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Single cell genomic variation induced by mutational processes in cancer

How cell-to-cell copy number alterations that underpin genomic instability in human cancers drive genomic and phenotypic variation, and consequently cancer evolution, remains understudied. Here, applying scaled single cell whole genome sequencing to wildtype, TP53-deficient and TP53/BRCA1/2-deficient mammary epithelial cells (n=13,818 genomes) and primary triple negative breast (TNBC) and high grade serous ovarian cancers (HGSC) (n=22,057 genomes), we identified three distinct ‘foreground’ mutational patterns defined by cell-to-cell copy number and structural variation properties occurring in the ‘background’ of cancer-associated genomic instability. Cell and clone-specific high level amplifications (HLAMPs), parallel allele-specific copy number alterations and copy number segment length variation (serrate structural variations) exhibited measurable phenotypic and evolutionary consequences. Clone-specific HLAMPs in known oncogenes were highly prevalent in fold back inversion (FBI)-bearing tumors and associated with increased clone-to-clone phenotypic variation in gene expression inferred from matched single cell RNASeq. Parallel allele-specific alterations were linked with phylogenetically determined evolutionary diversity and clone-specific mono-allelic expression. Serrate patterns present across all clones were increased in FBI tumors, most prominently on a tetraploid background and were highly correlated with increased genomic diversity of cellular populations. Taken together, we show that cell-to-cell structural-copy number variation significantly impacts the phenotypes and evolutionary diversity of TNBC and HGSC, revealing previously hidden genomic states of cancer cells.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001009111 Illumina HiSeq 2500 1
EGAD00001009112 Illumina HiSeq 2500 1
EGAD00001009113 Illumina HiSeq 2500 1
EGAD00001009114 Illumina HiSeq 2500 1
EGAD00001009115 BGISEQ-500 1
EGAD00001009116 Illumina HiSeq 2500 1
EGAD00001009117 Illumina HiSeq 2500 1
EGAD00001009118 Illumina HiSeq 2500 1
EGAD00001009119 NextSeq 500 1
EGAD00001009120 Illumina HiSeq 2500 1
EGAD00001009121 NextSeq 500 1
EGAD00001009122 NextSeq 500 1
EGAD00001009123 NextSeq 500 1
EGAD00001009124 NextSeq 500 1
EGAD00001009125 NextSeq 500 1
EGAD00001009126 NextSeq 500 1
EGAD00001009127 NextSeq 500 1
EGAD00001009128 Illumina HiSeq 2500 1
EGAD00001009129 NextSeq 500 1
EGAD00001009130 NextSeq 500 1
EGAD00001009131 NextSeq 500 1
EGAD00001009132 NextSeq 500 1
EGAD00001009133 HiSeq X Ten 1
EGAD00001009134 HiSeq X Ten 1
EGAD00001009135 Illumina HiSeq 2500 1
EGAD00001009136 Illumina HiSeq 2500 1
EGAD00001009137 Illumina HiSeq 2500 1
EGAD00001009138 Illumina HiSeq 2500 1
EGAD00001009139 NextSeq 500 1
EGAD00001009140 NextSeq 500 1
EGAD00001009141 Illumina HiSeq 2500 1
EGAD00001009142 NextSeq 500 1
EGAD00001009143 HiSeq X Ten 1
EGAD00001009144 HiSeq X Ten 1
EGAD00001009145 NextSeq 500 1
EGAD00001009146 HiSeq X Ten 1
EGAD00001009147 Illumina HiSeq 2500 1
EGAD00001009148 NextSeq 500 1
EGAD00001009149 BGISEQ-500 1
EGAD00001009150 Illumina HiSeq 2500 1
EGAD00001009151 HiSeq X Ten 1
EGAD00001009152 BGISEQ-500 1
EGAD00001009153 Illumina HiSeq 2500 1
EGAD00001009154 Illumina HiSeq 2500 1
EGAD00001009155 HiSeq X Ten 1
EGAD00001009156 HiSeq X Ten 1
EGAD00001009157 Illumina HiSeq 2500 1
EGAD00001009158 HiSeq X Ten 1
EGAD00001009159 NextSeq 500 1
EGAD00001009160 HiSeq X Ten 1
EGAD00001009177 Illumina HiSeq 2500 1
EGAD00001009178 Illumina HiSeq 2500 1
EGAD00001009179 Illumina HiSeq 2500 1
EGAD00001009180 Illumina HiSeq 2500 1
EGAD00001009181 Illumina HiSeq 2500 1
EGAD00001009182 Illumina HiSeq 2500 1
EGAD00001009183 Illumina HiSeq 2500 1
EGAD00001009184 Illumina HiSeq 2500 1
EGAD00001009185 Illumina HiSeq 2500 1
EGAD00001009186 Illumina HiSeq 2500 1
EGAD00001009187 Illumina HiSeq 2500 1
EGAD00001009188 Illumina HiSeq 2500 1
EGAD00001009189 Illumina HiSeq 2500 1
EGAD00001009190 Illumina HiSeq 2500 1
EGAD00001009191 Illumina HiSeq 2000 1
EGAD00001009192 Illumina HiSeq 2500 1
EGAD00001009193 Illumina HiSeq 2500 1
EGAD00001009194 Illumina HiSeq 2500 1
EGAD00001009195 Illumina HiSeq 2500 1
EGAD00001009196 Illumina HiSeq 2500 1
EGAD00001009197 Illumina HiSeq 2500 1
EGAD00001009198 Illumina HiSeq 2500 1
EGAD00001009199 Illumina HiSeq 2500 1
EGAD00001009200 Illumina HiSeq 2500 1
EGAD00001009201 Illumina HiSeq 2500 1
EGAD00001009202 Illumina HiSeq 2500 1
EGAD00001009203 Illumina HiSeq 2500 1
EGAD00001009204 Illumina HiSeq 2500 1
EGAD00001009205 Illumina HiSeq 2500 1
EGAD00001009206 Illumina HiSeq 2500 1
EGAD00001009207 Illumina HiSeq 2500 1
EGAD00001009208 Illumina HiSeq 2500 1
EGAD00001009209 Illumina HiSeq 2500 1
EGAD00001009210 Illumina HiSeq 2500 1
EGAD00001009211 Illumina HiSeq 2500 1
EGAD00001009212 Illumina HiSeq 2500 1
EGAD00001009213 Illumina HiSeq 2500 1
EGAD00001009214 Illumina HiSeq 2500 1
EGAD00001009215 Illumina HiSeq 2000 1
EGAD00001009216 Illumina HiSeq X 1
EGAD00001009217 Illumina HiSeq 2500 1
EGAD00001009218 Illumina HiSeq 2500 1
EGAD00001009219 Illumina HiSeq 2500 1
EGAD00001009220 Illumina HiSeq 2500 1
EGAD00001009221 Illumina HiSeq 2500 1
EGAD00001009222 Illumina HiSeq 2500 1
EGAD00001009223 Illumina HiSeq 2500 1
EGAD00001009224 Illumina HiSeq 2500 1
EGAD00001009225 Illumina HiSeq 2500 1
EGAD00001009226 Illumina HiSeq 2500 1
EGAD00001009227 Illumina HiSeq 2500 1
EGAD00001009228 Illumina HiSeq 2500 1
EGAD00001009229 Illumina HiSeq 2500 1
EGAD00001009230 Illumina HiSeq 2500 1
EGAD00001009231 Illumina HiSeq 2500 1
EGAD00001009232 Illumina HiSeq 2500 1
EGAD00001009233 Illumina HiSeq 2500 1
EGAD00001009234 Illumina HiSeq 2500 1
EGAD00001009235 Illumina HiSeq 2000 1
EGAD00001009236 Illumina HiSeq 2500 1
EGAD00001009237 Illumina HiSeq 2500 1
EGAD00001009238 Illumina HiSeq 2500 1
EGAD00001009239 Illumina HiSeq 2500 1
EGAD00001009240 Illumina HiSeq 2500 1
EGAD00001009241 Illumina HiSeq 2500 1
EGAD00001009242 Illumina HiSeq 2500 1
EGAD00001009243 Illumina HiSeq 2500 1
EGAD00001009244 Illumina HiSeq 2500 1
EGAD00001009245 Illumina HiSeq 2500 1
EGAD00001009246 Illumina HiSeq 2500 1
EGAD00001009247 Illumina HiSeq 2500 1
EGAD00001009248 Illumina HiSeq 2500 1
EGAD00001009249 Illumina HiSeq 2500 1
EGAD00001009250 Illumina HiSeq 2500 1
EGAD00001009251 Illumina HiSeq 2500 1
EGAD00001009252 Illumina HiSeq 2500 1
EGAD00001009253 Illumina HiSeq 2500 1
EGAD00001009254 Illumina HiSeq 2500 1
EGAD00001009255 Illumina HiSeq 2500 1
EGAD00001009256 Illumina HiSeq 2500 1
EGAD00001009257 Illumina HiSeq 2500 1
EGAD00001009258 Illumina HiSeq X 1
EGAD00001009259 Illumina HiSeq X 1
EGAD00001009260 Illumina HiSeq 2500 1
EGAD00001009261 Illumina HiSeq 2500 1
EGAD00001009262 Illumina HiSeq 2500 1
EGAD00001009316 NextSeq 550 15
EGAD00001009319 HiSeq X Ten 3
EGAD00001009320 HiSeq X Ten 3
EGAD00001009321 Illumina HiSeq 2500 7
EGAD00001009322 NextSeq 550 8
EGAD00001009323 HiSeq X Ten 3
EGAD00001009324 Illumina HiSeq 2500 4
EGAD00001009325 HiSeq X Ten 3
EGAD00001009326 HiSeq X Ten 2
EGAD00001009327 HiSeq X Ten 3
EGAD00001009340 Illumina HiSeq 2500 1
EGAD00001009341 Illumina HiSeq 2500 1
EGAD00001009342 Illumina HiSeq 2500 1
EGAD00001009343 Illumina HiSeq 2500 1
EGAD00001009344 Illumina HiSeq 2500 1
EGAD00001009345 Illumina HiSeq 2500 1
EGAD00001009346 Illumina HiSeq 2500 1
EGAD00001009347 Illumina HiSeq 2500 1
EGAD00001009348 Illumina HiSeq 2500 1
EGAD00001009349 Illumina HiSeq 2500 1
EGAD00001009350 Illumina HiSeq 2500 1
EGAD00001009351 Illumina HiSeq 2000 1
EGAD00001009352 Illumina HiSeq 2000 1
EGAD00001009353 Illumina HiSeq 2000 1
EGAD00001009354 Illumina HiSeq 2000 1
EGAD00001009355 Illumina HiSeq 2000 1
EGAD00001009356 Illumina HiSeq 2000 1
EGAD00001009357 Illumina HiSeq 2000 1
EGAD00001009358 Illumina HiSeq 2000 1
EGAD00001009359 Illumina HiSeq 2000 1
EGAD00001009360 Illumina HiSeq 2000 1
EGAD00001009361 Illumina HiSeq 2000 1
EGAD00001009362 Illumina HiSeq 2000 1
EGAD00001009363 Illumina HiSeq 2000 1
EGAD00001009364 Illumina HiSeq 2000 1
EGAD00001009365 Illumina HiSeq 2000 1
EGAD00001009366 Illumina HiSeq 2000 1
EGAD00001009367 Illumina HiSeq 2000 1
EGAD00001009368 Illumina HiSeq 2000 1
EGAD00001009369 Illumina HiSeq 2000 1
EGAD00001009370 Illumina HiSeq 2000 1
EGAD00001009371 Illumina HiSeq 2000 1
EGAD00001009372 Illumina HiSeq 2000 1
EGAD00001009373 Illumina HiSeq 2500 1
EGAD00001009374 Illumina HiSeq 2500 1
EGAD00001009375 Illumina HiSeq 2500 1
EGAD00001009376 Illumina HiSeq 2500 1
EGAD00001009377 Illumina HiSeq 2500 1
EGAD00001009378 Illumina HiSeq 2500 1
EGAD00001009379 Illumina HiSeq 2500 1
EGAD00001009380 Illumina HiSeq 2500 1
EGAD00001009381 Illumina HiSeq 2500 1
EGAD00001009382 Illumina HiSeq 2500 1
EGAD00001009383 Illumina HiSeq 2500 1
EGAD00001009428 HiSeq X Ten 3
EGAD00001009429 HiSeq X Ten 4
EGAD00001009430 HiSeq X Ten 4
EGAD00001009431 HiSeq X Ten 3
EGAD00001009432 HiSeq X Ten 4
EGAD00001009433 NextSeq 2000 4
EGAD00001009434 HiSeq X Ten 3
EGAD00001009435 HiSeq X Ten 6
EGAD00001009436 HiSeq X Ten 6
EGAD00001009437 HiSeq X Ten 6
EGAD00001009438 HiSeq X Ten 4
EGAD00001009439 HiSeq X Ten 6
EGAD00001009440 HiSeq X Ten 4
EGAD00001009441 HiSeq X Ten 4
EGAD00001009442 HiSeq X Ten 4
EGAD00001009443 HiSeq X Ten 4
EGAD00001009444 HiSeq X Ten 4
EGAD00001009445 HiSeq X Ten 4
EGAD00001009446 HiSeq X Ten 3
EGAD00001009447 HiSeq X Ten 3
EGAD00001009448 NextSeq 550 3
EGAD00001009449 NextSeq 550 3
EGAD00001009450 HiSeq X Ten 3
EGAD00001009451 HiSeq X Ten 7
EGAD00001009452 HiSeq X Ten 5
EGAD00001009453 NextSeq 550 6
EGAD00001009454 HiSeq X Ten 3
EGAD00001009455 HiSeq X Ten 3
EGAD00001009456 HiSeq X Ten 5
EGAD00001009457 HiSeq X Ten 5
EGAD00001009458 HiSeq X Ten 7
EGAD00001009459 HiSeq X Ten 7
EGAD00001009460 HiSeq X Ten 3
EGAD00001009461 HiSeq X Ten 3
EGAD00001009462 HiSeq X Ten 3
EGAD00001009463 HiSeq X Ten 3
EGAD00001009464 HiSeq X Ten 10
EGAD00001009465 HiSeq X Ten 3
EGAD00001009466 HiSeq X Ten 3
EGAD00001009467 HiSeq X Ten 5
EGAD00001009468 HiSeq X Ten 3
EGAD00001009469 HiSeq X Ten 3
EGAD00001009470 HiSeq X Ten 3
EGAD00001009471 HiSeq X Ten -
EGAD00001009472 HiSeq X Ten 3
EGAD00001009473 HiSeq X Ten 3
EGAD00001009474 HiSeq X Ten 3
EGAD00001009475 HiSeq X Ten 3
EGAD00001009476 HiSeq X Ten 5
EGAD00001009477 HiSeq X Ten 5
EGAD00001009478 NextSeq 550 11
EGAD00001009479 HiSeq X Ten 6
EGAD00001009480 HiSeq X Ten 4
EGAD00001009481 HiSeq X Ten 6
EGAD00001009486 HiSeq X Ten -
EGAD00001009487 Illumina HiSeq 2500 1
EGAD00001009488 Illumina HiSeq 2500 3
EGAD00001009489 HiSeq X Ten 3
EGAD00001009513 HiSeq X Ten 212
EGAD00001009517 Illumina HiSeq 2000 1
EGAD00001009518 Illumina HiSeq 2500 1
EGAD00001009519 Illumina HiSeq 2000 1
EGAD00001009520 Illumina HiSeq 2500 1
EGAD00001009521 Illumina HiSeq 2500 1
EGAD00001009522 Illumina HiSeq 2000 1
EGAD00001009523 Illumina HiSeq X 1
EGAD00001009524 Illumina HiSeq X 1
EGAD00001009525 Illumina HiSeq X 1
EGAD00001009526 Illumina HiSeq X 1
EGAD00001009527 Illumina HiSeq X 1
EGAD00001009528 Illumina HiSeq X 1
EGAD00001009529 Illumina HiSeq X 1
EGAD00001009530 Illumina HiSeq X 1
EGAD00001009531 Illumina HiSeq X 1
EGAD00001009532 Illumina HiSeq X 1
EGAD00001009533 Illumina HiSeq X 1
EGAD00001009534 Illumina HiSeq X 1
EGAD00001009535 Illumina HiSeq X 1
EGAD00001009536 Illumina HiSeq X 1
EGAD00001009537 Illumina HiSeq X 1
EGAD00001009538 Illumina HiSeq X 1
EGAD00001009539 Illumina HiSeq X 1
EGAD00001009540 Illumina HiSeq X 1
EGAD00001009541 Illumina HiSeq X 1
EGAD00001009542 Illumina HiSeq X 1
EGAD00001009543 Illumina HiSeq 2000 1
EGAD00001009544 Illumina HiSeq X 1
EGAD00001009545 Illumina HiSeq X 1
EGAD00001009546 Illumina HiSeq X 1
EGAD00001009547 Illumina HiSeq X 1
EGAD00001009548 Illumina HiSeq X 1
EGAD00001009549 Illumina HiSeq X 1
EGAD00001009550 Illumina HiSeq X 1
EGAD00001009551 Illumina HiSeq X 1
EGAD00001009552 Illumina HiSeq X 1
EGAD00001009553 Illumina HiSeq X 1
EGAD00001009554 Illumina HiSeq X 1
EGAD00001009555 Illumina HiSeq 2000 1
EGAD00001009556 Illumina HiSeq X 1
EGAD00001009557 Illumina HiSeq X 1
EGAD00001009558 Illumina HiSeq X 1
EGAD00001009559 Illumina HiSeq X 1
EGAD00001009560 Illumina HiSeq X 1
EGAD00001009561 Illumina HiSeq X 1
EGAD00001009562 Illumina HiSeq X 1
EGAD00001009563 Illumina HiSeq 2500 1
EGAD00001009564 Illumina HiSeq 2500 1
EGAD00001009565 Illumina HiSeq X 1
EGAD00001009566 Illumina HiSeq 2500 1
EGAD00001009567 Illumina HiSeq X 1
EGAD00001009568 Illumina HiSeq X 1
EGAD00001009569 Illumina HiSeq 2500 1
EGAD00001009570 Illumina HiSeq 2500 1
EGAD00001009571 Illumina HiSeq 2000 1
EGAD00001009572 Illumina HiSeq 2500 1
EGAD00001009573 Illumina HiSeq X 1
EGAD00001009574 Illumina HiSeq X 1
EGAD00001009575 Illumina HiSeq X 1
EGAD00001009576 Illumina HiSeq X 1
EGAD00001009577 Illumina HiSeq 2000 1
EGAD00001009578 Illumina HiSeq 2500 1
EGAD00001009579 Illumina HiSeq 2000 1
EGAD00001009580 Illumina HiSeq 2000 1
EGAD00001009581 Illumina HiSeq X 1
EGAD00001009582 Illumina HiSeq 2500 1
EGAD00001009583 Illumina HiSeq 2500 1
EGAD00001009584 Illumina HiSeq 2500 1
EGAD00001009585 Illumina HiSeq 2500 1
EGAD00001009586 Illumina HiSeq X 1
EGAD00001009587 Illumina HiSeq X 1
EGAD00001009588 Illumina HiSeq X 1
EGAD00001009589 Illumina HiSeq X 1
EGAD00001009590 Illumina HiSeq X 1
EGAD00001009591 Illumina HiSeq X 1
EGAD00001009592 Illumina HiSeq X 1
EGAD00001009593 Illumina HiSeq X 1
EGAD00001009594 Illumina HiSeq X 1
EGAD00001009595 Illumina HiSeq X 1
EGAD00001009596 Illumina HiSeq 2000 1
EGAD00001009597 Illumina HiSeq 2500 1
EGAD00001009598 Illumina HiSeq X 1
EGAD00001009599 Illumina HiSeq X 1
EGAD00001009600 Illumina HiSeq 2000 1
EGAD00001009601 Illumina HiSeq 2500 1
EGAD00001009602 Illumina HiSeq 2000 1
EGAD00001009603 Illumina HiSeq X 1
EGAD00001009604 Illumina HiSeq 2500 1
EGAD00001009605 Illumina HiSeq X 1
EGAD00001009606 Illumina HiSeq X 1
EGAD00001009607 Illumina HiSeq X 1
EGAD00001009608 Illumina HiSeq X 1
EGAD00001009609 Illumina HiSeq X 1
EGAD00001009610 Illumina HiSeq X 1
EGAD00001009611 Illumina HiSeq X 1
EGAD00001009612 Illumina HiSeq X 1
EGAD00001009613 Illumina HiSeq 2500 1
EGAD00001009614 Illumina HiSeq X 1
EGAD00001009615 Illumina HiSeq X 1
EGAD00001009616 Illumina HiSeq X 1
EGAD00001009617 Illumina HiSeq 2500 1
EGAD00001009618 Illumina HiSeq X 1
EGAD00001009619 Illumina HiSeq X 1
EGAD00001009620 Illumina HiSeq X 1
EGAD00001009621 Illumina HiSeq X 1
EGAD00001009644 HiSeq X Ten 5
EGAD00001009645 HiSeq X Ten 6
EGAD00001009646 HiSeq X Ten -
EGAD00001009672 Illumina HiSeq X 1
EGAD00001009673 Illumina HiSeq X 1
EGAD00001009674 Illumina HiSeq X 1
EGAD00001009777 HiSeq X Ten 1
Publications Citations
Single-cell genomic variation induced by mutational processes in cancer.
Nature 612: 2022 106-115
36
Allele-specific transcriptional effects of subclonal copy number alterations enable genotype-phenotype mapping in cancer cells.
Nat Commun 15: 2024 2482
3
Single-cell mtDNA dynamics in tumors is driven by coregulation of nuclear and mitochondrial genomes.
Nat Genet 56: 2024 889-899
1