Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: The role of massively parallel sequencing

Molecular Oncology - Tập 8 - Trang 150-158 - 2014
Leticia De Mattos-Arruda1,2, Francois-Clement Bidard3,4, Helen H. Won3, Javier Cortes1,5, Charlotte K.Y. Ng3, Vicente Peg2,6, Paolo Nuciforo1, Achim A. Jungbluth7, Britta Weigelt3, Michael F. Berger7,8, Joan Seoane1,2,9, Jorge S. Reis-Filho7,10
1Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
2Universitat Autònoma de Barcelona, Barcelona, Spain
3Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4Department of Medical Oncology, Institut Curie, Paris, France
5Medica Scientia Innovation Research (MedSIR), Barcelona, Spain
6Pathology Department, Vall d’Hebron University Hospital, Barcelona, Spain
7Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
8Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
9Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
10Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Tóm tắt

In this proof‐of‐principle study, we sought to define whether targeted capture massively parallel sequencing can be employed to determine the origin of metastatic deposits in cases of synchronous primary malignancies and metastases in distinct anatomical sites. DNA samples extracted from synchronous tumor masses in the breast, adnexal, and pelvic‐peritoneal regions from a 62‐year‐old BRCA1 germline mutation carrier were subjected to targeted massively parallel sequencing using a platform comprising 300 cancer genes known to harbor actionable mutations. In addition to BRCA1 germline mutations, all lesions harbored somatic loss of the BRCA1 wild‐type allele and TP53 somatic mutations. The primary breast cancer displayed a TP53 frameshift (p.Q317fs) mutation, whereas and the adnexal lesion harbored a TP53 nonsense (p.R213*) mutation, consistent with a diagnosis of two independent primary tumors (i.e. breast and ovarian cancer). The adnexal tumor and all pelvic‐peritoneal implants harbored identical TP53 (p.R213*) and NCOA2 (p.G952R) somatic mutations. Evidence of genetic heterogeneity within and between lesions was observed, both in terms of somatic mutations and copy number aberrations. The repertoires of somatic genetic aberrations found in the breast, ovarian, and pelvic‐peritoneal lesions provided direct evidence in support of the distinct origin of the breast and ovarian cancers, and established that the pelvic‐peritoneal implants were clonally related to the ovarian lesion. These observations were consistent with those obtained with immunohistochemical analyses employing markers to differentiate between carcinomas of the breast and ovary, including WT1 and PAX8. Our results on this case of a patient with BRCA1‐mutant breast and ovarian cancer demonstrate that massively parallel sequencing may constitute a useful tool to define the relationship, clonality and intra‐tumor genetic heterogeneity between primary tumor masses and their metastatic deposits in patients with multiple primary malignancies and synchronous metastases.

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Molecular Oncology

Tập 8

150-158

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