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Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%–26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6–34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor. Plain Language Summary The integrity of the human genome is maintained via multiple pathways of DNA repair, one of the most important of which is homologous recombination repair (HRR), which uses a sister chromatid as a template for high-fidelity restoration of altered DNA sequences. This study aimed to determine the prevalence of deleterious mutations, i.e., changes in the genetic code that interfere with proper cellular function, in the breast cancer genes BRCA1 and BRCA2 and in 13 other genes involved in HRR in various types of solid tumors in patients with advanced or metastatic cancer. The researchers found that 4.7% of tumor samples had BRCA1/2 mutations, 13.6% had mutations in any of the HRR genes and 20.6% had genomic loss of heterozygosity (gLOH) of at least 16% i.e., loss of sections of chromosomes affecting 16% or more of the genome. BRCA1/2 mutations were most common in ovarian cancer (13.1%), prostate cancer (9.3%), breast cancer (8.2%) and pancreatic cancer (4.9%). Prevalence for mutations in HRR genes ranges from 2.4 to 26.0% and gLOH ≥16% ranged from 2.6 to 34.4% depending on the tumor type. In conclusion, the prevalence of mutations in the BRCA1/2 genes, HRR genes and gLOH ≥16% varied widely across 15 tumor types. Tweetable Abstract Among 9457 patients across 15 solid tumor types, we found that 4.7% had BRCA1/2 mutations, 13.6% had mutations in homologous recombination repair genes and 20.6% had gLOH ≥16%. The prevalence of mutations varied by tumor type. The prevalence of mutations in homologous recombination repair (HRR) genes and of genomic loss of heterozygosity (gLOH) and the allelic and hereditary status of these mutations across solid tumor types are not well described. This study reports the prevalence of mutations in BRCA1/2 and in 13 other HRR genes and of gLOH across 15 tumor types, including tumor types beyond those more commonly associated with these biomarkers. Almost 5% of tumor samples had BRCA1/2 mutations, 14% had mutations in any of the HRR genes and 21% had a high prevalence of gLOH (gLOH ≥16%). The highest prevalences of were BRCA1/2 mutations in ovarian (13.1%), prostate (9.3%), breast (8.2%) and pancreatic (4.9%) cancers. The prevalence of BRCA1/2 mutations in mesothelioma, bladder cancer, endometrial cancer and gastric cancer were not negligible. Among tumors where biallelic status was determined, the biallelic proportions of BRCA1/2 mutations were 95% in prostate, 86% in ovarian, 83% in breast, 77% in pancreatic cancer and from 23% (gastric cancer) to 38% (bladder cancer) in other tumor types. Among tumors where heritable status was determined, germline BRCA1/2 mutations predominated in pancreatic and breast cancers, whereas somatic mutations were the majority in ovarian and most of the other tumor types. Across all tumor types, the proportion of gLOH ≥16% was highest in those with biallelic mutations of BRCA1, BRCA2 and PALB2. The prevalence of mutations in HRR genes varied considerably across tumor types. Evaluation of HRR gene alterations and gLOH may enable identification of tumors that are susceptible to drugs that act by causing double-strand DNA breaks. [ABSTRACT FROM AUTHOR]

The classification of undifferentiated pleomorphic sarcoma (UPS) has been evolving with advances in immunohistochemistry and genomic profiling over the past 20 years. There is a lack of current information on UPS incidence. Due to the lack of designated histology codes for UPS in the Surveillance, Epidemiology, and End Results (SEERs) program, we estimated UPS incidence by three different definitions based on clinical opinions using the 2000–2020 data from 22 registries of the SEER program. The incidence varied widely across the three definitions with 0.06 per 100,000 persons for the least inclusive definition and 0.67 per 100,000 persons for the most inclusive definition in 2016–2020, making it challenging to estimate the exact incidence of UPS. Regardless, all the incidences decreased between 2000 and 2020. Guidelines in UPS diagnosis and classification need to be better implemented in the US. [ABSTRACT FROM AUTHOR]

Background: Oncology databases that integrate genomic and clinical data have become valuable resources for precision medicine. However, the generalizability of these databases has not been comprehensively assessed. Objectives: To describe the demographics, clinical characteristics, treatments, and overall survival of breast cancer cohorts in GENIE‐BPC and three other databases. Methods: This study utilized GENIE‐BPC, SEER, SEER‐Medicare, and Merative MarketScan Research Databases. Women with invasive breast cancer were identified through EHR, cancer registries or ICD‐9/10‐CM codes. The ages were 18+ years or per database requirement. Treatments were based on EHR or HCPCS/NDC codes in claims. Overall survival was estimated as time from diagnosis to death. Results: Of female breast cancer patients in GENIE‐BPC (n = 775), SEER (n = 548 336), SEER‐Medicare (n = 68 914), and Marketscan (n = 109 499) databases, the median ages at initial diagnosis were 44, 62, 74, and 57 years, respectively. A greater proportion of patients in GENIE‐BPC, compared to SEER/SEER‐Medicare, had higher nuclear grades (%III–%IV: 57% vs. 26%/24%), advanced disease stage (%IV: 25.3% vs. 5%/3.6%), percent of triple negative breast cancer (19.7% vs. 10.2%/8.5%), and receipt of chemotherapy (85.0% vs. NA/22.3%). The 1‐, 3‐, and 5‐year overall survival rates were lower in GENIE‐BPC (78.5%, 60.5%, 55.5%) than in SEER (95.8%, 89.5%, 85.5%) and SEER‐Medicare (91.6%, 81.4%, 75.0%). Conclusion: Breast cancer patients in GENIE‐BPC were younger, had more advanced disease, had a higher proportion of triple negative breast cancer and recipients of chemotherapy, and had poorer overall survival. Researchers must use statistical adjustment when extrapolating results (e.g., biomarker prevalence) from GENIE‐BPC to the larger breast cancer population. [ABSTRACT FROM AUTHOR]

PURPOSE: Evaluating whether patient populations in clinico-genomic oncology databases are comparable with whom in other databases without genomic component is important. METHODS: Four databases were compared for colorectal cancer (CRC) cases and stage IV CRC cases: American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (GENIE-BPC), The Cancer Genome Atlas (TCGA), SEER-Medicare, and MarketScan Commercial and Medicare Supplemental claims databases. These databases were also compared with the SEER registry database which serves as national benchmarks. Demographics, clinical characteristics, and overall survival were compared in patients with newly diagnosed CRC and patients with stage IV CRC across databases. Treatment patterns were further compared in patients with stage IV CRC. RESULTS: A total of 65,976 patients with CRC and 13,985 patients with stage IV CRC were identified. GENIE-BPC had the youngest patient population (mean age [years]: CRC, 54.1; stage IV CRC, 52.7). SEER-Medicare had the oldest patient population (CRC, 77.7; stage IV CRC, 77.3). Most patients were male and of White race across databases. GENIE-BPC had the highest proportion of patients with stage IV CRC (48.4% v other databases 13.8%-25.4%) and patients receiving treatments (95.7% v 37.6%-59.1%). Infusional fluorouracil, leucovorin, and oxaliplatin with or without bevacizumab was the most common regimen across databases accounting for 47.3%-78.5% of patients receiving first line of therapy. The median survival from diagnosis was 36, 94, 44 months (CRC) and 23, 36, 15 months (stage IV CRC) for patients in GENIE-BPC after left truncation, TCGA, and SEER-Medicare databases, respectively. CONCLUSION: Compared with other databases, GENIE-BPC had the youngest patients with CRC with the most advanced disease and the largest proportion of patients receiving treatment. Investigators should consider adjustments when extrapolating results from clinico-genomic databases to the general CRC population. GENIE-BPC had the youngest patients with most advanced CRC. Interdatabase differences should be considered. [ABSTRACT FROM AUTHOR]

There is significant improvement in the outcomes following treatment with PARP inhibitors among patients with certain tumors that have BRCA mutations (BRCAm), homologous recombination repair (HRR) gene mutations, or homologous recombination deficiency (HRD) positivity. We performed a literature review and meta‐analysis to evaluate the prevalence of BRCA1/2m, HRR gene mutations, and HRD positivity across multiple cancers. There were 265 publications on BRCA1/2 mutation prevalence, 189 on HRR gene mutation prevalence, and 7 on HRD positivity prevalence. The prevalences of germline BRCA1m and BRCA2m were 7.8% and 5.7% for breast cancer, 13.5% and 6.6% for ovarian cancer, 0.5% and 3.5% for prostate cancer, and 1.1% and 4.1% for pancreatic cancer, respectively. The prevalences of somatic BRCA1m and BRCA2m were 3.4% and 2.7% for breast cancer, 4.7% and 2.9% for ovarian cancer, 5.7% and 3.2% for prostate cancer, and 1.2% and 2.9% for pancreatic cancer, respectively. We identified 189 studies with over 418,649 samples across 25 tumor types that examined mutations in one or more HRR genes other than BRCA1/2. The prevalence of mutations among HRR genes remained low (less than 1%), with ATM (5.2%), CHEK2 (1.6%), and PALB2 (0.9%) exhibiting the highest prevalence. Seven studies evaluated HRD positivity in breast, ovarian, and prostate cancer patients. The prevalence of HRD positivity was 56% overall (95% CI = 48%–64%). The understanding of biomarker prevalence across tumor types and standardization of biomarker assays could have important clinical implications. [ABSTRACT FROM AUTHOR]

Data are limited on the real-world utilization and costs of brentuximab vedotin (BV) among patients with relapsed/refractory Hodgkin lymphoma (rrHL) in the United States. A total of 219 BV patients identified from the Truven MarketScan® databases were followed up for a median of 2.9 years before and 1.0 year after initiation of BV. Of these patients, 109 (50.6%) received systemic therapy after BV (post-BV ST). Median duration of treatment was short for BV (2.1 months) and post-BV ST treatment (1.3 months); time to next treatment was 6.2 and 9.1 months, respectively. Average total US dollar 2014 costs/person for BV and post-BV ST line of therapy were $167,152 and $132,115, respectively; mean per-patient-per-month costs for BV and post-BV ST were $30,434 and $29,138, respectively. Findings underscore the unmet medical need and substantial economic burden in BV-treated patients with rrHL. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prevalence and prognostic role of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in patients with non-immunotherapy-treated advanced cervical cancer., Methods: Clinical data were retrospectively collected from medical records between January 1, 2008, and December 31, 2016, at Asan Medical Center (Korea); archived tumor samples were assessed for PD-L1 expression (combined positive score [CPS] ≥1) and TMB (≥175 mutations/exome). Overall survival (OS) was defined as time from advanced diagnosis or initiation of first-line or second-line systemic therapy until death/last follow-up. The association of OS with PD-L1 expression and TMB were analyzed using the log-rank test and Cox proportional hazards model adjusted for covariates., Results: Of 267 patients, 76.0% had squamous cell carcinoma (SCC), 24.0% had adenocarcinoma (AC)/adenosquamous carcinoma (ASC), 64.4% had PD-L1 CPS ≥1, and 32.6% had TMB ≥175 mutations/exome. PD-L1 CPS ≥1 and TMB ≥175 mutations/exome were more prevalent in SCC than in AC/ASC (73.9% and 37.2% vs. 34.4% and 17.7%). There was no association between OS and PD-L1 expression (CPS ≥1 vs. <1: adjusted hazard ratio [HR]=1.14; 95% confidence interval [CI]=0.84-1.53 from advanced diagnosis); OS trended shorter for the subgroup with TMB ≥175 versus <175 mutations/exome (adjusted HR=1.29; 95% CI=0.95-1.75)., Conclusion: Retrospective analysis of non-immunotherapy-treated patients with advanced cervical cancer demonstrated a higher prevalence of PD-L1 CPS ≥1 and TMB ≥175 mutations/exome in SCC versus AC/ASC. PD-L1 CPS ≥1 was not associated with OS; TMB ≥175 mutations/exome showed a trend toward shorter OS. Additional studies are needed to confirm these findings., Competing Interests: J-YP and M-HB have nothing to disclose. LC, CS, and PJ are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock in Merck & Co., Inc., Rahway, NJ, USA. CT and XYJ are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. RC is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, owns stock in Merck & Co., Inc., Rahway, NJ, USA, and has two pending patents (Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists; patent WO 2020/167619). SI is an employee of MSD Korea (employment [JCAP asso RDMA]), registered pharmacist (Korea), and stockholder of Merck & Co., Inc., Rahway, NJ, USA., (© 2024. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)

Staphylococcus aureus is an important human pathogen whose virulence relies on the secretion of many different proteins. In general, the secretion of most proteins in S. aureus, as well as other bacteria, is dependent on the type I signal peptidase (SPase)-mediated cleavage of the N-terminal signal peptide that targets a protein to the general secretory pathway. The arylomycins are a class of natural product antibiotics that inhibit SPase, suggesting that they may be useful chemical biology tools for characterizing the secretome. While wild-type S. aureus (NCTC 8325) is naturally resistant to the arylomycins, sensitivity is conferred via a point mutation in its SPase. Here, we use a synthetic arylomycin along with a sensitized strain of S. aureus and multidimensional protein identification technology (MudPIT) mass spectrometry to identify 46 proteins whose extracellular accumulation requires SPase activity. Forty-four possess identifiable Sec-type signal peptides and thus are likely canonically secreted proteins, while four also appear to possess cell wall retention signals. We also identified the soluble C-terminal domains of two transmembrane proteins, lipoteichoic acid synthase, LtaS, and O-acyteltransferase, OatA, both of which appear to have noncanonical, internal SPase cleavage sites. Lastly, we identified three proteins, HtrA, PrsA, and SAOUHSC&#95;01761, whose secretion is induced by arylomycin treatment. In addition to elucidating fundamental aspects of the physiology and pathology of S. aureus, the data suggest that an arylomycin-based therapeutic would reduce virulence while simultaneously eradicating an infection.

The p53 tumor suppressor gene plays an essential role in tumorigenesis, and the chromosomal region maintenance 1 (CRM1) has been suggested to export p53 protein from the nucleus to the cytoplasm. The objectives of the present study were to evaluate p53 expression and subcellular localization as well as CRM1 expression using immunohistochemistry in our established bitransgenic mouse lung tumor model. In this model, expression of the mutant human Ki-rasG12C allele was regulated in a doxycycline (DOX)-inducible, lung-specific manner. Following treatment with curcumin, we found that although overall p53 expression levels were not significantly changed among the three groups, lung lesions in mice treated with DOX alone had the highest proportion of N>C (nucleus predominant) p53 staining (46±7%), followed by lung lesions in mice co-treated with DOX and curcumin (31±12%) and controls (17±4%). CRM1 expression was dramatically inhibited in lung lesions in mice treated with DOX (0±0) as compared to controls (90±17, P=0.001), and could be partially reversed after curcumin treatment (47±21, P=0.028, DOX vs. DOX+curcumin). Collectively, the results from this study demonstrated that p53 accumulated in the nucleus in lung lesions in mice expressing the mutant Ki-rasG12C transgene as a result of down-regulation of CRM1. Furthermore, these alterations could be partially reversed by curcumin treatment. p53 subcellular localization resulting from CRM1 alterations may play an important role in lung tumorigenesis.

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [corrected] (NNK), a known tobacco-specific human lung carcinogen, is notorious for causing DNA damage. The tumor suppressor gene p53 has multiple functions in response to DNA damage. Besides being regulated by posttranslational modifications (PTMs), p53 function is modulated by nucleocytoplasmic shuttling factors (NSFs). In this study, the alterations of p53 protein after NNK exposure and the molecular mechanisms involved p53 PTMs and NSFs in human bronchial epithelial cells BEAS-2B were investigated. NNK induced p53 nuclear accumulation and upregulated the expression of p21, a p53 target gene. Among the five NSFs examined, chromosomal region maintenance 1 (CRM1), interacting with p53 and exporting p53 from nucleus to cytoplasm, was significantly downregulated after NNK exposure. Increases of p53 phosphorylation and poly(ADP-ribosyl)ation were found in NNK-treated cells as compared with the controls. The upregulation of p53 poly(ADP-ribosyl)ation was induced by the enhanced expression of poly(ADP-ribose) polymerase 1 after NNK exposure. Collectively, p53 went through PTMs in response to DNA damage, and the modified p53 had a tendency for nuclear accumulation, which could result from CRM1 downregulation. Consequently, the activation of p53 led to subsequent induction of its downstream targets. These data could facilitate the better understanding of chemical carcinogenesis induced by NNK.