bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022‒05‒29
ten papers selected by
Sergio Marchini
Humanitas Research

  1. JCO Precis Oncol. 2022 May;6 e2200085
      PURPOSE: Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, BRCA1/2 alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated.METHODS: We obtained data sets of all solid tumors in The Cancer Genome Atlas and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, per-sample genomic scar scores, ie, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic TP53 mutations, sex, and clinical information including chemotherapeutic regimens.
    RESULTS: Biallelic alterations in HRR genes other than BRCA1/2 were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic TP53 mutations. HRD cases determined by a combination of these indices also showed HRD features in gene expression analysis and were associated with better survival when treated with DNA-damaging agents.
    CONCLUSION: This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.
  2. Cancers (Basel). 2022 May 19. pii: 2504. [Epub ahead of print]14(10):
      The survival of patients with advanced or recurrent ovarian cancer has improved tremendously in the past decade, mainly due to the establishment of maintenance therapy with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) after conservative chemotherapies. Despite their superior efficacy, resistance to PARPis has been reported, and patients with resistance have a much worse prognosis. Therefore, the development of novel treatment strategies to overcome PARPi resistance is urgently needed. The present review article focuses on the molecular mechanisms of how PARPis exert cytotoxic effects on cancer cells through DNA repair processes, especially the genetic background and tumor microenvironment favored by PARPis. Furthermore, currently available information on PARPi resistance mechanisms is introduced and discussed to develop a novel therapeutic approach against them.
    Keywords:  DNA damage response; PARP inhibitor; cGAS/STING; cytosolic immunity; homologous recombination deficiency; maintenance therapy; ovarian cancer; replication fork
  3. Gynecol Oncol. 2022 Jun;pii: S0090-8258(21)01624-3. [Epub ahead of print]165(3): 560-567
      OBJECTIVE: Low-grade serous carcinoma (LGSOC) is a rare epithelial ovarian/peritoneal cancer characterized by younger age at diagnosis, relative chemoresistance, prolonged overall survival (OS), and mutations in the mitogen activated protein kinase (MAPK) pathway compared to high-grade serous carcinoma. We describe the genomic profile of LGSOC by next generation sequencing (NGS) and evaluated its potential relationship to clinical outcomes.METHODS: The study included 215 women with LGSOC with: 1) pathologically confirmed LGSOC, 2) availability of NGS data, and 3) adequate clinical data. Clinical subgroups were compared for progression-free survival (PFS) and OS. Multivariable Cox regression analysis was performed.
    RESULTS: Median age at diagnosis was 46.6 years. The majority had a stage III ovarian primary. One or more mutations were identified in 140 (65.1%) cases; 75 (34.9%) had none. The most common mutations were KRAS (n = 71; 33.0%), NRAS (n = 24; 11.2%), and BRAF (n = 18; 8.4%). Patients with MAPK-mutated tumors (n = 113) (52.6%) had a significantly longer OS compared to those with tumors lacking MAPK pathway mutations (n = 102) (47.4%) [median OS, 147.8 months (95% CI,119.0-176.6) versus 89.5 months (95% CI, 61.4-117.7) (p = 0.01)], respectively. Median OS for patients with MAPK-mutated tumors was also significantly better than for patients whose tumors had no mutations (n = 75) [median OS, 147.8 months (95% CI, 119.0-176.6) versus 78.0 months (95% CI, 57.6-98.3)], respectively (p = 0.001). Median OS for patients with non-MAPK-mutated tumors (n = 27) was 125.1 months (95% CI, 83.9-166.3). In multivariable analysis, having a MAPK mutation was associated with improved OS.
    CONCLUSIONS: Patients with MAPK-mutated tumors have a significantly improved OS compared to those without MAPK-mutated tumors.
  4. Front Endocrinol (Lausanne). 2022 ;13 863541
      Ovarian cancer (OC) is one of the most lethal gynecologic malignancies globally. In spite of positive responses to initial therapy, the overall survival rates of OC patients remain poor due to the development of drug resistance and consequent cancer recurrence. Indeed, intensive studies have been conducted to unravel the molecular mechanisms underlying OC therapeutic resistance. Besides, emerging evidence suggests a crucial role for epigenetic modifications, namely, DNA methylation, histone modifications, and non-coding RNA regulation, in the drug resistance of OC. These epigenetic modifications contribute to chemoresistance through various mechanisms, namely, upregulating the expression of multidrug resistance proteins (MRPs), remodeling of the tumor microenvironment, and deregulated immune response. Therefore, an in-depth understanding of the role of epigenetic mechanisms in clinical therapeutic resistance may improve the outcome of OC patients. In this review, we will discuss the epigenetic regulation of OC drug resistance and propose the potential clinical implications of epigenetic therapies to prevent or reverse OC drug resistance, which may inspire novel treatment options by targeting resistance mechanisms for drug-resistant OC patients.
    Keywords:  DNA methylation; cancer epigenetics; drug resistance; epigenetic therapy; histone modifications; non-coding RNA; ovarian cancer
  5. Exp Ther Med. 2022 Jun;23(6): 423
      Ovarian cancer is the leading cause of death among gynecological malignancies and its incidence is rising in the last decades especially in developed countries. High-grade serous ovarian cancer (HGSOC) represents 70% of ovarian cancers. Oral contraceptive use and salpingo-oophorectomy or salpingectomy are well known protective factors against development of ovarian cancer. Identification of specific mutations associated with a high risk of developing ovarian cancer, especially BRCA1/2 mutation and TP53 mutations, has paved the way for implementation of new strategies for early diagnosis and therapy. Hereditary forms of ovarian cancer account for 5-10% and have BRCA1/2 gene mutations or TP53 mutations. BRCA1/2 gene mutations appear in 22% of HGSOC and are associated with the defective homologous repair (HR)/DNA repair pathway. Genetic testing in ovarian cancer is important for risk assessment and therapeutic options. Although 'universal genetic testing' is not recommended yet, the procedure remains highly recommended in women with high risk. Genes involved in the development of ovarian cancer as TP53 may be targeted by gene therapy. Poly (ADP-ribose) polymerase (PARP) inhibitors may enhance the cytotoxic effect of DNA-damaging chemotherapy, and induce synthetic lethality in cases with BRCA1/2 mutations. Other strategies are designed to target pathways driven by various gene mutations, including the use of tyrosine kinase inhibitors in low-grade serous ovarian cancer (LGSOC), or the use of drugs, which target growth factors, or epigenetic events including methylation, and acetylation of genes. The tubal involvement in ovarian carcinogenesis provides an important tool for the clinician to implement risk-reducing strategies including salpingo-oophorectomy or salpingectomy in high-risk cases at appropriate ages.
    Keywords:  carcinogenesis; genes; ovarian cancer; risk-reducing strategies; targeted therapy
  6. J Transl Med. 2022 May 26. 20(1): 244
      BACKGROUND: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort.METHODS: We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line.
    RESULTS: We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells.
    CONCLUSION: We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.
    Keywords:  Cancer somatic mutation; Epithelial ovarian cancer; Mutated genes; Non-mutated genes; RNA-Seq; RNAi; Simulated mutation; Unmutated genes
  7. J Pers Med. 2022 Apr 19. pii: 655. [Epub ahead of print]12(5):
      Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient's age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient's age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.
    Keywords:  copy number alterations; hormone therapy; metastatic endometrial carcinoma; mutations; predictive factors; protein expression
  8. Nat Commun. 2022 May 24. 13(1): 2896
      Tumor gene expression is predictive of patient prognosis in some cancers. However, RNA-seq and whole genome sequencing data contain not only reads from host tumor and normal tissue, but also reads from the tumor microbiome, which can be used to infer the microbial abundances in each tumor. Here, we show that tumor microbial abundances, alone or in combination with tumor gene expression, can predict cancer prognosis and drug response to some extent-microbial abundances are significantly less predictive of prognosis than gene expression, although similarly as predictive of drug response, but in mostly different cancer-drug combinations. Thus, it appears possible to leverage existing sequencing technology, or develop new protocols, to obtain more non-redundant information about prognosis and drug response from RNA-seq and whole genome sequencing experiments than could be obtained from tumor gene expression or genomic data alone.
  9. Nat Med. 2022 May 26.
      Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment.
  10. Cancers (Basel). 2022 May 22. pii: 2548. [Epub ahead of print]14(10):
      Soft tissue sarcomas are malignant tumors of mesenchymal origin, encompassing a large spectrum of entities that were historically classified according to their histological characteristics. Over the last decades, molecular biology has allowed a better characterization of these tumors, leading to the incorporation of multiple molecular features in the latest classification of sarcomas as well as to molecularly-guided therapeutic strategies. This review discusses the main uses of molecular biology in current practice for the diagnosis and treatment of soft tissue sarcomas, in addition to perspectives for this rapidly evolving field of research.
    Keywords:  molecular biology; soft tissue sarcomas; targeted therapy