Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 457-466 |
| Number of pages | 10 |
| Journal | Journal of Pathology |
| Volume | 236 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - Aug 1 2015 |
Fingerprint
Keywords
- breast cancer
- genomic heterogeneity
- multicentric
- multifocal
- oncogenic mutations
- targeted sequencing
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Medicine(all)
Cite this
Uncovering the genomic heterogeneity of multifocal breast cancer. / Desmedt, Christine; Fumagalli, Debora; Pietri, Elisabetta; Zoppoli, Gabriele; Brown, David; Nik-Zainal, Serena; Gundem, Gunes; Rothé, Françoise; Majjaj, Samira; Garuti, Anna; Carminati, Enrico; Loi, Sherene; Van Brussel, Thomas; Boeckx, Bram; Maetens, Marion; Mudie, Laura; Vincent, Delphine; Kheddoumi, Naima; Serra, Luigi; Massa, Ilaria; Ballestrero, Alberto; Amadori, Dino; Salgado, Roberto; De Wind, Alexandre; Lambrechts, Diether; Piccart, Martine; Larsimont, Denis; Campbell, Peter J.; Sotiriou, Christos.
In: Journal of Pathology, Vol. 236, No. 4, 01.08.2015, p. 457-466.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Uncovering the genomic heterogeneity of multifocal breast cancer
AU - Desmedt, Christine
AU - Fumagalli, Debora
AU - Pietri, Elisabetta
AU - Zoppoli, Gabriele
AU - Brown, David
AU - Nik-Zainal, Serena
AU - Gundem, Gunes
AU - Rothé, Françoise
AU - Majjaj, Samira
AU - Garuti, Anna
AU - Carminati, Enrico
AU - Loi, Sherene
AU - Van Brussel, Thomas
AU - Boeckx, Bram
AU - Maetens, Marion
AU - Mudie, Laura
AU - Vincent, Delphine
AU - Kheddoumi, Naima
AU - Serra, Luigi
AU - Massa, Ilaria
AU - Ballestrero, Alberto
AU - Amadori, Dino
AU - Salgado, Roberto
AU - De Wind, Alexandre
AU - Lambrechts, Diether
AU - Piccart, Martine
AU - Larsimont, Denis
AU - Campbell, Peter J.
AU - Sotiriou, Christos
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
KW - breast cancer
KW - genomic heterogeneity
KW - multicentric
KW - multifocal
KW - oncogenic mutations
KW - targeted sequencing
UR - http://www.scopus.com/inward/record.url?scp=84937518723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84937518723&partnerID=8YFLogxK
U2 - 10.1002/path.4540
DO - 10.1002/path.4540
M3 - Article
VL - 236
SP - 457
EP - 466
JO - Journal of Pathology
JF - Journal of Pathology
SN - 0022-3417
IS - 4
ER -