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Lawrence, Michael

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Lawrence

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Michael

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Lawrence, Michael
Author's Publications: search.filters.isAuthorOfPublication.1dce00de-15cd-438a-b325-70219dc65251

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Now showing 1 - 7 of 7
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    NetSig: network-based discovery from cancer genomes
    (2018) Horn, Heiko; Lawrence, Michael; Chouinard, Candace R.; Shrestha, Yashaswi; Hu, Jessica Xin; Worstell, Elizabeth; Shea, Emily; Ilic, Nina; Kim, Eejung; Kamburov, Atanas; Kashani, Alireza; Hahn, William; Campbell, Joshua D.; Boehm, Jesse S.; Getz, Gad; Lage, Kasper
    Approaches that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes, but are challenging to validate at scale and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks and data from 4,742 tumor exomes and used it to accurately classify known driver genes in 60% of tested tumor types and to predict 62 new candidates. We designed a quantitative experimental framework to compare the in vivo tumorigenic potential of NetSig candidates, known oncogenes and random genes in mice showing that NetSig candidates induce tumors at rates comparable to known oncogenes and 10-fold higher than random genes. By reanalyzing nine tumor-inducing NetSig candidates in 242 patients with oncogene-negative lung adenocarcinomas, we find that two (AKT2 and TFDP2) are significantly amplified. Overall, we illustrate a scalable integrated computational and experimental workflow to expand discovery from cancer genomes.
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    Altered biochemical specificity of G-quadruplexes with mutated tetrads
    (Oxford University Press, 2016) Švehlová, Kateřina; Lawrence, Michael; Bednárová, Lucie; Curtis, Edward A.
    A fundamental motif in canonical nucleic acid structure is the base pair. Mutations that disrupt base pairs are typically destabilizing, but stability can often be restored by a second mutation that replaces the original base pair with an isosteric variant. Such concerted changes are a way to identify helical regions in secondary structures and to identify new functional motifs in sequenced genomes. In principle, such analysis can be extended to non-canonical nucleic acid structures, but this approach has not been utilized because the sequence requirements of such structures are not well understood. Here we investigate the sequence requirements of a G-quadruplex that can both bind GTP and promote peroxidase reactions. Characterization of all 256 variants of the central tetrad in this structure indicates that certain mutations can compensate for canonical G-G-G-G tetrads in the context of both GTP-binding and peroxidase activity. Furthermore, the sequence requirements of these two motifs are significantly different, indicating that tetrad sequence plays a role in determining the biochemical specificity of G-quadruplex activity. Our results provide insight into the sequence requirements of G-quadruplexes, and should facilitate the analysis of such motifs in sequenced genomes.
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    Tumor suppressor genes that escape from X-inactivation contribute to cancer sex bias
    (2016) Dunford, Andrew; Weinstock, David; Savova, Virginia; Schumacher, Steven E.; Cleary, John P.; Yoda, Akinori; Sullivan, Timothy J.; Hess, Julian M.; Gimelbrant, Alexander; Beroukhim, Rameen; Lawrence, Michael; Getz, Gad; Lane, Andrew
    There is a striking and unexplained male predominance across many cancer types. A subset of X chromosome (chrX) genes can escape X-inactivation, which would protect females from complete functional loss by a single mutation. To identify putative “Escape from X-Inactivation Tumor Suppressor” (EXITS) genes, we compared somatic alterations from >4100 cancers across 21 tumor types for sex bias. Six of 783 non-pseudoautosomal region (PAR) chrX genes (ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3) more frequently harbored loss-of-function mutations in males (based on false discovery rate <0.1), compared to zero of 18,055 autosomal and PAR genes (P<0.0001). Male-biased mutations in genes that escape X-inactivation were observed in combined analysis across many cancers and in several individual tumor types, suggesting a generalized phenomenon. We conclude that biallelic expression of EXITS genes in females explains a portion of the reduced cancer incidence compared to males across a variety of tumor types.
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    The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis
    (2016) Gibson, William; Hoivik, Erling A.; Halle, Mari K.; Taylor-Weiner, Amaro; Cherniack, Andrew D.; Berg, Anna; Holst, Frederik; Zack, Travis Ian; Werner, Henrica M. J.; Staby, Kjersti M.; Rosenberg, Mara; Stefansson, Ingunn M.; Kusonmano, Kanthida; Chevalier, Aaron; Mauland, Karen K.; Trovik, Jone; Krakstad, Camilla; Giannakis, Marios; Hodis, Eran; Woie, Kathrine; Bjorge, Line; Vintermyr, Olav K.; Wala, Jeremiah; Lawrence, Michael; Getz, Gad; Carter, Scott; Beroukhim, Rameen; Salvesen, Helga B.
    Recent studies have detailed the genomic landscape of primary endometrial cancers, but their evolution into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors, and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed TCGA-data, identifying novel recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor NRIP1 in 12% of patients. We found that likely driver events tended to be shared by primary and metastatic tissue-samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity within endometrial cancers and relative homogeneity across metastatic sites.
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    Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas
    (2016) Campbell, Joshua David; Alexandrov, Anton; Kim, Jaegil; Wala, Jeremiah; Hawley, Alice; Pedamallu, Chandra Sekhar; Shukla, Sachet A.; Guo, Guangwu; Brooks, Angela; Murray, Bradley A.; Imielinski, Marcin; Hu, Xin; Ling, Shiyun; Akbani, Rehan; Rosenberg, Mara; Cibulskis, Carrie; Ramachandran, Aruna; Collisson, Eric A.; Kwiatkowski, David; Lawrence, Michael; Weinstein, John N.; Verhaak, Roel G. W.; Wu, Catherine; Hammerman, Peter S.; Cherniack, Andrew D.; Getz, Gad; Artyomov, Maxim N.; Schreiber, Robert; Govindan, Ramaswamy; Meyerson, Matthew
    To compare lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SqCC) and to identify new drivers of lung carcinogenesis, we examined exome sequences and copy number profiles of 660 lung ADC and 484 lung SqCC tumor/normal pairs. Recurrent alterations in lung SqCCs were more similar to other squamous carcinomas than to lung ADCs. Novel significantly mutated genes included PPP3CA, DOT1L, and FTSJD1 in lung ADC, RASA1 in lung SqCC, and KLF5, EP300, and CREBBP in both tumor types. Novel amplification peaks encompassed MIR21 in lung ADC, MIR205 in lung SqCC, and MAPK1 in both. Lung ADCs lacking receptor tyrosine kinase/Ras/Raf alterations revealed mutations in SOS1, VAV1, RASA1, and ARHGAP35. Regarding neoantigens, 47% of the lung ADC and 53% of the lung SqCC tumors had at least 5 predicted neoepitopes. While targeted therapies for lung ADC and lung SqCC are largely distinct, immunotherapies may aid in treatment for both subtypes.
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    Analysis of Somatic Microsatellite Indels Identifies Driver Events in Human Tumors
    (Springer Science and Business Media LLC, 2017-09-11) Maruvka, Yosef; Mouw, Kent; Karlic, Rosa; Parasuraman, Prasanna; Kamburov, Atanas; Polak, Paz; Haradhvala, Nicholas; Hess, Julian; Rheinbay, Esther; Brody, Yehuda; Koren, Amnon; Braunstein, Lior; D'Andrea, Alan; Lawrence, Michael; Bass, Adam; Bernards, Andre; Michor, Franziska; Getz, Gad
    Microsatellites (MSs) are tracts of variable-length repeats of short DNA motifs that exhibit high rates of mutation in the form of insertions or deletions (indels) of the repeated motif. Despite their prevalence, the contribution of somatic MS indels to cancer has been largely unexplored, owing to difficulties in detecting them in short-read sequencing data. Here we present two tools: MSMuTect, for accurate detection of somatic MS indels, and MSMutSig, for identification of genes containing MS indels at a higher frequency than expected by chance. Applying MSMuTect to whole-exome data from 6,747 human tumors representing 20 tumor types, we identified >1,000 previously undescribed MS indels in cancer genes. Additionally, we demonstrate that the number and pattern of MS indels can accurately distinguish microsatellite-stable tumors from tumors with microsatellite instability, thus potentially improving classification of clinically relevant subgroups. Finally, we identified seven MS indel driver hotspots: four in known cancer genes (ACVR2A, RNF43, JAK1, and MSH3) and three in genes not previously implicated as cancer drivers (ESRP1, PRDM2, and DOCK3).
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    Molecular signatures of circulating melanoma cells for monitoring early response to immune checkpoint therapy
    (National Academy of Sciences, 2018) Hong, Xin; Sullivan, Ryan; Kalinich, Mark; Kwan, Tanya Todorova; Giobbie-Hurder, Anita; Pan, Shiwei; LiCausi, Joseph A.; Milner, John D.; Nieman, Linda T.; Wittner, Ben; Ho, Uyen; Chen, Tianqi; Kapur, Ravi; Lawrence, Donald; Flaherty, Keith; Sequist, Lecia; Ramaswamy, Sridhar; Miyamoto, David; Lawrence, Michael; Toner, Mehmet; Isselbacher, Kurt; Maheswaran, Shyamala; Haber, Daniel
    A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival [hazard ratio (HR), 0.17; P = 0.008] and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.