Uncovering the genomic heterogeneity of multifocal breast cancer

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

C2 - 25850943

AN - SCOPUS:84937518723

VL - 236

SP - 457

EP - 466

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 4

ER -