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Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

ABSTRACT: Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early-replicating regions, superenhancers, and breast or ovarian cancers. Rigma comprise "chasms" of low-JCN deletions enriched in late-replicating fragile sites and gastrointestinal carcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold-back inversions associated with expressed protein-coding fusions, breakend hypermutation, and acral, but not cutaneous, melanomas. Clustering of tumors according to genome graph-derived features identified subgroups associated with DNA repair defects and poor prognosis.

SUBMITTER: Hadi K

PROVIDER: S-EPMC7912537 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Hadi Kevin K Yao Xiaotong X Behr Julie M JM Deshpande Aditya A Xanthopoulakis Charalampos C Tian Huasong H Kudman Sarah S Rosiene Joel J Darmofal Madison M DeRose Joseph J Mortensen Rick R Adney Emily M EM Shaiber Alon A Gajic Zoran Z Sigouros Michael M Eng Kenneth K Wala Jeremiah A JA Wrzeszczyński Kazimierz O KO Arora Kanika K Shah Minita M Emde Anne-Katrin AK Felice Vanessa V Frank Mayu O MO Darnell Robert B RB Ghandi Mahmoud M Huang Franklin F Dewhurst Sally S Maciejowski John J de Lange Titia T Setton Jeremy J Riaz Nadeem N Reis-Filho Jorge S JS Powell Simon S Knowles David A DA Reznik Ed E Mishra Bud B Beroukhim Rameen R Zody Michael C MC Robine Nicolas N Oman Kenji M KM Sanchez Carissa A CA Kuhner Mary K MK Smith Lucian P LP Galipeau Patricia C PC Paulson Thomas G TG Reid Brian J BJ Li Xiaohong X Wilkes David D Sboner Andrea A Mosquera Juan Miguel JM Elemento Olivier O Imielinski Marcin M

Cell 20201001 1

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g., deletion) or complex (e.g., chromothripsis) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,778 tumor whole-genome sequences, we uncovered three novel complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated w ...[more]

PMID: 33007263

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Project description:AbtractForkhead box A1 (FOXA1) is a pioneer transcription factor that is essential for the normal development of several endoderm-derived organs, including the prostate gland1,2. FOXA1 is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumours3-8. However, it is unclear how FOXA1 alterations affect the development of cancer, and FOXA1 has previously been ascribed both tumour-suppressive9-11 and oncogenic12-14 roles. Here we assemble an aggregate cohort of 1,546 prostate cancers and show that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles, with a collective prevalence of 35%. Class-1 activating mutations originate in early prostate cancer without alterations in ETS or SPOP, selectively recur within the wing-2 region of the DNA-binding forkhead domain, enable enhanced chromatin mobility and binding frequency, and strongly transactivate a luminal androgen-receptor program of prostate oncogenesis. By contrast, class-2 activating mutations are acquired in metastatic prostate cancers, truncate the C-terminal domain of FOXA1, enable dominant chromatin binding by increasing DNA affinity and-through TLE3 inactivation-promote metastasis driven by the WNT pathway. Finally, class-3 genomic rearrangements are enriched in metastatic prostate cancers, consist of duplications and translocations within the FOXA1 locus, and structurally reposition a conserved regulatory element-herein denoted FOXA1 mastermind (FOXMIND)-to drive overexpression of FOXA1 or other oncogenes. Our study reaffirms the central role of FOXA1 in mediating oncogenesis driven by the androgen receptor, and provides mechanistic insights into how the classes of FOXA1 alteration promote the initiation and/or metastatic progression of prostate cancer. These results have direct implications for understanding the pathobiology of other hormone-receptor-driven cancers and rationalize the co-targeting of FOXA1 activity in therapeutic strategies.

Dataset Information

Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Publications

Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs.

Similar Datasets

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