Genomic characterization of metastatic breast cancers

Bertucci, François; Ng, Charlotte K.Y.; Patsouris, Anne; Droin, Nathalie; Piscuoglio, Salvatore; Carbuccia, Nadine; Soria, Jean Charles; Dien, Alicia Tran; Adnani, Yahia; Kamal, Maud; Garnier, Séverine; Meurice, Guillaume; Jimenez, Marta; Doğan, Semih; Verret, Benjamin; Chaffanet, Max; Bachelot, Thomas; Campone, Mario; Lefeuvre, Claudia; Bonnefoi, Hervé; Dalenc, Florence; Jacquet, Alexandra; Filippo, Maria Rosaria De; Babbar, Naveen; Birnbaum, Daniel; Filleron, Thomas; Tourneau, Christophe Le; André, Fabrice

doi:10.1038/s41586-019-1056-z

Cited by 539 publications

(530 citation statements)

References 57 publications

Supporting

Mentioning

468

Contrasting

Unclassified

Order By: Relevance

“…For instance, metastases have been reported to originate from a single cell or clone in the primary tumor (monoclonal seeding) [1][2][3][4] or multiple clones (polyclonal seeding) [5][6][7] , but the prevalence of these patterns across distinct tumor types is unknown as is the impact of therapy and the timing of metastatic seeding [8][9][10] . While several recent studies have genomically characterized metastatic lesions [11][12][13] in the absence of the matched primary tumor, it is not feasible to disentangle the drivers of metastasis from those that are treatment associated since metastases are often sampled after treatment. However, comparisons of paired primary tumors and metastases have been far more limited due to the challenge in obtaining such samples 5,8,[14][15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

View full text Add to dashboard Cite

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and patterns of systemic spread are poorly understood. We analyzed exome sequencing data from 458 paired primary tumors (P) or metastasis (M) samples from 136 breast, colorectal and lung cancer patients, including both untreated (n=98) and treated (n=101) metastases. We find that treated metastases often harbored private driver gene mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in lymph node metastases (n=19/35, 54%; mostly untreated) and untreated distant metastases (n=20/70, 29%), but less frequent in treated metastases (n=9/90, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which commonly occurred several years prior to diagnosis in breast (2.4 years, range 0−3.3), lung (3.6 years, range 2.8 − 3.7) and colorectal (4.1 years, range 3.1 − 4.6) cancers. Thus, this pan-cancer analysis reveals early systemic spread in three common cancer types. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but are instead associated with drug resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The involvement of DNA repair might also explain why tumors deficient in the p53 DNA damage checkpoint regulatory pathway accumulate more 5-FU mutations, as shown here for the first time. Interestingly, breast tumors with high contribution of Signature 17 mutations were recently shown to have poor prognosis (Bertucci et al 2019).…”

Section: Discussionmentioning

confidence: 99%

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

Christensen

Roest

Besselink

et al. 2019

Preprint

View full text Add to dashboard Cite

5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures. The use of 5-Fluorouracil (5-FU) as an anticancer agent became routine practice soon after its primary synthesis in 1957, and remains essential in many chemotherapeutic regimens today (Longley, Harkin, and Johnston 2003). The fluoropyrimidines, especially 5-FU, capecitabine, tegafur and cytarabine, are currently the third most commonly used anticancer drug in the treatment of solid cancers, including colorectal and breast cancers, and over two million patients are estimated to be treated with fluoropyrimidines each year (Ezzeldin and Diasio 2004). Response rates of 5-FU as a single drug are 10-15%, but increase drastically (>50% response) when given in combination therapies with leucovorin together with oxaliplatin or irinotecan (i.e. FOLFOX and FOLFIRI, respectively) (de Gramont et al. 2000;Boige et al. 2010;Cameron, Gabra, and Leonard 1994).The antifolate property of fluoropyrimidines is thought to be the principal mechanism of action. Fluoropyrimidines are intracellularly converted into the antifolate 5-fluorodeoxyuridine monophosphate (5-FdUMP) that can form a covalent intermediate with the folate-dependent enzyme thymidylate synthase (TYMS) (Sommer and Santi 1974). Consequently, the formation of dTMP from dUMP is inhibited which results in an imbalance of the nucleotide pool that affects DNA synthesis, possibly through incorporation of uracil, and impairs genome replication, with negative consequences for rapidly dividing cells such as cancer cells. Moreover, it has been proposed that 5-fluorodeoxyuridine triphosphate (5-FdUTP) can be directly incorporated into genomic DNA as well (Pettersen et al. 2011;Huehls et al. 2016). Considering these properties, it is conceivable that fluoropyrimidines have mutagenic potential, although the mutational consequences of 5-FU tr...

show abstract

“…The motivation for the present work originates from the work of the Raphael Lab, centred around the Dendrix algorithm [23], and its later improvements including CoMEt [9]. Both algorithms are in widespread use in whole-genome analysis-for instance, in [16,17,4,20]. Building on those foundations, our work extends in the following two directions: First, the two key notions of exclusivity and coverage are abstracted here by the two simplicial complexes K ε and K η or, more precisely, by the filtrations of simplicial complexes K ε 0 ⊂ · · · ⊂ K ε and K η 0 ⊂ · · · ⊂ K η , where we allow the two parameters to vary: ε 0 ≤ ε ≤ ε and η 0 ≤ η ≤ η .…”

Section: Related Workmentioning

confidence: 99%

“…The dimensions β i := dim(H i (K)) are called Betti numbers and provide the formal description of the concept of shape measurements. 4 We move now to the notion of persistent homology and make it a bit more precise. For that, let us reintroduce the persistent parameter ε and let K ε be again an independence complex.…”

Section: A Primer On Persistent Homologymentioning

confidence: 99%

“…84 0, 1,3,4,10,12,13,14,18,19,21,22,23,25,28,29,31,32,33,35,36,37,38,39,40,45,46,51,52,53,54,56,58,59,63 , 64 Intermediate 85 9, 10, 4, 6 Intermediate 86 0, 1, 3 Intermediate 87 0, 1, 10, 3, 4 Intermediate 88 34, 43, 37, 11, 15, 16, 17, 62, 24, 57, 26, 27, 60, 61, 30 Intermediate 89 0, 1, 3 Intermediate 90 0, 1, 2, 3, 5, 7, 8, 64, 44, 61, 15, 50, 51, 20, 53, 57, 33, 27, 37, 30, 31 Intermediate 91 0, 1, 2, 3 , 5, 6, 7, 9, 12, 15, 18, 19, 23, 27, 28, 30, 31, 33, 35, 37, 40, 42, 46, 48, 49, 51, 52, 53, 54, 55, 57, 59, 60, 61, 63, 64 Intermediate 92 0, 32, 34, 43, 38, 33, 11, 12, 14, 15, 16, 17, 21, 25, 24, 57, 26, 27, 28, 30, 31 Intermediate 93 59, 37, 41, 47, 16, 52, 26, 15, 60, 61, 62 Intermediate 94 0, 1, 2, 3 , 4, 5, 7, 8, 9, 10, 39, 44, 45, 14, 47, 49, 50, 20, 32, 22, 6,8,9,11,12,…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Topology of Mutated Driver Pathways

Dridi

Alghassi

Obeidat

et al. 2019

Preprint

View full text Add to dashboard Cite

Much progress has been made, and continues to be made, towards identifying candidate mutated driver pathways in cancer. However, no systematic approach to understanding how candidate pathways relate to each other for a given cancer (such as Acute myeloid leukemia), and how one type of cancer may be similar or different from another with regard to their respective pathways (Acute myeloid leukemia vs. Glioblastoma multiforme for instance), has emerged thus far. Our work attempts to contribute to the understanding of space of pathways through a novel topological framework. We illustrate our approach, using mutation data (obtained from TCGA) of two types of tumors: Acute myeloid leukemia (AML) and Glioblastoma multiforme (GBM). We find that the space of pathways for AML is homotopy equivalent to a sphere, while that of GBM is equivalent to a genus-2 surface. We hope to trigger new types of questions (i.e., allow for novel kinds of hypotheses) towards a more comprehensive grasp of cancer.

show abstract

Genomic characterization of metastatic breast cancers

Cited by 539 publications

References 57 publications

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

The Topology of Mutated Driver Pathways

Contact Info

Product

Resources

About