Article révisé par les pairs
Résumé : Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER, and HER2 status. Mutations were classified as 'oncogenic' in the case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep resequencing using an orthogonal platform. Whole-genome rearrangement screen was further conducted in 8/36 patients. Twenty-four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three-quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter-lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3, and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than homogeneous lesions. Genome-wide analyses of a limited number of patients identified a common somatic background in all studied MFBCs, including those with no mutation in common between the lesions. To conclude, as the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings highlight the presence of genomic inter-lesion heterogeneity in one-third, despite similar pathological features. This implies that deeper molecular characterization of all MFBC lesions is warranted for the adequate management of those cancers.

Documents en relation

DI-fusion

  • Uncovering the genomic heterogeneity of multifocal breast cancer.
    par Desmedt, Christine , Fumagalli, Debora , Pietri, E , Zoppoli, Gabriele , Nik-Zainal, Serena , Gundem, Gunes , Brown, David Norman , Rothé, Françoise , Majjaj, Samira , Garuti, A , Carminati, E , Loi, Sherene , Van Brussel, T , Maetens, Marion M. , Mudie, Laura , Vincent, Delphine , Kheddoumi, Naima , Serra, L , Massa, I , Ballesteros, Juan Antonio , Amadori, Dino , Salgado, Roberto , De Wind, A. , Lambrechts, Diether , Piccart-Gebhart, Martine , Larsimont, Denis , Campbell, Peter J , Sotiriou, Christos
    Publication 2015-04
  • Uncovering the genomic heterogeneity of multifocal breast cancer
    par Desmedt, Christine , Fumagalli, Debora , Pietri, E , Zoppoli, Gabriele , Nik-Zainal, Serena , Gundem, Gunes , Brown, David Norman , Rothé, Françoise , Majjaj, Samira , Garuti, A , Carminati, E , Loi, Sherene , Van Brussel, T , Maetens, Marion M. , Mudie, Laura , Vincent, D. , Kheddoumi, Naima , Serra, L , Massa, I , Ballestrero, Alessandro , Amadori, Dino , Salgado, Roberto , De Wind, A. , Lambrechts, Diether , Piccart-Gebhart, Martine , Larsimont, Denis , Campbell, Peter J , Sotiriou, Christos
    Publication 2015-08-01
  • Timing evolution of lobular breast cancer through phylogenetic analysis.
    par Fimereli, Danai , Venet, David , Rediti, Mattia , Boeckx, Bram , Maetens, Marion , Majjaj, Samira , Rouas, Ghizlane , Marchio, Caterina , Bertucci, François , Mariani, Odette , Capra, Maria , Bonizzi, Giuseppina , Contaldo, Federica , Galant, Christine , Van den Eynden, Gert , Salgado, Roberto , Biganzoli, Elia , Vincent-Salomon, Anne , Pruneri, Giancarlo , Larsimont, Denis , Lambrechts, Diether , Desmedt, Christine , Brown, David Norman , Rothé, Françoise , Sotiriou, Christos
    Publication 2022-08-01
  • Differential benefit of metronomic chemotherapy among triple negative breast cancer subtypes treated in the IBCSG Trial 22-00.
    par Joaquin Garcia, Andrea , Rediti, Mattia , Venet, David , Majjaj, Samira , Kammler, Roswitha , Munzone, Elisabetta , Gianni, Lorenzo , Thürlimann, Beat , Láng, I , Colleoni, Marco Angelo , Loi, Sherene , Viale, Giuseppe , Regan, Meredith M , Buisseret, Laurence , Rothé, Françoise , Sotiriou, Christos
    Publication 2023-09-01
  • First-in-human study of SBRT and adenosine pathway blockade to potentiate the benefit of immunochemotherapy in early-stage luminal B breast cancer: results of the safety run-in phase of the Neo-CheckRay trial.
    par De Caluwe, Alex , Romano, Emanuela , Poortmans, Philip , Gombos, Andrea , Agostinetto, Elisa , Marta, Guilherme Nader , Denis, Zoe , Drisis, Stylianos , Vandekerkhove, Christophe , Desmet, Antoine , Philippson, Catherine , Craciun, Ligia , Veys, Isabelle , Larsimont, Denis , Paesmans, Marianne , Van Gestel, Dirk , Salgado, Roberto , Sotiriou, Christos , Piccart-Gebhart, Martine , Ignatiadis, Michail , Buisseret, Laurence
    Publication 2023-12-01