bims-ovdlit 2024-09-01 papers

Issue of 2024–09–01
six papers selected by
Lara Paracchini, Humanitas Research

Nat Commun. 2024 Aug 27. 15(1): 7386

Cell-free DNA from germline TP53 mutation carriers reflect cancer-like fragmentation patterns.

Derek Wong, Maha Tageldein, Ping Luo, Erik Ensminger, Jeffrey Bruce, Leslie Oldfield, Haifan Gong, Nicholas William Fischer, Brianne Laverty, Vallijah Subasri, Scott Davidson, Reem Khan, Anita Villani, Adam Shlien, Raymond H Kim, David Malkin, Trevor J Pugh.

Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710-1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.

DOI: https://doi.org/10.1038/s41467-024-51529-w

Am J Epidemiol. 2024 Aug 27. pii: kwae301. [Epub ahead of print]

Rare germline genetic variation in PAX8 transcription factor binding sites and susceptibility to epithelial ovarian cancer.

Suzana A M Ezquina, Michelle Jones, Ed Dicks, Amber de Vries, Pei-Chen Peng, Kate Lawrenson, Rosario I Corona, Jonathan Tyrer, Dennis Hazelett, James Brenton, Antonis Antoniou, Simon A Gayther, Paul D P Pharoah.

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.

Keywords: Breast; Cancer; Colorectal; Endometrial; Ovarian; PAX8; burden test; non-coding; rare variants; transcription factor; whole genome

DOI: https://doi.org/10.1093/aje/kwae301

Genome Med. 2024 Aug 28. 16(1): 108

Large-scale copy number alterations are enriched for synthetic viability in BRCA1/BRCA2 tumors.

BACKGROUND: Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear.
METHODS: We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher's exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations.
RESULTS: We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation.
CONCLUSIONS: This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

Keywords: BRCA1; BRCA2; CRISPR-Cas9 knockout; Copy number alterations; DNA repair; Gene expression; ICGC; Synthetic viability; TCGA

DOI: https://doi.org/10.1186/s13073-024-01371-y

Nat Immunol. 2024 Aug 23.

Mapping spatial organization and genetic cell-state regulators to target immune evasion in ovarian cancer.

Christine Yiwen Yeh, Karmen Aguirre, Olivia Laveroni, Subin Kim, Aihui Wang, Brooke Liang, Xiaoming Zhang, Lucy M Han, Raeline Valbuena, Michael C Bassik, Young-Min Kim, Sylvia K Plevritis, Michael P Snyder, Brooke E Howitt, Livnat Jerby.

The drivers of immune evasion are not entirely clear, limiting the success of cancer immunotherapies. Here we applied single-cell spatial and perturbational transcriptomics to delineate immune evasion in high-grade serous tubo-ovarian cancer. To this end, we first mapped the spatial organization of high-grade serous tubo-ovarian cancer by profiling more than 2.5 million cells in situ in 130 tumors from 94 patients. This revealed a malignant cell state that reflects tumor genetics and is predictive of T cell and natural killer cell infiltration levels and response to immune checkpoint blockade. We then performed Perturb-seq screens and identified genetic perturbations-including knockout of PTPN1 and ACTR8-that trigger this malignant cell state. Finally, we show that these perturbations, as well as a PTPN1/PTPN2 inhibitor, sensitize ovarian cancer cells to T cell and natural killer cell cytotoxicity, as predicted. This study thus identifies ways to study and target immune evasion by linking genetic variation, cell-state regulators and spatial biology.

DOI: https://doi.org/10.1038/s41590-024-01943-5

Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00113-8. [Epub ahead of print]387 xiii-xvii

Epigenetic regulation of cancer.

Sheila Spada, Lorenzo Galluzzi.

DOI: https://doi.org/10.1016/S1937-6448(24)00113-8

Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00045-5. [Epub ahead of print]387 77-98

Epigenetic regulation in ovarian cancer.

Hue Vu Thi, Anh-Dao Ngo, Dinh-Toi Chu.

Ovarian cancer is one of the diseases that have the highest mortality rate for women, especially women over 50 years old. In the future, incidence and mortality rates are predicted to extend in countries with low HDI. Instability in the structure and function of genetic factors has long been known as a cause of cancer, including ovarian cancer. Besides understanding gene mutations, epigenetic alterations have emerged as another aspect leading to the pathogenesis of ovarian neoplasm. The development and progression of this fatal disease have been found to be associated with abnormalities of epigenetic regulation. DNA methylation, histone modification, and non-coding RNAs-based gene silencing are processes of interest in developing ovarian carcinoma and are also new targets for cancer detection or treatment.

Keywords: DNA methylation; Epigenetic regulation; Histone modification; Ovarian cancer; Ovarian cancer diagnosis; Ovarian cancer therapy

DOI: https://doi.org/10.1016/bs.ircmb.2024.03.006