Comparative genetic profiling aids diagnosis and clinical decision making in challenging cases of CUP syndrome.
Aged
Ataxia Telangiectasia Mutated Proteins
/ genetics
BRCA1 Protein
/ genetics
BRCA2 Protein
/ genetics
Clinical Decision-Making
Clone Cells
/ chemistry
Female
Formaldehyde
High-Throughput Nucleotide Sequencing
/ methods
Humans
Male
Middle Aged
Mutation
Neoplasms, Unknown Primary
/ diagnosis
Paraffin Embedding
Sequence Analysis, DNA
/ methods
Tissue Embedding
Tumor Suppressor Proteins
/ genetics
Ubiquitin Thiolesterase
/ genetics
cancer of unknown primary
clonal relationship
germline mutation
metastasis
next-generation sequencing
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 12 2019
01 12 2019
Historique:
received:
20
12
2018
revised:
15
03
2019
accepted:
26
03
2019
pubmed:
10
4
2019
medline:
1
2
2020
entrez:
10
4
2019
Statut:
ppublish
Résumé
Cancer of unknown primary (CUP) denotes cancer cases where metastatic spread is histologically confirmed, but no respective primary tumor can be identified. The challenging diagnosis of CUP is further complicated in cases with previously identified malignancies or with dubious clonal relationship between metastatic sites due to ambiguous histology. Our study aims at elucidating clonal relationships by comparing the respective mutational spectra. Targeted next-generation sequencing (NGS) employing formalin-fixed and paraffin-embedded (FFPE) tumor tissue was performed on 174 consecutive CUP patients. Among these, 43/174 (24.7%) patients had a documented prior malignancy. Data on pairwise targeted NGS testing to address clonal relationships between the previous malignancy and the presumed CUP (n = 11) or between different CUP metastatic sites (n = 7) was available in 18 patients. NGS could clarify clonal relationships in 16/18 cases. Among the 11 CUP patients with antecedent malignancies, four cases were clonally independent of the previous malignancy but harbored deleterious germline mutations in BRCA/BAP1/ATM genes. Seven CUP cases were clonally related to the antecedent malignancy, changing the CUP diagnosis to relapse of the prior malignancy. In the seven CUP cases, with doubtfully related metastatic sites, NGS confirmed clonal relationship in five cases and was inconclusive in two. In conclusion, NGS proved an efficient tool to elucidate clonal relationships in clinically challenging CUP cases. Our study cautions against a premature diagnosis of CUP. Relapses of antecedent malignancies should be carefully considered. CUPs clonally independent from the antecedent malignancy should raise a red flag of a potential cancer-predisposing germline mutation.
Substances chimiques
BAP1 protein, human
0
BRCA1 Protein
0
BRCA1 protein, human
0
BRCA2 Protein
0
BRCA2 protein, human
0
Tumor Suppressor Proteins
0
Formaldehyde
1HG84L3525
ATM protein, human
EC 2.7.11.1
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Ubiquitin Thiolesterase
EC 3.4.19.12
Types de publication
Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2963-2973Informations de copyright
© 2019 UICC.
Références
Massard C, Loriot Y, Fizazi K. Carcinomas of an unknown primary origin-diagnosis and treatment. Nat Rev Clin Oncol 2011;8:701-10.
Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012;379:1428-35.
Varadhachary GR, Raber MN. Carcinoma of unknown primary site. N Engl J Med 2014;371:2040.
Fizazi K, Greco FA, Pavlidis N, et al. Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26(Suppl 5):v133-8.
Ross JS, Wang K, Gay L, et al. Comprehensive genomic profiling of carcinoma of unknown primary site: new routes to targeted therapies. JAMA Oncol 2015;1:40-9.
Tothill RW, Li J, Mileshkin L, et al. Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. J Pathol 2013;231:413-23.
Gatalica Z, Millis SZ, Vranic S, et al. Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of unknown primary site: analysis of 1806 cases. Oncotarget 2014;5:12440-7.
Loffler H, Pfarr N, Kriegsmann M, et al. Molecular driver alterations and their clinical relevance in cancer of unknown primary site. Oncotarget 2016;7:44322-9.
Varghese AM, Arora A, Capanu M, et al. Clinical and molecular characterization of patients with cancer of unknown primary in the modern era. Ann Oncol 2017;28:3015-21.
Gatalica Z, Xiu J, Swensen J, et al. Comprehensive analysis of cancers of unknown primary for the biomarkers of response to immune checkpoint blockade therapy. Eur J Cancer 2018;94:179-86.
Clynick B, Dessauvagie B, Sterrett G, et al. Genetic characterisation of molecular targets in carcinoma of unknown primary. J Transl Med 2018;16:185.
Bochtler T, Endris V, Reiling A, et al. Integrated histogenetic analysis reveals BAP1-mutated epithelioid mesothelioma in a patient with cancer of unknown primary. J Natl Compr Canc Netw 2018;16:677-82.
Endris V, Penzel R, Warth A, et al. Molecular diagnostic profiling of lung cancer specimens with a semiconductor-based massive parallel sequencing approach: feasibility, costs, and performance compared with conventional sequencing. J Mol Diagn 2013;15:765-75.
Leichsenring J, Volckmar AL, Kirchner M, et al. Targeted deep sequencing of effusion cytology samples is feasible, informs spatiotemporal tumor evolution, and has clinical and diagnostic utility. Genes Chromosomes Cancer 2018;57:70-9.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.
Robinson JT, Thorvaldsdottir H, Winckler W, et al. Integrative genomics viewer. Nat Biotechnol 2011;29:24-6.
Robinson DR, Wu YM, Lonigro RJ, et al. Integrative clinical genomics of metastatic cancer. Nature 2017;548:297-303.
Hemminki K, Bevier M, Sundquist J, et al. Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries? Ann Oncol 2012;23:2720-4.
Hemminki K, Ji J, Sundquist J, et al. Familial risks in cancer of unknown primary: tracking the primary sites. J Clin Oncol 2011;29:435-40.
Samadder NJ, Smith KR, Hanson H, et al. Familial risk in patients with carcinoma of unknown primary. JAMA Oncol 2016;2:340-6.
Roepman P, Heuvel AT, Scheidel KC, et al. Added value of 50-gene panel sequencing to distinguish multiple primary lung cancers from pulmonary metastases-a systematic investigation. J Mol Diagn 2018;20:436-45.
Wu RC, Veras E, Lin J, et al. Elucidating the pathogenesis of synchronous and metachronous tumors in a woman with endometrioid carcinomas using a whole-exome sequencing approach. Cold Spring Harb Mol Case Stud 2017;3:a001693.
Kim TM, Jung SH, An CH, et al. Subclonal genomic architectures of primary and metastatic colorectal cancer based on Intratumoral genetic heterogeneity. Clin Cancer Res 2015;21:4461-72.
Melchardt T, Magnes T, Hufnagl C, et al. Clonal evolution and heterogeneity in metastatic head and neck cancer-An analysis of the Austrian study Group of Medical Tumour Therapy study group. Eur J Cancer 2018;93:69-78.
Caswell DR, Swanton C. The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome. BMC Med 2017;15:133.
Jamal-Hanjani M, Wilson GA, McGranahan N, et al. Tracking the evolution of non-small-cell lung cancer. N Engl J Med 2017;376:2109-21.
Reiter JG, Makohon-Moore AP, Gerold JM, et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 2018;361:1033-7.
Jesinghaus M, Wolf T, Pfarr N, et al. Distinctive spatiotemporal stability of somatic mutations in metastasized microsatellite-stable colorectal cancer. Am J Surg Pathol 2015;39:1140-7.
Lih CJ, Harrington RD, Sims DJ, et al. Analytical validation of the next-generation sequencing assay for a Nationwide signal-finding clinical trial: molecular analysis for therapy choice clinical trial. J Mol Diagn 2017;19:313-27.