3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets

Gao, Jianjiong; Chang, Matthew T.; Johnsen, Hannah C.; Gao, Sizhi Paul; Sylvester, Brooke E.; Sumer, S. Onur; Zhang, Hongxin; Solit, David B.; Taylor, Barry S.; Schultz, Nikolaus; Sander, Chris

doi:10.1186/s13073-016-0393-x

Cited by 187 publications

(191 citation statements)

References 45 publications

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“…Of these 16, the only nonsynonymous alteration in a gene previously associated with oncogenic signaling (Brastianos et al, 2015; Futreal et al, 2004) was a clonal missense mutation in PTEN , with evidence of heterozygous loss of the wild-type copy (81 variant reads out of 101 total reads) (Figure 2C). This alteration occurred within a 3D hotspot (Gao et al, 2017) in the tyrosine phosphatase domain of PTEN (Figure 2C) at the same locus as mutations observed in glioblastoma (Brennan et al, 2013) and colorectal cancer (Giannakis et al, 2016), suggesting a functional role. It was not detected in the pre-treatment tumor despite 165 reads at this locus (Figure 2C).…”

Section: Resultsmentioning

confidence: 59%

Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma

George

Miao

Demetri³

et al. 2017

Immunity

421

320

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Summary Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers may inform immunotherapy mediators. We identified a treatment-naïve patient with metastatic uterine leiomyosarcoma who experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2, with sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p=0.02). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutation and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.

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Section: Resultsmentioning

confidence: 59%

Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma

George

Miao

Demetri³

et al. 2017

Immunity

421

320

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“…Some tools analyze a re-ordered version of the protein's sequence based on the distance between residues in three dimensions 30 or use network algorithms on the graph derived from the structure 31 . However, most Type II algorithms try to identify three-dimensional clusters using the protein structure directly and calculate empirical p-values by re-shuffling the mutations in the structure 32 . Nevertheless, their specific details can be very different, as some use spheres of varying radii 33 , while others use the closeness in the structure-derived residue network 6 , the Shannon entropy of the region 17 or weighted-scoring functions 16 .…”

Section: Resultsmentioning

confidence: 99%

Comparison of algorithms for the detection of cancer drivers at subgene resolution

et al. 2017

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Understanding genetic events that lead to cancer initiation and progression remains one of the biggest challenges in cancer biology. Traditionally most algorithms for cancer driver identification look for genes that have more mutations than expected from the average background mutation rate. However, there is now a wide variety of methods that look for non-random distribution of mutations within proteins as a signal they have a driving role in cancer. Here we classify and review the progress of such sub-gene resolution algorithms, compare their findings on four distinct cancer datasets from The Cancer Genome Atlas and discuss how predictions from these algorithms can be interpreted in the emerging paradigms that challenge the simple dichotomy between driver and passenger genes.

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“…These PPP2R1A mutations frequently recurred at the same positions (P179, R183 and S256) across different cancer types, as indicated by several comprehensive studies [143,144,145]. In type II ECs, these so-called PPP2R1A hotspot mutations were recurrently found in codons: P179, R182, R183 (HEAT repeat 5) and S256, W257 (HEAT repeat 7) (Figure 2) [17,44,45,48,52,54,144,146,147].…”

Section: Therapeutic Potential Of Targeting Kinases and Phosphatasmentioning

confidence: 98%

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

Remmerie

Janssens

2018

IJMS

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Type II endometrial carcinomas (ECs) are responsible for most endometrial cancer-related deaths due to their aggressive nature, late stage detection and high tolerance for standard therapies. However, there are no targeted therapies for type II ECs, and they are still treated the same way as the clinically indolent and easily treatable type I ECs. Therefore, type II ECs are in need of new treatment options. More recently, molecular analysis of endometrial cancer revealed phosphorylation-dependent oncogenic signalling in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways to be most frequently altered in type II ECs. Consequently, clinical trials tested pharmacologic kinase inhibitors targeting these pathways, although mostly with rather disappointing results. In this review, we highlight the most common genetic alterations in type II ECs. Additionally, we reason why most clinical trials for ECs using targeted kinase inhibitors had unsatisfying results and what should be changed in future clinical trial setups. Furthermore, we argue that, besides kinases, phosphatases should no longer be ignored in clinical trials, particularly in type II ECs, where the tumour suppressive phosphatase protein phosphatase type 2A (PP2A) is frequently mutated. Lastly, we discuss the therapeutic potential of targeting PP2A for (re)activation, possibly in combination with pharmacologic kinase inhibitors.

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3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets

Cited by 187 publications

References 45 publications

Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma

Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma

Comparison of algorithms for the detection of cancer drivers at subgene resolution

Targeted Therapies in Type II Endometrial Cancers: Too Little, but Not Too Late

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