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Characterization of individual foci of multicentric/multifocal breast cancer using targeted next generation sequencing

Multifocality or multicentricity in breast cancer may be defined as the presence of two or more tumor foci within a single quadrant of the breast or within different quadrants of the same breast, respectively. This original classification of the breast cancer as multicentric or multifocal was based on the assumption that cancers arising in the same quadrant were more likely to arise from the same ductal structures than those occurring in separate areas of the breast. The problem with these definitions is that the ?quadrants? of the breast are arbitrary external designations, as no internal boundaries do exist. This project will therefore focus both on synchronous multifocal and multicentric tumors. The incidence of multifocal and multicentric breast cancers was reported to be between 13 and 75% depending on the definition used, the extent of the pathologic sampling of the breast and whether in situ disease is considered evidence of multicentricity (1). Although this incidence is variable, those figures show that it is a frequent phenomenon. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic management of the cancer. Multifocality or multicentricity has been associated with a number of more aggressive features including an increased rate of regional lymph node metastases and adverse patient outcome when compared with unifocal tumors (2-3), and a possible increased risk of local recurrence following breast conserving surgery (4). For the moment, the literature is divided on whether there is a corresponding impact on survival outcomes. Today, the current convention to stage and to treat multifocal and multicentric tumors is the classical tumor-node-metastasis (TNM) staging guidelines with which tumor size is assessed by the largest tumor focus without taking other foci of disease into consideration. If some papers, as the recent one from Lynch and colleagues, support the current staging convention (3), others, however, as Boyages et al. suggested that aggregate size and not the size of the largest lesion should be considered in order to refine the prognostic assessment of those tumors (5). On the top of that, the question whether multifocal/multicentric carcinomas are due to the spread of a single carcinoma throughout the breast or is due to multiple carcinomas arising simultaneously has been a matter of debate. Some studies suggested that multifocal breast cancer may result from either intramammary spread from a single primary tumor or multiple synchronous primary tumors; whereas others suggest that multiple breast carcinomas always arise from the same clone (6-8). Recently, Pietri and colleagues analyzed the biological characterization of a series of 113 multifocal/multicentric breast cancers (8) which were diagnosed over a 5-year period. The expression of estrogen (ER) and progesterone (PgR) receptors, Ki-67 proliferative index, expression of HER2 and tumor grading were prospectively determined in each tumor focus, and mismatches among foci were recorded. Mismatches in ER status were present in 5 (4.4%) cases and PgR in 18 (15.9%) cases. Mismatches in tumor grading were present in 21 cases (18.6%), proliferative index (Ki-67) in 17 (15%) cases and HER2 status in 11 (9.7%) cases. Interestingly, this heterogeneity among foci has led to 14 (12.4%) patients receiving different adjuvant treatments compared with what would have been indicated if we had only taken into account the biologic status of the primary tumor. This study therefore showed that differences in biological characteristics of multifocal/multicentric lesions play a crucial role in the adjuvant treatment decision making process. In this study, we will concentrate on a larger series of patients with multifocal invasive ductal breast cancer lesions. We aim at: 1. Evaluating the incidence of multifocality according to the different breast cancer molecular subtypes (ER-/HER2-, HER2+, ER+/HER2-). 2. Evaluating the incidence of multifocality in patients with hereditary breast cancer disease (presence of germline BRCA1 or BRCA2 mutations). Moreover, we would like to investigate if multifocal lesions with BRCA1 or BRCA2 mutations exhibit a characteristic combination of substitution mutation signatures and a distinctive profile of deletions as demonstrated recently by Nik-Zainal and colleagues (9). 3. Correlating multifocality with clinical information in order to define its influence on patients? survival (DFS and OS). 4. Carrying high coverage targeted gene sequencing of driver cancer genes and genes whose mutation is of therapeutic importance in order to compare clinically-relevant genetic differences between several multifocal breast cancer lesions. 5. Evaluating the impact of the distance between the different lesions on the clinical outcome but also on the genetic differences. 6. Comparing gene expression patterns between several multifocal breast cancer lesions and correlate them with the results of the targeted genes screen. 7. Characterizing the genomic and transcriptomic status of cancer related genes in metastatic lesions (local recurrence, positive lymph node or distant metastatic sites) from the same multifocal invasive ductal breast cancer patients in order to evaluate the consequence of genomic and transcriptomic heterogeneity of multifocal lesions on metastatic lesions. Multiple (multifocal/multicentric) breast carcinomas, especially when occurring in the same breast, represent a real challenge for both pathologists and clinicians in terms of identifying the cellular origin and the best therapeutic choice. This project has the potential to identify genetic/transcriptomic differences existing between several lesions constituting multifocal breast cancers, which in the routine clinical practice are usually considered to be homogeneous among them. We foresee validating significant results in a larger series of patients and this, in turn, could have a remarkable impact on the treatment and clinical management of multifocal breast cancers. Indeed, we hope to provide some evidence whether or not each focus matters in multifocal and multicentric breast cancer to define the adequate therapeutic approach, especially in the context of targeted therapies. The work to be done at Sanger will be target gene screen pooling of 1400 samples.

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Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001000407 Cancer Genomics

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00000230666 bam 829.7 MB
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EGAF00000231628 bam 1.0 GB
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EGAF00000697241 cram 1.2 GB
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EGAF00000697243 cram 1.2 GB
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EGAF00000697247 cram 1.2 GB
EGAF00000697248 cram 1.2 GB
EGAF00000697249 cram 911.6 MB
EGAF00000697250 cram 1.0 GB
EGAF00000697251 cram 967.9 MB
EGAF00000697252 cram 965.0 MB
EGAF00000697253 cram 952.4 MB
EGAF00000697254 cram 814.9 MB
EGAF00000697255 cram 1.1 GB
EGAF00000697256 cram 1.3 GB
EGAF00000697257 cram 998.4 MB
EGAF00000697258 cram 1.1 GB
EGAF00000697259 cram 1.3 GB
EGAF00000697260 cram 931.1 MB
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EGAF00000697262 cram 1.0 GB
EGAF00000697263 cram 1.0 GB
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EGAF00000697265 cram 914.0 MB
EGAF00000697266 cram 720.2 MB
EGAF00000697267 cram 725.6 MB
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EGAF00000697280 cram 879.0 MB
EGAF00000697281 cram 810.1 MB
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EGAF00000697283 cram 1.2 GB
EGAF00000697284 cram 1.1 GB
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EGAF00000697286 cram 1.0 GB
EGAF00000697287 cram 1.2 GB
EGAF00000697288 cram 1.3 GB
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EGAF00000697290 cram 1.4 GB
EGAF00000697291 cram 1.4 GB
EGAF00000697292 cram 1.1 GB
EGAF00000697293 cram 1.1 GB
EGAF00000697294 cram 1.2 GB
EGAF00000697295 cram 1.6 GB
EGAF00000697296 cram 1.6 GB
EGAF00000697297 cram 1.9 GB
EGAF00000697298 cram 1.9 GB
EGAF00000697299 cram 2.1 GB
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EGAF00000697301 cram 2.3 GB
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EGAF00000697303 cram 1.7 GB
EGAF00000697304 cram 1.6 GB
EGAF00000697305 cram 1.9 GB
EGAF00000697306 cram 1.4 GB
EGAF00000697307 cram 1.5 GB
EGAF00000697308 cram 1.7 GB
EGAF00000697309 cram 1.7 GB
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EGAF00000697313 cram 1.4 GB
EGAF00000697314 cram 1.5 GB
EGAF00000697315 cram 1.3 GB
EGAF00000697316 cram 1.4 GB
EGAF00000697317 cram 1.5 GB
EGAF00000697318 cram 1.5 GB
EGAF00000697319 cram 1.4 GB
EGAF00000697320 cram 1.4 GB
EGAF00000697321 cram 1.3 GB
EGAF00000697322 cram 2.9 GB
EGAF00000697323 cram 3.2 GB
EGAF00000697324 cram 2.9 GB
EGAF00000697325 cram 3.3 GB
EGAF00000697326 cram 3.3 GB
EGAF00000697327 cram 2.9 GB
EGAF00000697328 cram 3.1 GB
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EGAF00000697331 cram 1.6 GB
EGAF00000697332 cram 1.7 GB
EGAF00000697333 cram 1.7 GB
EGAF00000697334 cram 1.8 GB
EGAF00000697335 cram 1.5 GB
EGAF00000697336 cram 1.6 GB
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EGAF00000697338 cram 1.5 GB
EGAF00000697339 cram 1.8 GB
EGAF00000697340 cram 1.8 GB
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EGAF00000697342 cram 1.3 GB
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EGAF00000697344 cram 1.3 GB
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EGAF00000697352 cram 1.2 GB
EGAF00000697353 cram 1.2 GB
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EGAF00000697359 cram 1.5 GB
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EGAF00000697362 cram 1.6 GB
EGAF00000697363 cram 1.7 GB
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EGAF00000697366 cram 1.8 GB
EGAF00000697367 cram 1.8 GB
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EGAF00000697371 cram 1.2 GB
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EGAF00000697376 cram 1.2 GB
EGAF00000697377 cram 1.1 GB
EGAF00000697378 cram 1.3 GB
EGAF00000697379 cram 1.2 GB
EGAF00000697380 cram 1.1 GB
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EGAF00000697382 cram 1.1 GB
EGAF00000697383 cram 1.1 GB
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EGAF00000697388 cram 1.2 GB
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EGAF00000697391 cram 1.1 GB
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EGAF00000697394 cram 1.1 GB
EGAF00000697395 cram 1.0 GB
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EGAF00000697397 cram 1.0 GB
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EGAF00000697400 cram 1.2 GB
EGAF00000697401 cram 1.3 GB
EGAF00000697402 cram 1.2 GB
EGAF00000697403 cram 1.1 GB
EGAF00000697404 cram 1.2 GB
EGAF00000697405 cram 993.6 MB
EGAF00000697406 cram 945.0 MB
EGAF00000697407 cram 995.9 MB
EGAF00000697408 cram 1.1 GB
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EGAF00000697410 cram 1.4 GB
EGAF00000697411 cram 1.1 GB
EGAF00000697412 cram 1.1 GB
EGAF00000697413 cram 927.4 MB
EGAF00000697414 cram 1.1 GB
EGAF00000697415 cram 1.2 GB
EGAF00000697416 cram 1.6 GB
EGAF00000697417 cram 805.8 MB
EGAF00000697418 cram 1.3 GB
EGAF00000697419 cram 1.4 GB
EGAF00000697420 cram 1.2 GB
EGAF00000697421 cram 1.2 GB
EGAF00000697422 cram 1.3 GB
EGAF00000697423 cram 1.3 GB
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EGAF00000697425 cram 1.3 GB
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EGAF00000697429 cram 1.3 GB
EGAF00000697430 cram 1.2 GB
EGAF00000697431 cram 1.3 GB
EGAF00000697432 cram 1.2 GB
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EGAF00000697434 cram 1.3 GB
EGAF00000697435 cram 1.5 GB
EGAF00000697436 cram 1.3 GB
EGAF00000697437 cram 1.2 GB
EGAF00000697438 cram 1.3 GB
EGAF00000697439 cram 1.6 GB
EGAF00000697440 cram 1.6 GB
EGAF00000697441 cram 1.2 GB
EGAF00000697442 cram 1.2 GB
EGAF00000697443 cram 1.4 GB
EGAF00000697444 cram 1.4 GB
EGAF00000697445 cram 1.3 GB
EGAF00000697446 cram 1.4 GB
EGAF00000697447 cram 1.6 GB
EGAF00000697448 cram 1.3 GB
EGAF00000697449 cram 1.5 GB
EGAF00000697450 cram 1.3 GB
EGAF00000697451 cram 1.2 GB
EGAF00000697452 cram 1.3 GB
EGAF00000697453 cram 1.4 GB
EGAF00000697454 cram 1.3 GB
EGAF00000697455 cram 1.3 GB
EGAF00000697456 cram 1.4 GB
EGAF00000697457 cram 1.3 GB
EGAF00000697458 cram 1.4 GB
EGAF00000697459 cram 1.3 GB
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EGAF00000697461 cram 1.2 GB
EGAF00000697462 cram 1.3 GB
EGAF00000697463 cram 1.3 GB
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EGAF00000697465 cram 1.7 GB
EGAF00000697466 cram 1.7 GB
EGAF00000697467 cram 1.4 GB
EGAF00000697468 cram 1.5 GB
EGAF00000697469 cram 1.5 GB
EGAF00000697470 cram 1.6 GB
EGAF00000697471 cram 1.7 GB
EGAF00000697472 cram 1.5 GB
EGAF00000697473 cram 1.6 GB
EGAF00000697474 cram 1.5 GB
EGAF00000697475 cram 1.0 GB
EGAF00000697476 cram 937.1 MB
EGAF00000697477 cram 962.4 MB
EGAF00000697478 cram 964.7 MB
EGAF00000697479 cram 896.9 MB
EGAF00000697480 cram 1.2 GB
EGAF00000697481 cram 1.1 GB
EGAF00000697482 cram 974.7 MB
EGAF00000697483 cram 1.0 GB
EGAF00000697484 cram 1.1 GB
EGAF00000697485 cram 1.1 GB
EGAF00000697486 cram 991.2 MB
EGAF00000697487 cram 994.2 MB
EGAF00000697488 cram 1.0 GB
EGAF00000697489 cram 1.5 GB
EGAF00000697490 cram 1.4 GB
EGAF00000697491 cram 1.1 GB
EGAF00000697492 cram 1.1 GB
EGAF00000697493 cram 1.1 GB
EGAF00000697494 cram 1.1 GB
EGAF00000697495 cram 1.0 GB
EGAF00000697496 cram 1.0 GB
EGAF00000697497 cram 1.1 GB
EGAF00000697498 cram 1.1 GB
EGAF00000697499 cram 924.1 MB
EGAF00000697500 cram 1.2 GB
EGAF00000697501 cram 1.1 GB
EGAF00000697502 cram 1.1 GB
EGAF00000697503 cram 1.1 GB
EGAF00000697504 cram 1.1 GB
EGAF00000697505 cram 1.3 GB
EGAF00000697506 cram 1.1 GB
EGAF00000697507 cram 1.1 GB
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EGAF00000697509 cram 1.1 GB
EGAF00000697510 cram 1.1 GB
EGAF00000697511 cram 1.1 GB
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EGAF00000697513 cram 1.2 GB
EGAF00000697514 cram 1.0 GB
EGAF00000697515 cram 914.5 MB
EGAF00000697516 cram 1.9 GB
EGAF00000697517 cram 1.9 GB
EGAF00000697518 cram 2.1 GB
EGAF00000697519 cram 1.8 GB
EGAF00000697520 cram 1.8 GB
EGAF00000697521 cram 1.8 GB
EGAF00000697522 cram 2.0 GB
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EGAF00000697524 cram 1.2 GB
EGAF00000697525 cram 1.0 GB
EGAF00000697526 cram 970.7 MB
EGAF00000697527 cram 1.1 GB
EGAF00000697528 cram 1.1 GB
EGAF00000697529 cram 1.0 GB
EGAF00000697530 cram 948.3 MB
EGAF00000697531 cram 926.1 MB
EGAF00000697532 cram 958.9 MB
EGAF00000697533 cram 889.3 MB
EGAF00000697534 cram 948.2 MB
EGAF00000697535 cram 1.1 GB
EGAF00000697536 cram 1.0 GB
EGAF00000697537 cram 824.7 MB
EGAF00000697538 cram 971.1 MB
EGAF00000697539 cram 954.0 MB
EGAF00000697540 cram 854.4 MB
EGAF00000697541 cram 895.3 MB
EGAF00000697542 cram 897.1 MB
EGAF00000697543 cram 1.1 GB
EGAF00000697544 cram 1.2 GB
EGAF00000697545 cram 1.3 GB
EGAF00000697546 cram 1.0 GB
EGAF00000697547 cram 1.0 GB
EGAF00000697548 cram 912.1 MB
EGAF00000697549 cram 1.8 GB
EGAF00000697550 cram 1.8 GB
EGAF00000697551 cram 1.9 GB
EGAF00000697552 cram 1.7 GB
EGAF00000697553 cram 1.6 GB
EGAF00000697554 cram 1.7 GB
EGAF00000697555 cram 1.8 GB
EGAF00000697556 cram 1.6 GB
EGAF00000697557 cram 1.8 GB
EGAF00000697558 cram 1.7 GB
EGAF00000697559 cram 1.6 GB
EGAF00000697560 cram 1.5 GB
EGAF00000697561 cram 1.5 GB
EGAF00000697562 cram 1.4 GB
EGAF00000697563 cram 1.4 GB
EGAF00000697564 cram 1.7 GB
EGAF00000697565 cram 1.6 GB
EGAF00000697566 cram 1.5 GB
EGAF00000697567 cram 1.8 GB
EGAF00000697568 cram 1.8 GB
EGAF00000697569 cram 1.4 GB
EGAF00000697570 cram 1.4 GB
EGAF00000697571 cram 1.4 GB
EGAF00000697572 cram 1.5 GB
EGAF00000697573 cram 1.5 GB
EGAF00000697574 cram 1.6 GB
EGAF00000697575 cram 1.5 GB
EGAF00000697576 cram 1.0 GB
EGAF00000697577 cram 1.0 GB
EGAF00000697578 cram 1.2 GB
EGAF00000697579 cram 1.1 GB
EGAF00000697580 cram 1.1 GB
EGAF00000697581 cram 964.5 MB
EGAF00000697582 cram 985.9 MB
EGAF00000697583 cram 949.1 MB
EGAF00000697584 cram 905.7 MB
EGAF00000697585 cram 996.9 MB
EGAF00000697586 cram 934.3 MB
EGAF00000697587 cram 974.6 MB
EGAF00000697588 cram 838.6 MB
EGAF00000697589 cram 1.0 GB
EGAF00000697590 cram 959.3 MB
EGAF00000697591 cram 1.1 GB
EGAF00000697592 cram 1.0 GB
EGAF00000697603 cram 1.7 GB
EGAF00000697604 cram 1.6 GB
EGAF00000697605 cram 1.7 GB
EGAF00000697606 cram 1.6 GB
EGAF00000697607 cram 1.7 GB
EGAF00000697608 cram 1.5 GB
EGAF00000697609 cram 1.8 GB
EGAF00000697610 cram 1.5 GB
EGAF00000697611 cram 1.7 GB
EGAF00000697612 cram 1.5 GB
EGAF00000697613 cram 1.3 GB
EGAF00000697614 cram 1.5 GB
EGAF00000697615 cram 1.7 GB
EGAF00000697616 cram 1.7 GB
EGAF00000697617 cram 1.6 GB
EGAF00000697618 cram 1.7 GB
EGAF00000697619 cram 1.6 GB
EGAF00000697620 cram 1.4 GB
EGAF00000697621 cram 1.5 GB
EGAF00000697622 cram 1.5 GB
EGAF00000697623 cram 1.5 GB
EGAF00000697624 cram 1.6 GB
EGAF00000697625 cram 1.6 GB
EGAF00000697626 cram 1.7 GB
EGAF00000697627 cram 1.7 GB
EGAF00000697628 cram 1.0 GB
EGAF00000697629 cram 1.0 GB
1959 Files (1.4 TB)