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

• Published in: Molecular oncology Vol. 8; no. 1; pp. 150 - 158
• Main Authors: De Mattos-Arruda, Leticia, Bidard, Francois-Clement, Won, Helen H., Cortes, Javier, Ng, Charlotte K.Y., Peg, Vicente, Nuciforo, Paolo, Jungbluth, Achim A., Weigelt, Britta, Berger, Michael F., Seoane, Joan, Reis-Filho, Jorge S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier B.V 01.02.2014; John Wiley & Sons, Inc; John Wiley and Sons Inc
• Subjects: Abdomen; BRCA1; BRCA1 protein; BRCA1 Protein - genetics; Breast - metabolism; Breast - pathology; Breast cancer; Breast carcinoma; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Clonality; Copy number; Deposits; Disease; Female; Frameshift mutation; Gene expression; Genetic counseling; Genetic disorders; Genetic Predisposition to Disease; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Laboratories; Lesions; Massively parallel sequencing; Menopause; Metastases; Metastasis; Middle Aged; Mutation; Neoplasm Metastasis - genetics; Neoplasm Metastasis - pathology; NMR; Nuclear magnetic resonance; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Ovary - metabolism; Ovary - pathology; p53 Protein; Pathology; Patients; Pax8 protein; Peritoneum; Studies; Tumors; United Kingdom > UK; Spain; Massively parallel sequencing; Clonality; Breast cancer; Metastasis; BRCA1; Ovarian cancer
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1016/j.molonc.2013.10.006

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. •Massively parallel sequencing can help define the origin of metastatic deposits in patients with multiple primary tumors.•Genetic heterogeneity was observed within and between lesions from the same patient.•Synchronous metastatic deposits may differ in their repertoire of somatic genetic aberrations.