_:b536099636 "2"^^ . . _:b536099639 "2"^^ . _:b26116338 "expression: NPBWR2, NEFH, GLRA3, CHAT and NDRG4 and those with a function in cell growth, differentiation, mitotic cycle and oncogenic transformation, such as PTPN11\u2014a member of the protein tyrosine phosphatase family (Pruitt et al., >>2012<<)." . _:b536099453 . _:b536099638 "2"^^ . _:b536099633 "2"^^ . _:b26116322 "(Stupp et al., 2009), GBM invariably recur within months following initial diagnosis (Konishi et al., 2012) and typically become resistant to the first line therapy they have been exposed (Fan et al., 2010; Lomonaco et al., >>2009<<). An SP with stem-like properties, the cancer stem cells, is one potential culprit for recurrence and therapy resistance in GBM (Chen et al., 2012; Schonberg et al., 2013)." . _:b536099604 . _:b536099632 "2"^^ . _:b536099589 . _:b536099570 . _:b536099635 "2"^^ . . . _:b536099463 . _:b536099588 . _:b536099488 . _:b536099634 "2"^^ . _:b536099465 . _:b536099581 . _:b536099591 . _:b26116316 . . _:b536099590 . _:b536099644 "2"^^ . _:b26116317 . . _:b536099616 . _:b536099617 . _:b536099585 . _:b536099618 . _:b536099575 . . _:b26116318 . _:b536099619 . _:b536099620 . . _:b536099584 . _:b536099621 . _:b536099622 . _:b536099623 . _:b26116319 . . _:b536099624 . _:b536099625 . _:b536099587 . . _:b536099641 "2"^^ . _:b536099626 . _:b536099627 . _:b536099628 . . _:b536099629 . _:b536099586 . _:b536099630 . _:b536099640 "2"^^ . _:b536099631 . . _:b536099632 . . . _:b536099597 . _:b536099593 . _:b536099633 . _:b536099419 . _:b536099643 "2"^^ . _:b536099634 . . _:b536099635 . _:b536099636 . _:b536099637 . _:b536099596 . _:b536099638 . _:b536099642 "2"^^ . _:b536099639 . _:b26116315 . _:b536099640 . . _:b536099641 . _:b536099599 . _:b536099642 . _:b536099643 . _:b26116324 . _:b536099644 . _:b536099598 . _:b536099631 . _:b536099487 . _:b536099502 . _:b26116325 . _:b536099584 . _:b536099585 . _:b536099593 . _:b536099586 . _:b536099587 . _:b26116326 . _:b536099588 . _:b536099589 . _:b536099592 . _:b536099590 . _:b536099591 . _:b26116327 . _:b536099592 . _:b536099593 . _:b26116331 "Clonal architecture analyses as previously performed for acute lymphoblastic leukemia single cells (Anderson et al., 2011; Navin et al., >>2011<<) are difficult to perform for solid tumors that are a tight mix of distinct SPs and various fractions of non-neoplastic cells." . _:b536099595 . . _:b536099594 . _:b536099595 . _:b26116320 . _:b536099596 . . . _:b536099594 . _:b536099597 . _:b536099598 . _:b536099599 . _:b26116321 . _:b536099600 . _:b536099601 . _:b536099605 . _:b536099602 . _:b536099587 . _:b536099560 . _:b536099603 . _:b26116322 . _:b536099604 . _:b536099605 . _:b26116340 "Not surprisingly, the top 20 significant hits identified by MutSig were enriched for genes previously known to be involved in gliomagenesis: TP53, PTEN, PIK3R1 and TGFA (Pruitt et al., >>2012<<). The enrichment of these gene alterations in SPD suggests that they are highly prevalent in individual tumors and further corroborate their role as GBM driver mutations. A detailed view of the intra-tumoral prevalence of known GBM driver" . _:b536099604 . _:b536099606 . _:b536099607 . _:b26116323 . _:b536099608 . . _:b536099609 . _:b536099607 . _:b536099610 . _:b536099611 . _:b26116332 . _:b26116332 . _:b536099612 . _:b536099544 . . _:b536099606 . _:b536099613 . _:b536099614 . . _:b26116333 . _:b536099615 . _:b536099601 . _:b536099444 . _:b26116334 . _:b536099600 . _:b26116320 "aggressive standard therapy, consisting of surgery, radiation and adjuvant chemotherapy with the DNA alkylating drug temozolomide (Stupp et al., 2009), GBM invariably recur within months following initial diagnosis (Konishi et al., >>2012<<) and typically become resistant to the first line therapy they have been exposed (Fan et al., 2010; Lomonaco et al., 2009)." . _:b536099422 . _:b26116335 . . . . . _:b536099603 . _:b536099452 . _:b536099620 . _:b536099588 . _:b26116328 . _:b536099602 . _:b26116329 . _:b536099613 . _:b536099464 . _:b26116330 . . _:b536099612 . _:b26116331 . _:b536099615 . _:b536099470 . . _:b26116340 . . _:b536099614 . _:b536099530 . _:b26116341 . _:b26116319 . . _:b536099609 . . _:b26116342 . _:b536099608 . _:b26116343 . . _:b536099611 . _:b26116336 . _:b536099610 . . . _:b26116337 . _:b536099607 . _:b536099621 . _:b26116338 . _:b26116350 . . _:b536099620 . _:b536099580 . _:b26116339 . _:b536099447 . _:b536099623 . _:b26116348 . . _:b536099407 . . _:b536099622 . _:b26116349 . _:b536099617 . _:b26116346 . _:b26116350 . _:b536099520 . _:b536099616 . _:b26116335 "Nik-Zainal et al. modeled the observed patterns of clonal and subclonal mutations with a hierarchical Bayesian Dirichlet process (Nik-Zainal et al., >>2012<<). This approach was designed specifically for the mutations detected in the whole genome of a hypermutated breast cancer, sequenced at high coverage (188-fold)." . _:b536099619 . . _:b26116344 . _:b26116344 . _:b536099529 . _:b26116343 . _:b536099618 . . _:b26116345 . _:b536099629 . . _:b536099413 . _:b26116346 . _:b26116324 "GBM exhibit substantial subclonal diversity as evidenced by previous comparative genomic hybridization (CGH) analyses (Harada et al., >>1998<<), fluorescence in situ hybridization studies (Little et al., 2012; Snuderl et al., 2011; Szerlip et al., 2012) and areal sampling of surgical tissue followed by molecular analyses (Sottoriva et al., 2013)." . _:b536099413 . . _:b536099628 . _:b536099445 . _:b536099641 . _:b536099412 . _:b26116347 . . _:b536099631 . . _:b536099492 . _:b536099415 . . _:b536099630 . _:b536099493 . _:b26116321 "DNA alkylating drug temozolomide (Stupp et al., 2009), GBM invariably recur within months following initial diagnosis (Konishi et al., 2012) and typically become resistant to the first line therapy they have been exposed (Fan et al., >>2010<<; Lomonaco et al., 2009). An SP with stem-like properties, the cancer stem cells, is one potential culprit for recurrence and therapy resistance in GBM (Chen et al., 2012; Schonberg et al., 2013)." . _:b536099414 . _:b536099625 . _:b536099409 . _:b536099624 . _:b536099408 . _:b536099540 . . _:b536099627 . _:b536099545 . . . _:b536099411 . _:b536099438 . _:b536099626 . _:b536099420 . _:b536099410 . . _:b536099637 . . . _:b536099421 . _:b536099636 . . _:b536099563 . _:b536099420 . _:b536099639 . . _:b536099423 . _:b536099638 . _:b536099475 . _:b26116348 "Copy-number segments were calculated using an approach similar to ExomeCNV (Sathirapongsasuti et al., >>2011<<). SNVs outlying autosomes or that cannot be explained by an SP present in 10% or more of the sample (i.e. AF \u00D7 CN < 0.1) were excluded." . _:b536099422 . _:b26116337 "results" . _:b536099633 . _:b536099585 . . _:b536099417 . _:b536099632 . _:b536099416 . . _:b536099635 . _:b26116347 "system and methods" . _:b536099419 . _:b536099634 . . . _:b536099459 . _:b536099418 . _:b536099627 . _:b536099531 . . _:b536099429 . _:b536099644 . . _:b536099428 . . _:b536099431 . _:b536099615 . _:b536099430 . _:b536099641 . _:b536099425 . _:b536099640 . _:b536099424 . _:b536099643 . . _:b536099427 . _:b536099642 . _:b536099426 . . _:b536099430 . _:b536099407 "21"^^ . _:b536099633 . _:b536099437 . _:b536099409 . _:b536099440 . . _:b536099436 . _:b536099408 "17"^^ . _:b536099414 "10"^^ . _:b536099439 . _:b536099409 "16"^^ . _:b536099415 "9"^^ . _:b536099513 . _:b536099438 . _:b536099413 "11"^^ . _:b536099410 "15"^^ . . . _:b536099433 . _:b536099412 "11"^^ . . . _:b536099432 . _:b536099411 "13"^^ . _:b536099435 . . . _:b536099434 . _:b536099445 . _:b536099444 . _:b536099422 "8"^^ . _:b536099638 . _:b26116318 "Cancer therapies are hypothesized to eliminate some but not all SPs within a tumor, resulting in altered SP composition of tumors that recur post-treatment (Aktipis et al., 2011; Merlo and Maley, >>2010<<). A better understanding of the SP composition and dynamics of individual tumors is expected to have significant clinical implications especially for highly recurrent and therapy resistant tumors." . . _:b536099447 . _:b536099423 "8"^^ . . _:b536099446 . _:b536099420 "8"^^ . _:b536099441 . . _:b536099421 "8"^^ . _:b26116340 . _:b536099440 . . . _:b536099418 "9"^^ . . _:b26116341 . _:b536099478 . _:b536099443 . _:b536099419 "9"^^ . . . _:b26116338 . _:b536099442 . _:b536099416 "9"^^ . _:b536099521 . . _:b536099522 . _:b536099453 . _:b536099473 . . _:b536099417 "9"^^ . _:b536099430 "6"^^ . _:b26116315 _:b26116316 . _:b536099621 . _:b536099452 . _:b26116315 _:b26116317 . _:b26116315 _:b26116318 . _:b26116315 _:b26116319 . _:b536099431 "6"^^ . . _:b536099455 . _:b536099454 . _:b536099608 . _:b536099428 "7"^^ . _:b536099500 . _:b536099429 "6"^^ . _:b26116315 _:b26116328 . _:b536099449 . _:b26116315 _:b26116329 . . _:b26116315 _:b26116330 . _:b26116315 _:b26116331 . . _:b26116315 _:b26116332 . _:b536099426 "7"^^ . . _:b536099448 . _:b26116315 _:b26116333 . _:b26116315 _:b26116334 . _:b26116315 _:b26116335 . _:b26116315 _:b26116320 . _:b536099427 "7"^^ . _:b536099451 . _:b26116315 _:b26116321 . _:b26116315 _:b26116322 . _:b536099516 . _:b26116315 _:b26116323 . _:b536099549 . _:b26116315 _:b26116324 . _:b536099450 . _:b26116315 _:b26116325 . _:b536099424 "8"^^ . _:b26116315 _:b26116326 . _:b26116333 "These are, however, desirable parameters when quantifying genetic heterogeneity, an emerging biomarker for clinical outcome (Merlo et al., 2010, Mroz et al., >>2013<<)." . _:b536099524 . _:b536099490 . . _:b26116315 _:b26116327 . _:b536099461 . _:b536099425 "8"^^ . _:b26116346 "EXPANDS allows for quantification of tumor purity and of heterogeneity via Shannon index, Simpsons index and genetic divergence (Merlo et al., >>2010<<). In the future, EXPANDS will be applied to a larger patient group for which sequencing data are available to determine tumor purity and SP composition." . _:b536099460 . _:b536099508 . _:b536099437 "5"^^ . . _:b536099494 . _:b26116315 _:b26116336 . _:b536099463 . . _:b536099436 "5"^^ . . _:b536099462 . _:b536099439 "5"^^ . _:b26116349 . _:b536099471 . _:b536099457 . _:b536099438 "5"^^ . _:b536099485 . _:b536099456 . _:b536099415 . _:b536099469 . . _:b536099446 . . _:b536099433 "5"^^ . . _:b536099459 . . _:b26116336 . _:b536099432 "6"^^ . _:b536099460 . _:b536099458 . _:b536099600 . . _:b536099495 . _:b536099435 "5"^^ . _:b536099429 . _:b536099469 . _:b536099552 . _:b536099434 "5"^^ . _:b536099468 . _:b536099622 . _:b536099445 "4"^^ . . _:b536099471 . _:b536099444 "4"^^ . _:b536099594 . _:b536099470 . _:b536099447 "4"^^ . _:b536099465 . _:b536099527 . _:b536099446 "4"^^ . . . _:b536099464 . _:b536099595 . _:b536099441 "4"^^ . . . . _:b536099506 . _:b536099467 . . . _:b536099440 "5"^^ . _:b536099586 . . _:b536099466 . _:b536099443 "4"^^ . _:b536099532 . . . _:b536099477 . . _:b536099442 "4"^^ . _:b26116336 "The authors inferred a plethora of information about the evolution and subclonal structure of this cancer genome by using various ways to look at the data as described in Nik-Zainal et al. (>>2012<<), yet their combined approaches are not available as one automated method." . _:b536099476 . _:b536099453 "4"^^ . _:b26116335 . _:b536099412 . _:b536099479 . _:b536099452 "4"^^ . _:b536099625 . _:b536099478 . _:b536099455 "4"^^ . _:b536099473 . _:b26116326 . _:b536099454 "4"^^ . _:b26116316 "that a single cell of origin or \u2018clone\u2019 that underwent transformation from a normal to a cancerous state undergoes clonal expansion and through successive acquisition of mutations generates genetically diverse subclones (Nowell, >>1976<<). Subsequent pressure from the cancer microenvironment selects the fittest subclone(s), driving their expansion into subpopulations (SPs)." . _:b536099564 . . _:b536099472 . . _:b26116342 _:b26116344 . _:b26116342 _:b26116345 . _:b536099449 "4"^^ . _:b26116342 _:b26116346 . _:b536099475 . _:b536099448 "4"^^ . . _:b536099582 . _:b26116328 . _:b536099606 . _:b26116342 _:b26116343 . _:b536099486 . . _:b536099474 . _:b536099451 "4"^^ . _:b536099611 . . _:b536099485 . _:b536099450 "4"^^ . _:b26116337 _:b26116338 . . _:b26116337 _:b26116339 . _:b26116337 _:b26116340 . _:b536099484 . _:b536099461 "3"^^ . _:b26116337 _:b26116341 . . _:b536099460 "3"^^ . _:b26116339 "We then applied MutSig (Lawrence et al., >>2013<<) on 5173 somatic SNVs assigned to 136 SPD from 69 primary GBM patients whereby we identified genes that were mutated in SPD more often than expected by chance." . _:b536099568 . _:b536099487 . _:b536099456 . _:b536099481 . _:b536099463 "3"^^ . _:b536099486 . _:b536099499 . . _:b536099481 . _:b536099462 "3"^^ . _:b536099457 "3"^^ . _:b536099480 . . . _:b536099584 . _:b536099553 . _:b536099483 . _:b536099456 "3"^^ . _:b536099459 "3"^^ . _:b536099482 . _:b536099510 . _:b26116337 . _:b536099543 . _:b536099458 "3"^^ . _:b536099493 . _:b536099562 . . _:b26116342 . _:b536099492 . _:b536099469 "3"^^ . _:b26116347 _:b26116348 . _:b536099424 . _:b26116347 _:b26116349 . . _:b26116347 _:b26116350 . . _:b536099495 . _:b536099468 "3"^^ . _:b26116347 . _:b536099448 . _:b536099436 . _:b536099471 "3"^^ . _:b536099494 . . _:b536099470 "3"^^ . _:b536099489 . . _:b536099628 . _:b536099503 . _:b536099468 . _:b536099434 . . _:b536099488 . _:b536099484 . _:b536099465 "3"^^ . _:b536099589 . _:b26116325 . _:b536099496 . _:b536099514 . _:b536099464 "3"^^ . _:b536099550 . _:b536099491 . _:b536099410 . . _:b536099450 . _:b536099435 . _:b536099612 . _:b536099490 . _:b536099467 "3"^^ . _:b536099472 . _:b536099466 "3"^^ . _:b536099501 . _:b536099441 . _:b536099547 . _:b536099477 "3"^^ . _:b536099500 . . . _:b536099476 "3"^^ . _:b536099503 . _:b26116315 . _:b536099479 "3"^^ . _:b26116318 . _:b536099502 . _:b536099478 "3"^^ . _:b536099497 . . _:b536099644 . _:b536099473 "3"^^ . _:b536099496 . _:b536099504 . _:b26116330 "Clonal architecture analyses as previously performed for acute lymphoblastic leukemia single cells (Anderson et al., >>2011<<; Navin et al., 2011) are difficult to perform for solid tumors that are a tight mix of distinct SPs and various fractions of non-neoplastic cells." . _:b536099472 "3"^^ . _:b536099499 . _:b536099592 . _:b536099601 . _:b536099539 . _:b536099475 "3"^^ . _:b536099498 . _:b536099411 . _:b26116320 . _:b536099474 "3"^^ . _:b536099509 . _:b536099614 . _:b536099485 "3"^^ . _:b536099508 . _:b536099484 "3"^^ . _:b536099511 . . . _:b536099510 . _:b536099487 "3"^^ . . _:b536099537 . _:b536099486 "3"^^ . _:b536099505 . . _:b536099603 . _:b536099515 . _:b536099481 "3"^^ . _:b536099504 . . _:b536099642 . _:b536099480 "3"^^ . _:b536099538 . _:b536099507 . . . _:b536099528 . _:b536099483 "3"^^ . _:b536099506 . . _:b536099482 "3"^^ . _:b536099517 . _:b536099497 . _:b536099493 "3"^^ . _:b536099516 . . _:b536099519 . _:b536099492 "3"^^ . _:b536099551 . _:b536099495 "2"^^ . _:b536099518 . _:b536099561 . _:b536099579 . . _:b536099513 . _:b536099494 "3"^^ . _:b26116334 "Shah et al. have developed another bioinformatic approach to predict the number and distribution of subclones from deep-sequenced selected mutated genes and to infer the clonal evolution of triple negative breast cancer (Shah et al., >>2012<<). By this method, two SPs with the same mutation in the region that was deep sequenced would be indistinguishable even if greatly divergent in other areas of the genome." . _:b26116344 "Studies in Barrett's esophagus (Merlo et al., >>2010<<) and head and neck squamous cell carcinoma (Mroz et al., 2013) showed that high genetic heterogeneity estimated from geographical studies predicts poor prognosis." . . _:b26116330 . . _:b536099512 . _:b536099489 "3"^^ . _:b26116339 . _:b536099566 . . _:b536099572 . _:b536099515 . _:b536099488 "3"^^ . . . _:b26116327 . . _:b536099514 . _:b536099491 "3"^^ . _:b536099408 . . _:b536099498 . _:b536099490 "3"^^ . _:b536099525 . _:b536099501 "2"^^ . _:b536099524 . _:b536099500 "2"^^ . _:b536099527 . _:b536099503 "2"^^ . _:b536099526 . _:b26116349 "We estimated the prediction accuracy of EXPANDS on mutations detected in a hypermutated ER-positive breast cancer genome\u2014PD4120a (Nik-Zainal et al., >>2012<<). The whole genome of this breast cancer has been sequenced at 188-fold coverage, providing high-quality data to investigate how representative different areas of the genome are of coexisting SPs. We applied EXPANDS to 7175 mutations" . . _:b536099502 "2"^^ . _:b536099521 . _:b536099442 . _:b536099497 "2"^^ . _:b536099640 . _:b536099520 . . _:b536099496 "2"^^ . _:b536099523 . . . . _:b536099449 . _:b536099499 "2"^^ . _:b536099522 . . _:b26116323 . _:b536099498 "2"^^ . _:b536099505 . _:b536099533 . _:b536099479 . _:b536099509 "2"^^ . _:b536099532 . . _:b536099507 . _:b536099508 "2"^^ . _:b536099535 . _:b536099511 "2"^^ . _:b536099534 . . _:b536099577 . _:b536099510 "2"^^ . _:b536099571 . _:b536099529 . _:b536099565 . _:b536099505 "2"^^ . _:b536099528 . _:b536099504 "2"^^ . _:b536099418 . _:b536099531 . . _:b536099507 "2"^^ . _:b536099530 . _:b26116325 "GBM exhibit substantial subclonal diversity as evidenced by previous comparative genomic hybridization (CGH) analyses (Harada et al., 1998), fluorescence in situ hybridization studies (Little et al., >>2012<<; Snuderl et al., 2011; Szerlip et al., 2012) and areal sampling of surgical tissue followed by molecular analyses (Sottoriva et al., 2013)." . _:b536099506 "2"^^ . _:b26116341 "Among the 20 most significantly mutated genes were regulators of transforming growth factor beta signaling (RBBP9 and DPT) and regulators of AKT signaling (TCL1B) (Pruitt et al., >>2012<<) as well as other genes that have not been tested specifically for their role in GBM recurrence (Supplementary Table S3)." . _:b536099541 . . _:b536099556 . _:b536099517 "2"^^ . _:b536099540 . . . _:b536099516 "2"^^ . . _:b536099543 . . _:b536099591 . _:b536099519 "2"^^ . _:b536099542 . _:b536099518 "2"^^ . _:b536099537 . _:b26116334 . _:b536099574 . _:b536099513 "2"^^ . _:b536099536 . _:b536099423 . . _:b26116350 "The Shannon index is a common measure of species diversity in ecology and has recently been adopted to quantify diversity in tumor samples (Merlo et al., >>2010<<). Fig. 4." . _:b536099512 "2"^^ . _:b536099433 . _:b536099539 . _:b536099467 . _:b536099519 . _:b536099515 "2"^^ . . _:b536099538 . . _:b536099512 . _:b536099514 "2"^^ . _:b536099549 . _:b536099525 "2"^^ . . _:b536099548 . _:b536099517 . _:b536099524 "2"^^ . _:b536099551 . _:b536099527 "2"^^ . _:b536099550 . _:b536099526 "2"^^ . . _:b536099545 . . . _:b536099521 "2"^^ . _:b26116322 . _:b536099544 . . . . _:b26116317 "Cancer therapies are hypothesized to eliminate some but not all SPs within a tumor, resulting in altered SP composition of tumors that recur post-treatment (Aktipis et al., >>2011<<; Merlo and Maley, 2010). A better understanding of the SP composition and dynamics of individual tumors is expected to have significant clinical implications especially for highly recurrent and therapy resistant tumors." . _:b536099520 "2"^^ . _:b536099547 . _:b536099554 . _:b536099613 . . _:b536099523 "2"^^ . _:b536099546 . _:b536099522 "2"^^ . _:b536099557 . _:b536099557 . _:b536099576 . . _:b26116332 "These are, however, desirable parameters when quantifying genetic heterogeneity, an emerging biomarker for clinical outcome (Merlo et al., >>2010<<, Mroz et al., 2013)." . . . _:b536099533 "2"^^ . _:b536099480 . _:b536099556 . _:b536099541 . _:b536099616 . _:b536099532 "2"^^ . . _:b536099559 . _:b536099552 . _:b536099553 . _:b536099554 . _:b536099535 "2"^^ . _:b536099555 . _:b536099558 . _:b536099556 . _:b26116343 "In contrast, Tolliver et al. describes tumor mixture separation from gene expression or aCGH data but requires convex combinations of SP sizes\u2014that is, the approach detects SPs with mutually exclusive properties (Tolliver et al., >>2010<<). This is achieved based on the assumptions that genes/probes with similar patterns across multiple subpopulations are eliminated in a principal component analysis step." . . _:b536099557 . _:b536099558 . _:b536099534 "2"^^ . _:b536099559 . _:b536099634 . _:b536099553 . . _:b536099560 . _:b536099561 . _:b536099562 . _:b536099529 "2"^^ . _:b536099563 . _:b536099552 . _:b536099564 . _:b536099565 . _:b536099596 . _:b536099566 . _:b26116329 "Moreover, heterogeneity within GBM is maintained by cross-talk between genetically distinct tumor cell SPs (Inda et al., >>2010<<). However, genome-wide analyses of intra-tumoral heterogeneity and the clonal cellular SP dynamics within GBM have yet to be performed." . _:b536099528 "2"^^ . _:b536099567 . _:b536099555 . . _:b536099568 . _:b536099569 . . _:b536099531 "2"^^ . _:b536099570 . . _:b536099554 . _:b536099571 . _:b536099572 . _:b536099573 . _:b536099526 . . _:b536099574 . _:b536099530 "2"^^ . . _:b536099565 . _:b536099575 . . _:b536099576 . _:b536099577 . _:b536099578 . _:b536099541 "2"^^ . _:b536099579 . _:b536099564 . _:b536099580 . _:b536099581 . _:b536099582 . _:b536099540 "2"^^ . _:b536099583 . _:b536099567 . . _:b536099520 . _:b536099521 . _:b536099522 . _:b536099543 "2"^^ . _:b536099523 . _:b536099566 . _:b536099524 . _:b536099525 . _:b536099526 . _:b536099542 "2"^^ . _:b536099527 . _:b536099561 . _:b536099528 . . _:b536099529 . _:b536099530 . _:b536099537 "2"^^ . _:b536099531 . _:b536099560 . _:b536099532 . _:b536099511 . _:b536099533 . _:b536099534 . _:b536099536 "2"^^ . . _:b536099563 . _:b536099535 . _:b536099536 . _:b536099537 . _:b536099538 . _:b536099539 "2"^^ . _:b536099539 . _:b536099562 . _:b536099540 . _:b536099541 . _:b536099542 . _:b26116316 . _:b536099538 "2"^^ . _:b536099543 . _:b536099573 . _:b536099558 . _:b536099544 . _:b536099545 . _:b536099546 . _:b536099549 "2"^^ . _:b536099547 . _:b536099572 . _:b536099548 . _:b536099549 . _:b536099550 . _:b26116345 . _:b536099548 "2"^^ . _:b536099551 . _:b536099575 . _:b536099488 . _:b536099489 . _:b536099490 . _:b536099551 "2"^^ . _:b536099491 . _:b536099574 . _:b536099451 . . _:b536099492 . _:b536099493 . _:b536099494 . _:b536099550 "2"^^ . _:b536099495 . _:b536099569 . _:b536099426 . . _:b536099496 . _:b536099497 . _:b536099498 . _:b536099545 "2"^^ . _:b536099499 . _:b536099568 . _:b536099482 . _:b536099500 . _:b536099501 . . _:b536099502 . _:b536099544 "2"^^ . _:b536099503 . _:b536099602 . _:b536099571 . _:b536099504 . _:b536099619 . _:b536099505 . _:b536099506 . _:b536099547 "2"^^ . _:b536099507 . _:b536099570 . _:b536099508 . _:b536099509 . _:b536099569 . . _:b536099510 . _:b536099546 . _:b536099546 "2"^^ . _:b536099511 . _:b536099581 . _:b536099512 . _:b536099513 . _:b536099514 . _:b536099557 "2"^^ . _:b536099461 . _:b536099515 . _:b536099580 . . _:b536099516 . _:b536099517 . _:b536099518 . _:b536099556 "2"^^ . . . _:b536099519 . _:b536099583 . _:b536099456 . _:b536099457 . _:b536099462 . _:b536099458 . _:b536099559 "2"^^ . _:b536099459 . _:b536099582 . _:b536099460 . _:b536099461 . _:b536099555 . . _:b536099462 . _:b536099558 "2"^^ . . . _:b536099463 . _:b536099577 . _:b536099464 . _:b536099465 . _:b536099466 . _:b536099553 "2"^^ . . _:b536099467 . _:b536099576 . _:b536099468 . _:b536099469 . _:b536099470 . _:b26116333 . _:b536099552 "2"^^ . _:b536099471 . _:b536099579 . _:b536099472 . . _:b536099473 . _:b536099474 . _:b536099555 "2"^^ . . _:b536099475 . _:b536099578 . _:b536099476 . . _:b536099477 . . _:b536099478 . _:b536099554 "2"^^ . _:b536099479 . _:b536099480 . _:b536099481 . . _:b536099482 . _:b536099565 "2"^^ . _:b536099483 . . _:b536099484 . _:b536099485 . _:b536099525 . _:b536099486 . _:b536099564 "2"^^ . _:b536099487 . . _:b536099424 . _:b536099425 . _:b536099455 . _:b536099426 . _:b536099567 "2"^^ . _:b536099427 . _:b26116319 "Despite aggressive standard therapy, consisting of surgery, radiation and adjuvant chemotherapy with the DNA alkylating drug temozolomide (Stupp et al., >>2009<<), GBM invariably recur within months following initial diagnosis (Konishi et al., 2012) and typically become resistant to the first line therapy they have been exposed (Fan et al., 2010; Lomonaco et al., 2009)." . _:b536099428 . _:b536099489 . . _:b536099429 . _:b536099643 . _:b536099430 . _:b26116329 . _:b536099566 "2"^^ . _:b536099431 . _:b536099583 . . _:b536099432 . _:b536099433 . . _:b536099434 . _:b536099561 "2"^^ . _:b536099435 . . _:b536099436 . _:b536099437 . _:b536099438 . _:b536099560 "2"^^ . _:b536099439 . _:b536099474 . _:b536099440 . _:b536099559 . _:b536099535 . _:b536099441 . _:b536099442 . _:b536099563 "2"^^ . . . _:b536099443 . . . _:b536099444 . _:b536099445 . _:b536099446 . _:b536099562 "2"^^ . _:b536099447 . . _:b536099448 . _:b536099449 . . _:b536099450 . _:b536099573 "2"^^ . . _:b536099451 . _:b536099452 . _:b536099453 . _:b536099454 . _:b536099572 "2"^^ . _:b536099466 . _:b536099455 . . _:b536099575 "2"^^ . . _:b536099574 "2"^^ . . . _:b26116327 "substantial subclonal diversity as evidenced by previous comparative genomic hybridization (CGH) analyses (Harada et al., 1998), fluorescence in situ hybridization studies (Little et al., 2012; Snuderl et al., 2011; Szerlip et al., >>2012<<) and areal sampling of surgical tissue followed by molecular analyses (Sottoriva et al., 2013)." . _:b536099483 . _:b536099569 "2"^^ . _:b536099421 . _:b536099568 "2"^^ . _:b536099407 . _:b536099626 . . _:b536099408 . _:b536099409 . _:b536099410 . _:b536099571 "2"^^ . _:b536099411 . _:b536099412 . . _:b536099413 . _:b536099414 . _:b536099570 "2"^^ . _:b536099415 . _:b536099416 . _:b26116317 . _:b536099417 . _:b536099418 . _:b536099581 "2"^^ . _:b536099419 . _:b536099420 . _:b536099421 . _:b536099632 . _:b536099422 . _:b536099610 . _:b536099580 "2"^^ . _:b536099509 . _:b536099423 . . . . _:b536099583 "2"^^ . _:b536099639 . _:b536099582 "2"^^ . . . _:b536099577 "2"^^ . _:b536099597 . _:b536099439 . . _:b536099576 "2"^^ . . _:b536099579 "2"^^ . _:b536099518 . _:b536099578 "2"^^ . _:b536099589 "2"^^ . _:b536099432 . _:b536099588 "2"^^ . . _:b536099591 "2"^^ . _:b26116321 . _:b26116315 "introduction" . _:b536099590 . _:b536099437 . _:b536099590 "2"^^ . . . _:b536099585 "2"^^ . . . _:b536099584 "2"^^ . "10.1093%2Fbioinformatics%2Fbtt622" . . _:b536099417 . _:b536099587 "2"^^ . _:b536099586 "2"^^ . . _:b536099597 "2"^^ . . _:b536099425 . . _:b536099599 . _:b536099596 "2"^^ . . . _:b536099428 . _:b536099523 . . _:b536099599 "2"^^ . . . _:b536099443 . _:b536099598 "2"^^ . _:b536099593 "2"^^ . . . _:b536099534 . _:b536099592 "2"^^ . . _:b536099536 . _:b536099637 . _:b536099623 . _:b536099457 . _:b536099595 "2"^^ . _:b536099533 . _:b536099548 . _:b536099594 "2"^^ . _:b536099407 . . _:b26116328 "(CGH) analyses (Harada et al., 1998), fluorescence in situ hybridization studies (Little et al., 2012; Snuderl et al., 2011; Szerlip et al., 2012) and areal sampling of surgical tissue followed by molecular analyses (Sottoriva et al., >>2013<<). Moreover, heterogeneity within GBM is maintained by cross-talk between genetically distinct tumor cell SPs (Inda et al., 2010)." . _:b536099605 "2"^^ . _:b536099491 . _:b26116345 "Studies in Barrett's esophagus (Merlo et al., 2010) and head and neck squamous cell carcinoma (Mroz et al., >>2013<<) showed that high genetic heterogeneity estimated from geographical studies predicts poor prognosis." . _:b536099635 . _:b536099604 "2"^^ . . _:b536099578 . _:b536099607 "2"^^ . . _:b536099606 "2"^^ . _:b536099601 "2"^^ . _:b536099600 "2"^^ . . _:b536099427 . _:b536099603 "2"^^ . . . _:b536099630 . _:b26116324 . _:b536099602 "2"^^ . _:b536099613 "2"^^ . _:b536099624 . _:b536099612 "2"^^ . . _:b536099615 "2"^^ . . _:b536099614 "2"^^ . . _:b536099609 "2"^^ . . . _:b26116323 "An SP with stem-like properties, the cancer stem cells, is one potential culprit for recurrence and therapy resistance in GBM (Chen et al., >>2012<<; Schonberg et al., 2013)." . _:b536099608 "2"^^ . . _:b536099629 . _:b536099611 "2"^^ . _:b536099458 . _:b536099431 . . _:b536099610 "2"^^ . _:b26116342 "discussion" . . _:b536099621 "2"^^ . _:b536099501 . . _:b26116326 "GBM exhibit substantial subclonal diversity as evidenced by previous comparative genomic hybridization (CGH) analyses (Harada et al., 1998), fluorescence in situ hybridization studies (Little et al., 2012; Snuderl et al., >>2011<<; Szerlip et al., 2012) and areal sampling of surgical tissue followed by molecular analyses (Sottoriva et al., 2013)." . _:b536099609 . . _:b536099454 . "PMC0" . _:b536099620 "2"^^ . . _:b536099617 . _:b536099623 "2"^^ . . _:b536099598 . . _:b536099622 "2"^^ . _:b536099605 . _:b536099617 "2"^^ . _:b536099414 . . _:b536099542 . _:b536099477 . . _:b536099616 "2"^^ . _:b536099619 "2"^^ . . _:b26116331 . . . _:b536099618 "2"^^ . . . . _:b536099629 "2"^^ . . _:b536099628 "2"^^ . _:b536099416 . _:b536099573 . _:b536099631 "2"^^ . _:b536099618 . _:b536099630 "2"^^ . _:b536099567 . _:b536099636 . . _:b536099625 "2"^^ . _:b536099624 "2"^^ . _:b536099627 "2"^^ . _:b26116348 . _:b536099626 "2"^^ . _:b536099476 . . . _:b536099637 "2"^^ .