years), were the most common cancer type (51%), and the main cause of death (p<0.0001). All cancers exhibited high mutation and microsatellite burden, and pathognomonic mutational signatures. CNS cancers were enriched for mutations in POLE/POLD1, TP53, IDH1, and RAS/MAPK compared to hematopoietic and other cancers. These mutations determined response to therapy. Germline MLH1/MSH2 variants caused earlier cancer and CNS tumor onset than PMS2/MSH6, and inferior survival (survival at 15 years: PMS2: 63%, MSH6: 49%, MLH1: 19%, MSH2: 0%, p<0.0001). Strikingly, frameshift/truncating variants within the same gene caused earlier cancers and inferior outcomes (p<0.0001). The deleterious impact of MLH1/MSH2 persisted despite overall improvement in survival following surveillance and immunotherapy. CONCLUSION The extreme cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis focusing on specific genotypes to perform precision approaches toward surveillance and immunotherapy. These data will guide the management of children and emerging adult survivors of CMMRD.

Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Immunotherapy guided precision medicine in solid tumors.

Cancer is no longer recognized as a single disease but a collection of diseases each with its defining characteristics and behavior. Even within the same cancer type, there can be substantial heterogeneity at the molecular level. Cancer cells often accumulate various genetic mutations and epigenetic alterations over time, leading to a coexistence of distinct subpopulations of cells within the tumor. This tumor heterogeneity arises not only due to clonal outgrowth of cells with genetic mutations, but also due to interactions of tumor cells with the tumor microenvironment (TME). The latter is a dynamic ecosystem that includes cancer cells, immune cells, fibroblasts, endothelial cells, stromal cells, blood vessels, and extracellular matrix components, tumor-associated macrophages and secreted molecules. The complex interplay between tumor heterogeneity and the TME makes it difficult to develop one-size-fits-all treatments and is often the cause of therapeutic failure and resistance in solid cancers. Technological advances in the post-genomic era have given us cues regarding spatial and temporal tumor heterogeneity. Armed with this knowledge, oncologists are trying to target the unique genomic, epigenetic, and molecular landscape in the tumor cell that causes its oncogenic transformation in a particular patient. This has ushered in the era of personalized precision medicine (PPM). Immunotherapy, on the other hand, involves leveraging the body's immune system to recognize and attack cancer cells and spare healthy cells from the damage induced by radiation and chemotherapy. Combining PPM and immunotherapy represents a paradigm shift in cancer treatment and has emerged as a promising treatment modality for several solid cancers. In this chapter, we summarise major types of cancer immunotherapy and discuss how they are being used for precision medicine in different solid tumors.

Distinct evolution of ST11 KL64 Klebsiella pneumoniae in Taiwan.

Carbapenem-resistant ST11_KL64 Klebsiella pneumoniae emerged as a significant public health concern in Taiwan, peaking between 2013 and 2015, with the majority of isolates exhibiting OXA-48 as the sole carbapenemase. In this study, we employed whole-genome sequencing to investigate the molecular underpinnings of ST11_KL64 isolates collected from 2013 to 2021. Phylogenomic analysis revealed a notable genetic divergence between the ST11_KL64 strains in Taiwan and those in China, suggesting an independent evolutionary trajectory. Our findings indicated that the ST11_KL64_Taiwan lineage originated from the ST11_KL64 lineage in Brazil, with recombination events leading to the integration of ICEKp11 and a 27-kb fragment at the tRNAASN sites, shaping its unique genomic landscape. To further elucidate this unique sublineage, we examined the plasmid contents. In contrast to ST11_KL64_Brazil strains, which predominantly carried blaKPC-2, ST11_KL64_Taiwan strains exhibited the acquisition of an epidemic blaOXA-48-carrying IncL plasmid. Additionally, ST11_KL64_Taiwan strains consistently harbored a multi-drug resistance IncC plasmid, along with a collection of gene clusters that conferred resistance to heavy metals and the phage shock protein system via various Inc-type plasmids. Although few, there were still rare ST11_KL64_Taiwan strains that have evolved into hypervirulent CRKP through the horizontal acquisition of pLVPK variants. Comprehensive characterization of the high-risk ST11_KL64 lineage in Taiwan not only sheds light on its epidemic success but also provides essential data for ongoing surveillance efforts aimed at tracking the spread and evolution of ST11_KL64 across different geographical regions. Understanding the molecular underpinnings of CRKP evolution is crucial for developing effective strategies to combat its emergence and dissemination.

CDH1-mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).

4587 Background: CDH1 mutated bladder cancers are characterized by plasmacytoid histology and are associated with an aggressive clinical course. Methods: Cohort 1: 6,676 clinically advanced UBC patients underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) as well as microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Tumor cell PD-L1 expression was determined by immunohistochemistry (Dako 22C3). GAs were compared between CDH1 mutated and wild-type (WT) patients using Chi-square. Cohort 2: 586 UBC patients underwent a RWCOS using the de-identified Flatiron Health-Foundation Medicine urothelial clinicogenomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) between January 2011 and April 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 UBC patients featured a CDH1 short variant mutation with 65.2% featuring plasmacytoid histology (PLC). The PLC cohort was slightly younger, with a higher proportion of male patients, and MSI-High status. Cell-Cycle regulatory GAs were significantly higher in the non-PLC cohort, specifically CDKN2A (25.5% vs 9.7%, p=0.01) and CDKN2B (23.6% vs 5.8%, p&lt;0.01). CDH1-mutated UBCs featured a higher MSI high frequency (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9mut/Mb p&lt;.0001), RB1 GA (52.5% vs 20.3%; p&lt;.0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but lower gLOH (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p&lt;.0001), MTAP loss (10.1% vs 25.1%; p&lt;.0001), and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GAs and PD-L1 expression levels were similar between groups. From cohort 2: 22 (3.7%) patients featured CDH1 mutations. When compared with the CDH1 WT patients, the age, gender, ethnicity and ECOG status were similar. CDH1 mutation was associated with less favorable outcomes for 270 UBC patients treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC patients treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months; p=.11) and rwOS (13.4 vs 13.4 months; p=0.83). Conclusions: In addition to its classic association with PLC histology, CDH1-mutated UBC features an unique genomic landscape including higher MSI and TMB, activating GAs in the MTOR pathway, but lower frequency of FGFR3 GAs. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatment, but does not systemic chemotherapy. These findings support CGP to guide therapeutic approaches based on the personalized genomic signature of UBC.

PD04-02 USING GENOMIC AND TRANSCRIPTOMIC PROPERTIES TO DETERMINE ANDROGEN RESPONSE IN DUCTAL PROSTATE CANCERS AND DETERMINE EFFICACY OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS WITH ANDROGEN SIGNALLING INHIBITORS THERAPY IN VITRO

You have accessJournal of UrologyCME1 Apr 2023PD04-02 USING GENOMIC AND TRANSCRIPTOMIC PROPERTIES TO DETERMINE ANDROGEN RESPONSE IN DUCTAL PROSTATE CANCERS AND DETERMINE EFFICACY OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS WITH ANDROGEN SIGNALLING INHIBITORS THERAPY IN VITRO Weranja Ranasinghe, Melbourne, Australia Patricia Troncoso, Mitchell Lawrence, Nicholas Choo, Birunthi Niranjan, Melissa Papargiris, Hong Wang, Andrew Ryan, Peter Shepherd, Bradley Broom, Ganiraju Manyam, Renea Taylor, Timothy Thompson, Nora Navone, Gail Risbridger, and Brian Chapin Weranja RanasingheWeranja Ranasinghe More articles by this author , Melbourne, Australia Patricia TroncosoMelbourne, Australia Patricia Troncoso More articles by this author , Mitchell LawrenceMitchell Lawrence More articles by this author , Nicholas ChooNicholas Choo More articles by this author , Birunthi NiranjanBirunthi Niranjan More articles by this author , Melissa PapargirisMelissa Papargiris More articles by this author , Hong WangHong Wang More articles by this author , Andrew RyanAndrew Ryan More articles by this author , Peter ShepherdPeter Shepherd More articles by this author , Bradley BroomBradley Broom More articles by this author , Ganiraju ManyamGaniraju Manyam More articles by this author , Renea TaylorRenea Taylor More articles by this author , Timothy ThompsonTimothy Thompson More articles by this author , Nora NavoneNora Navone More articles by this author , Gail RisbridgerGail Risbridger More articles by this author , and Brian ChapinBrian Chapin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The histologic variant prostatic ductal adenocarcinoma (DAC) has an aggressive biology with predisposition to metastasize early to visceral organs at low PSA levels. In contrast to acinar adenocarcinoma of the prostate (PAC), DACs have no effective systemic therapies, responding poorly to androgen deprivation therapy and chemotherapy. Poly(ADP-ribose) polymerase inhibitors (PARPi) may synergize with androgen signaling inhibitors (ARSI) inducing a “BRCAness” phenotype in castrate resistant prostate cancer (CRPC). A recent clinical trial demonstrated the efficacy of this combination therapy in CRPC, regardless of HR status. We aimed to characterize the genomic and transcriptomic properties of DAC to determine the androgen response and assess efficacy of PARPi+ARSI therapy in vivo. METHODS: 20 DAC and 10 PAC tumors, matched for stage, grade and volume, were micro-dissected from radical prostatectomy samples. Whole exome sequencing, RNA sequencing and Hallmark pathway analyses were performed. Validated BRCA2 heterozygous mutant (201.1A-Cx) and HR-proficient (287R) patient-derived DAC organoid models were treated with PARPi, enzalutamide and the combination of PARPi+enzalutamide. RESULTS: DACs had higher rates of mutations compared to matched PAC tumors (Figure 1). Unsupervised hierarchical clustering of RNA expression identified a distinct DAC cluster, with downregulation of AR pathways and enrichment of HR pathways, compared to PAC. Niraparib+Enzalutamide significantly reduced organoid viability of BRCA2 heterozygous mutant (201.1A-Cx) and HR proficient (287R) cells compared to control, Niraparib or Enzalutamide alone. Moreover, PARPi and ARSI were synergistic in these DAC models. Similarly, Talazoparib + Enzalutamide reduced the viability of the HR proficient 287R organoid compared to control, Talazoparib or Enzalutamide (65% vs 100% vs 91% vs 78%, p<0.01). CONCLUSIONS: In contrast to PACs, primary DACs have a unique genomic and transcriptomic landscape with high rates of mutations associated with intrinsic androgen resistance. PARPi+ARSI were more effective at decreasing DAC organoid viability than either treatment alone, regardless of the HR status. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e142 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Weranja Ranasinghe More articles by this author Melbourne, Australia Patricia Troncoso More articles by this author Mitchell Lawrence More articles by this author Nicholas Choo More articles by this author Birunthi Niranjan More articles by this author Melissa Papargiris More articles by this author Hong Wang More articles by this author Andrew Ryan More articles by this author Peter Shepherd More articles by this author Bradley Broom More articles by this author Ganiraju Manyam More articles by this author Renea Taylor More articles by this author Timothy Thompson More articles by this author Nora Navone More articles by this author Gail Risbridger More articles by this author Brian Chapin More articles by this author Expand All Advertisement PDF downloadLoading ...

Extracellular domain ERBB2 (ERBB2 ECD+) mutations in urothelial bladder cancer (UBC).

566 Background: Given the recent approval in lung cancer for the first anti-HER2 targeted therapy directed against activating kinase domain exon 20 ERBB2 insertion mutations, considerable interest has arisen in targeting additional locations in the ERBB2 gene in other tumor types. Methods: 5,485 UBC samples were sequenced using a hybrid capture-based comprehensive genomic profiling (CGP) assay to assess all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genomic loss of heterozygosity (gLOH), trinucleotide signatures and predominant genetic ancestry. Statistical comparisons utilized the Bonferroni correction. Results: 548 (10.0%) of UBC featured ERBB2 gene amplification (amp) and 219 (4.0%) featured an ERBB2 ECD+ sequence mutation (74% S310F and 26% S310Y). ERBB2 ECD+ mutations and ERBB2 amplification were mutually exclusive. 16.4% of ERBB2 ECD+ UBC had more than one E RBB2 sequence mutation. Central pathology review of the 219 ERBB2 ECD+ UBC revealed that 63 (28.8%) featured a micropapillary histologic appearance (MPUC). ERBB2 ECD+ UBC featured more patients with European ancestry than both ERBB2 WT (90.9% vs 84.2%; p=.03) and ERBB2 amp (90.9% vs 83.2%; p=.04). ECD mut+ UBC also featured lower association with African ancestry than ERBB2 amp (2.7% vs 7.8%; p=.04) and lower frequency of gLOH &gt; 16% (9.3% vs 19.1%; p=.04). MSI-High status was similar and rare in all 3 groups (range 0 to 0.9%). ERBB2 ECD+ UBC had a higher frequency of APOBEC signature than ERBB2 amp (82.9% vs 72.4%; p=.03). TMB &gt; 10 mut/mb was higher in ERBB2 amp (49.2% vs 31.4%; p&lt;.0001) and ERBB2 ECD+ (59.8% vs 31.4%; p&lt;.0001) compared to ERBB2 WT as was the mean TMB (11.8 and 17.4 mut/Mb respectively vs 8.9 mut/Mb, p&lt;0.001 for both). Among important UBC individual genes, FGFR3 GA were significantly higher in ERBB2 WT than both ERBB2 amp (19.9% vs 6.2%; p&lt;.0001) and ERBB2 ECD+ (19.9% vs 10.5%; p=.0002). CDKN2A GA were significantly higher in ERBB2 amp (39.1% vs 27.9% ERBB2 WT; p&lt;.0001) only. The higher frequency of KMT2D GA in MPUC+ ECD+ and MPUC- ECD+ UBC (63.4% vs 27.6%; p=.02) was the only genomic difference between these cohorts. Conclusions: ERBB2 ECD mutation driven UBC is a unique form of UBC featuring enrichment of MPUC histology and a unique clinical and genomic landscape including genomic signatures and ancestry.

Major hurdles of immune-checkpoint inhibitors in pancreatic ductal adenocarcinoma.

In 2030, pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related mortality in the world. Unfortunately, neither conventional chemotherapy nor novel immunotherapeutic strategies can provide durable responses and the survival prognosis remains very low. PDAC is notorious for its immune-resistant features and unique genomic landscape facilitating tumor escape from immunosurveillance. Novel immune-checkpoint inhibitors (ICI) failed to show promising efficacy and other multi-modal approaches are currently being validated in multiple clinical trials. In this paper, we provide our opinion on the major mechanisms responsible for PDAC resistance to ICI therapy and provide our view on future strategies which may overcome those barriers.

Genomic Landscape of t(11;14) in Multiple Myeloma

Background Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by multistep genetic alterations, including translocations, copy number aberrations (CNA), and mutations. Translocations involving the immunoglobulin heavy chain (IGH) locus contribute to plasma cell immortalization and consequent commitment to the MM disease pathway, however other genetic events largely underlie the complex genomic landscape of MM with molecular and clinical heterogeneity. The t(11;14) translocation is the most common IGH translocation in MM and has been identified as a predictive biomarker of response to venetoclax in relapsed/refractory MM. The objective of this study was to confirm that t(11;14) is stable across the course of disease and across lines of therapy, and to assess the unique genomic landscape of t(11;14) MM. Methods This was a retrospective, single-center, non-interventional study. To confirm t(11;14) stability, longitudinal assessment of 272 patients for t(11;14) status by plasma cell-enriched FISH using the Vysis IGH/CCND1 XT DF FISH probe was performed on bone marrow aspirates (BMAs) collected at diagnosis and relapse. To assess the genomic landscape, 139 patient BMAs were collected from an approved biobank with informed consent and were analyzed by a targeted NGS panel. NGS was performed as described in Bolli et al. (Bolli et al. 2016) using an Agilent capture panel for sequencing on the Illumina NextSeq platform. Raw sequencing data was processed by an in-house bioinformatics pipeline to detect mutations, copy number aberrations and structural variants (SVs). Protein coding mutations with variant allele frequency >10% and minimum sequencing depth >=20X were selected. CNAs were defined as log ratio above 0.3 (copy number gain) or below -0.4 (copy number loss). SVs with 5 or more supporting reads were examined to detect translocations within the IGH locus. Results Among the 272 patients assessed by longitudinal t(11;14) FISH, 118 were t(11;14)+ and 154 were t(11;14)-. All t(11;14)+ patients remained positive from their initial assessment to first and subsequent longitudinal assessments (Figure 1). The t(11;14) FISH fusion (F) patterns were also consistent across longitudinal assessments with 90% of patients possessing and maintaining either a 1F (18%), 2F (69%), or ≥3F (3%) translocation pattern. No t(11;14)- patients acquired the translocation at relapse. Among the 139 samples analyzed for t(11;14), 130 samples had results from both FISH and NGS with a 100% concordance rate; 66 were t(11;14)+ and 64 were t(11;14)-. The mutational landscape in highly recurrent genes was heterogeneous (Figure 2). MAPK pathway mutations were the most common (47/130 pts, 36.2%), with recurrent mutations in BRAF gene more prevalent in t(11;14)- vs t(11;14)+ pts (18.8% vs 6.1%, p<0.05). Conversely, mutations in DIS3 gene were more common in t(11;14)+ vs t(11;14)- pts (21.2% vs 4.7%, p<0.05). DIS3 and BRAF mutations have been associated with poor prognosis in MM. High CNAs are associated with increased genomic instability, resistance to therapy, and decreased survival in MM. Increased CNAs were observed in t(11;14)- vs t(11;14)+ MM (p<0.001). Conclusion This study confirms in a large, longitudinal cohort of patients with MM that t(11;14) is stable from diagnosis to relapse. These analyses also begin to delineate the differentiated genetic architecture of t(11;14) MM, including fewer CNAs associated with increased genomic stability, but increased rates of DIS3 mutations that confer poor prognosis in MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The unique genomic landscape and prognostic mutational signature of Chinese clear cell renal cell carcinoma

BackgroundThe genomic background affects the occurrence and metastasis of cancers, including clear cell renal cell carcinoma (ccRCC). However, reports focusing on the prognostic mutational signature of Chinese ccRCC are lacking. MethodsOverall, 929 patients, including a training cohort with Chinese patients (n = 201), a testing cohort with Caucasian patients (n = 274), and a validation cohort (n = 454) were analyzed for the genomic landscape of ccRCC. Then, machine-learning algorithms were used to identify and evaluate the genomic mutational signature (GMS) in ccRCC. Analyses for prognosis, immune microenvironment, association with independent clinicopathological features, and predictive responses for immune checkpoint therapies (ICTs) were performed. ResultsThe DNA variation data of 929 patients with ccRCC suggested markedly differential genomic mutational frequency of the most frequent genes, such as VHL, PBRM1, BAP1, SETD2, and KDM5C between the Chinese and Caucasian populations. PBRM1 showed significant co-occurrence with VHL and SETD2. We then successfully identified a seven-gene mutational signature (GMSMut) that included mutations in FBN1, SHPRH, CELSR1, COL6A6, DST, ABCA13, and BAP1. The GMSMut significantly predicted progressive progression (P < 0.0001, HR = 2.81) and poor prognosis (P < 0.0001, HR = 3.89) in the Chinese training cohort. Moreover, ccRCC patients with the GMSMut had poor survival rates in the testing cohort (P = 0.020) and poor outcomes were predicted for those treated with ICTs in the validation cohort (P = 0.036). Interestingly, a favorable clinical response to ICTs, elevated expression of immune checkpoints, and increased abundance of tumor-infiltrated lymphocytes, specifically CD8+ T cells, Tregs, and macrophages, were observed in the GMSMut cluster. ConclusionsThis study described the pro-tumorigenic GMSMut cluster that improved the prognostic accuracy in Chinese patients with ccRCC. Our discovery of the novel independent prognostic signature highlights the relationship between tumor phenotype and genomic mutational characteristics of ccRCC.

Abstract 5966: Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting

Abstract Since the incidence of Malignant melanoma (MM) is rising, we propose high quality patient samples bio-bank for proper understanding of the disease and with time analyze on a large scale proteogenomics. There is increased need to support research and help improved patient care and outcome. Bio-banking in MM will provide high quality and well define tissue and bio-fluid specimens. Materials and Methods: Large scale sample collection were done for 22 patients with histological diagnosis of MM. The patients consent and hospital ethical approval was sorted for the study, with patients' fresh frozen tissue and blood samples collected, fractionated and stored in an automated bio-bank. Five patients however did not consent for bio-banking of their samples. Results: Patients that consented to sample collection had proteogenomic studies and other studies were done on their specimens with possibilities of new treatments for the patients and precision oncology for these patients tailored on their unique genomic landscape. Conclusion: Bio -banking on a large scale is possible and helpful in MM patient especially in our environment where most patients are lost to follow up and have high degree of resistance and mortality during chemo radiation treatment. Citation Format: Kasimu Umar Adoke, Sanusi Mohammed Haruna. Melanoma revisited; The need for bio-banking and precision oncology, a study from a resource limited setting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5966.

Distinct Genomic Landscapes in Early-Onset and Late-Onset Endometrial Cancer.

The spectrum of somatic mutations among women with endometrial cancer (EC) younger than 50 years (early-onset EC) remains unknown. We investigated distinct somatic mutation patterns among early-onset and late-onset (age ≥ 50 years) EC patients. This cohort study included individuals age 18+ years diagnosed with pathologically confirmed EC in the American Association of Cancer Research (AACR) Genomics Evidence Neoplasia Information Exchange (GENIE, v9.1) consortium. We explored tumor mutational burden (TMB) and genomic patterns of EC by age at clinical sequencing using multivariable regression models adjusted for race, ethnicity, histology, sequencing assay, sample type, and TMB. Among 2,425 women with EC, 176 (7.3%) had early-onset EC and 1,923 (79.3%) had nonhypermutated (< 17.78 mutations/Mb) tumors. TMB significantly differed across age and histology groups. Among nonhypermutated ECs, early-onset patients had significantly lower odds of presenting with nonsilent FGFR2 and PIK3R1 somatic mutations compared with late-onset EC patients in adjusted models (FGFR2: odds ratio [OR] = 0.18, 95% CI, 0.04 to 0.76; PIK3R1: OR = 0.54, 95% CI, 0.31 to 0.92). By contrast, early-onset EC patients had increased odds of presenting with nonsilent CTNNB1 and BRCA2 mutations compared with late-onset patients (CTNNB1: OR = 3.32, 95% CI, 2.14 to 5.16; BRCA2: OR = 4.01, 95% CI, 1.55 to 10.38). Subsequent analyses stratified by race, ethnicity, and tumor histology identified distinct patterns of APC, KMT2D, KMT2C, and KRAS by race, ethnicity, and PTEN and APC patterns by histologic subtypes. Early-onset EC harbors a unique genomic landscape compared with late-onset disease. A distinct molecular phenotype of early-onset EC provides novel insights into a unique etiology and may yield clinical implications for developing targeted treatment modalities for younger patients.

High Level of Aristolochic Acid Detected With a Unique Genomic Landscape Predicts Early UTUC Onset After Renal Transplantation in Taiwan.

BackgroundThe unusual high dialysis prevalence and upper urinary tract urothelial carcinoma (UTUC) incidence in Taiwan may attribute to aristolochic acid (AA), which is nephrotoxic and carcinogenic, exposure. AA can cause a unique mutagenic pattern showing A:T to T:A transversions (mutational Signature 22) analyzed by whole exome sequencing (WES). However, a fast and cost-effective tool is still lacking for clinical practice. To address this issue, we developed an efficient and quantitative platform for the quantitation of AA and tried to link AA detection with clinical outcomes and decipher the genomic landscape of UTUC in Taiwan.Patients and MethodsWe recruited 61 patients with de novo onset of UTUC after kidney transplantation who underwent radical nephroureterectomy. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) platform was developed for the quantitation of AA. Pearson’s chi-square test, Kaplan–Meier method, and Cox proportional hazard model were utilized to assess the correlations among AA detection, clinicopathological characteristics, and clinical outcomes. Seven tumors and seven paired normal tissues were sequenced using WES (approximately 800x sequencing depth) and analyzed by bioinformatic tool.ResultsWe found that high level of 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AL-I) detected in paired normal tissues was significantly correlated with fast UTUC initiation times after renal transplantation (p = 0.035) and with no use of sirolimus (p = 0.046). Using WES analysis, we further observed that all tumor samples were featured by Signature 22 mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-associated gene mutations, p53 mutations, no fibroblast growth factor receptor 3 (FGFR3) mutation, and high tumor mutation burden (TMB). Especially, mammalian target of rapamycin (mTOR) activation predominated in dA-AL-I-detected samples compared with those without dA-AL-I detection and might be associated with UTUC initiation through cell proliferation and suppression of UTUC progression via autophagy inhibition.ConclusionAccordingly, dA-AL-I detection can provide more direct evidence to AA exposure and serve as a more specific predictive and prognostic biomarker for patients with de novo onset of UTUC after kidney transplantation.

Treatment of Platinum Nonresponsive Metastatic Malignant Peritoneal Mesothelioma With Combination Chemoimmunotherapy.

Malignant peritoneal mesothelioma is a rare cancer associated with minimal durable disease control with chemotherapy and poor overall survival. The efficacy of combined cytotoxic chemotherapy and immune checkpoint inhibitors (ICIs) in malignant peritoneal mesothelioma has not previously been studied. We describe the clinical course of 2 patients with metastatic peritoneal mesothelioma who both relapsed with platinum nonresponsive disease after initial cytoreductive surgery and chemotherapy. In both cases, addition of pembrolizumab to platinum and pemetrexed treatment resulted in a substantial partial and a near complete disease response. Notably, both patients possessed tumors without validated biomarkers of ICI response, including low tumor mutational burden and negative programmed death ligand-1. The unique genomic landscape of each patient may have enabled increased tumor immunorecognition and ICI efficacy. In addition, chemotherapy priming of the tumor microenvironment may have improved ICI response. This report supports future research to characterize the benefit of combination chemotherapy and ICI in peritoneal mesothelioma.

Distinct genomic profile in h. pylori-associated gastric cancer.

Gastric cancer is one of the most common and deadly cancer types. Currently, four subtypes have been identified with unique molecular alterations: Epstein–Barr virus (EBV)‐positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomic stable (GS) tumors. Notably, many gastric tumors are associated with the bacterium Helicobacter pylori but the genomic landscape of this subgroup of tumors remains largely unknown. Targeted sequencing covering 425 genes was performed retrospectively on 1703 gastric tumor tissues and matched normal blood samples. Nonsynonymous mutations, copy‐number variation (CNV), and MSI status were called from human DNA reads; nonhuman DNA reads were mapped to NCBI microbial reference genome using Kraken and significant species were identified. Overall, 37 (2.76%) from a total of 1703 samples were EBV‐positive, 200 (11.74%) samples were H. pylori‐positive, and 10 samples were positive for both. Among the rest, 59 (3.46%) samples were MSI, 380 (22.31%) were CIN, and 1017 (59.72%) were GS. Most of the 200 H. pylori‐positive samples tend to be genome stable (85.5%, p < 0.001) and microsatellite stable (95%, p = 0.04). Compared to 1017 GS tumors, mutations in AKT3, EPAS1, MLH1, and BKT and amplifications of NFE2L2, TERC, MCL1, and TOP1 were significantly enriched in H. pylori‐positive tumors. And compared to EBV‐positive tumors, mutations in PIK3CA, ARID1A, and PTEN were significantly depleted in H. pylori‐positive subtype while TP53 mutations were enriched. This study characterized the unique genomic landscape of H. pylori‐positive gastric tumors using targeted panel sequencing. The successful identification of DNA reads from infectious agents in tumor samples indicates that deep sequencing is a promising way to uncover characteristics of microbial environment in tumors.

Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms.

PURPOSEHigh-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape.PATIENTS AND METHODSNinety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs.RESULTSThe median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors (P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found.CONCLUSIONThis large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

Establishment and characterization of breast cancer organoids from a patient with mammary Paget\u2019s disease

BackgroundMammary Paget’s disease (MPD) is an uncommon cutaneous intraepithelial malignancy with ulceration of the nipple or areola. Its pathogenesis and genomic mutation remain largely unknown and no cell lines are established from primary tumors.MethodsWe collected surgical tumor specimens from a 65-year-old Chinese woman diagnosed with MPD and established patient-derived breast cancer (BC) organoids from MPD using organoid culture technology.ResultsWe successfully propagated BC organoids from a patient with MPD for more than 6 months. The organoids were cultured for long-term expansion without any change in spherical organoid morphology. Besides, the spherical organoid morphology did not change when they underwent cryopreservation after resuscitation. The H&E staining and immunohistochemistry analyses showed the similar morphological and histological features of the organoids compared with their paired original BC tissues. The organoids retained positive expression of breast cancer biomarkers: estrogen receptor, progesterone receptor, antigen Ki-67 and negative expression of human epidermal growth factor receptor 2. We also showed that MPD organoids recapitulated the unique genomic landscape including copy number alterations, mutational load, mutational signatures and cancer gene mutations by whole genome sequencing. In situ senescence-associated acid beta galactosidase assay confirmed senescence phenomenon existed in the process of organoids culture and there was no significant difference in the proportion of senescent organoids after organoid passage and resuscitation.ConclusionsOur results suggested that an effective platform for ex vivo BC organoids from MPD patients could be used to explore clinicopathological and genomic characteristics of these patients.

Abstract B57: Integrating RNA expression and visual features for immune infiltrate prediction

Abstract Patient responses to cancer immunotherapy are shaped by their unique genomic landscape and tumor microenvironment. Clinical advances in immunotherapy are changing the treatment landscape by enhancing a patient’s immune response to eliminate cancer cells. While this provides potentially beneficial treatment options for many patients, only a minority of these patients respond to immunotherapy. In this work, we examined RNA-seq data and digital pathology images from individual patient tumors to more accurately characterize the tumor-immune microenvironment. Several studies implicate an inflamed microenvironment and increased percentage of tumor-infiltrating immune cells with better response to specific immunotherapies in certain cancer types. We developed NEXT (Neural-based models for integrating gene EXpression and visual Texture features) to more accurately model immune infiltration in solid tumors. To demonstrate the utility of the NEXT framework, we predicted immune infiltrates across four different cancer types and evaluated our predictions against expert pathology review. Our analyses demonstrate that integration of imaging features improves prediction of the immune infiltrate. Of note, this effect was preferentially observed for natural killer, macrophage, and CD8 T cells. In sum, our work effectively integrates both RNA-seq and imaging data in a clinical setting and provides a more reliable and accurate prediction of the immune composition in individual patient tumors. Citation Format: Derek Reiman, Lingdao Sha, Irvin Ho, Timothy Tan, Denise Lau, Aly A Khan. Integrating RNA expression and visual features for immune infiltrate prediction [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B57.

High Expression of miR-206 Predicts Adverse Outcomes: A Potential Therapeutic Target for Esophageal Cancer.

MicroRNA-206 (miR-206) inhibits cell proliferation, invasion and migration in a variety of tumors, but the prognostic value of its Esophageal Cancer (EC) remains unclear. To study the role of miR-206 in EC. The datasets of RNA-Seq, miRNA-Seq, methylation, copy number variation (CNV), and clinical follow-up information were download from The Cancer Genome Atlas (TCGA). After integration and standardization, the prognostic value and potential function of miR-206 were analyzed. The important roles of miR-206 expression in EC genetic and epigenetic mechanisms were analyzed by RNA-Seq, miRNA-Seq, and methylation data. The potential mechanism of CNV in different miR-206 expression groups was analyzed using GISTIC. High expression of miR-206 was associated with poor outcome of EC (OS: p=0.005, AUC=0.69, N=178). Transforming growth factor β (TGF-β) signaling pathway, Wnt signaling pathway, mitogen-activated protein kinases (MAPK) signaling pathway, mammalian target of rapamycin (mTOR) signaling pathway were inhibited in high expression group. the aberrant methylation sites in the high and low expression groups were mainly distributed in the promoter region containing CpG islands, and there were different copy number patterns in the H and L samples, and the genes in the differential copy number were mainly enriched in cancer-related pathways, such as thyroid cancer, central carbon metabolism. This study explored the unique genomic and epigenetic landscape associated with the expression of miR-206, provided evidence of mir-206 as a prognostic biomarker or a potential therapeutic target for EC patients.