Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial.
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ABSTRACT:
SUBMITTER: Edelmann J
PROVIDER: S-EPMC5332302 | biostudies-literature | 2017 Mar
REPOSITORIES: biostudies-literature
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Frequent evolution of copy number alterations in CLL following first-line treatment with FC(R) is enriched with TP53 alterations: results from the CLL8 trial.
Edelmann J J Tausch E E Landau D A DA Robrecht S S Bahlo J J Fischer K K Fink A M AM Bloehdorn J J Holzmann K K Böttcher S S Werner L L Kneba M M Gribben J G JG Neuberg D S DS Wu C J CJ Hallek M M Döhner H H Stilgenbauer S S
Leukemia 20161102 3
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Project description:BackgroundPathogenic 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.
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Project description:IntroductionHead and neck squamous cell carcinomas (HNSCC) arise in the mucosal lining of the upper aerodigestive tract. Risk factors are exogenous carcinogen exposure, human papillomavirus (HPV) infection, and genetic predisposition such as Fanconi anemia (FA). Clinically, tumors are stratified based on stage, site and HPV-status. The majority of HPV-positive and -negative HNSCC is characterized by frequent copy number (CN) changes and an abrogated p53-pathway. A third genetically-defined HPV-negative subclass of HNSCC is emerging: tumors that lack gross chromosomal changes (CN-silent), are mostly TP53-proficient, and have a relatively favorable prognosis.MethodsA representative panel of HPV-positive, HPV-negative and FA-HNSCC-derived cell lines was genetically characterized.ResultsDespite apparent differences in etiology, FA-HNSCC cell lines show comparable genetic alterations as sporadic non-FA-HNSCC-derived cell lines. Furthermore, we identified a near diploid CN-silent HPV-negative HNSCC line: VU-SCC-040. Molecular characterization uncovers the absence of TP53 mutations, a functional p53-pathway and a CASP8 mutation. TP53 gene knockout using CRISPR-Cas9 resulted in resistance to MDM2 inhibition. Whereas p53-status is often proposed as a predictive biomarker for treatment response, TP53-knockout did not change sensitivity to cisplatin, Chk1 and Wee1 inhibition. Additionally, 84 CN-silent tumors were identified in the HNSCC PanCancer cohort and shown to be enriched for female gender, HRAS and CASP8 mutations.ConclusionFA-derived HNSCC cell lines share comparable CN-profiles and mutation patterns as sporadic HPV-negative HNSCC. In contrast, a subclass of CN-silent, HPV-negative and TP53 wild-type HNSCC separates from the majority of HNSCC tumors. We show that VU-SCC-040 is a HNSCC cell model representative of this subclass.
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Project description:BACKGROUND: Epithelial ovarian cancer is characterized by multiple genomic alterations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and can be broadly categorized into 4 main histotypes of clear cell, endometrioid, mucinous, and serous. To date, histotype-specific copy number alterations have been difficult to elucidate. The difficulty lies in having sufficient sample size in each histotype for statistical analyses. METHODS: To dissect the heterogeneity of ovarian cancer and identify histotype-specific alterations, we used an in silico hypothesis-driven approach on multiple datasets of epithelial ovarian cancer. RESULTS: In concordance with previous studies on global copy number alterations landscape, the study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here significant histotype-specific copy number alterations in ovarian cancer and showed that there is genomic diversity amongst the histotypes. 76 cancer genes were found to be significantly altered with several as potential copy number drivers, including ERBB2 in mucinous, and TPM3 in endometrioid histotypes. ERBB2 was found to have preferential alterations, where it was amplified in mucinous (28.6%) but deleted in serous tumors (15.1%). Validation of ERBB2 expression showed significant correlation with microarray data (p=0.007). There also appeared to be reciprocal relationship between KRAS mutation and copy number alterations. In mucinous tumors where KRAS mutation is common, the gene was not significantly altered. However, KRAS was significantly amplified in serous tumors where mutations are rare in high grade tumors. CONCLUSIONS: The study demonstrates that the copy number landscape is specific to the histotypes and identification of these alterations can pave the way for targeted drug therapy specific to the histotypes.
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