Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: the role of massively parallel sequencing.
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.
Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain.
Leticia
L
De Mattos-Arruda
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Department of Medical Oncology, Institut Curie, Paris, France.
Francois-Clement
FC
Bidard
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Helen H
HH
Won
Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Medica Scientia Innovation Research (MedSIR), Barcelona, Spain.
Javier
J
Cortes
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Charlotte K Y
CK
Ng
Universitat Autònoma de Barcelona, Barcelona, Spain; Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain.
Vicente
V
Peg
Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
Paolo
P
Nuciforo
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Achim A
AA
Jungbluth
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Britta
B
Weigelt
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Michael F
MF
Berger
Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain; Universitat Autònoma de Barcelona, Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address: jseoane@vhio.net.
Joan
J
Seoane
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address: reisfilj@mskcc.org.
Jorge S
JS
Reis-Filho
D019313:BRCA1 Protein / Q000235:genetics; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010053:Ovary / Q000378:metabolism / Q000473:pathology
D019313:BRCA1 Protein
BRCA1; Breast cancer; Clonality; Massively parallel sequencing; Metastasis; Ovarian cancer