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PLoS One. 2015 Nov 10;10(11):e0142487. doi: 10.1371/journal.pone.0142487. eCollection 2015.

Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.

Author information

1
Moores Cancer Center, University of California San Diego, La Jolla, CA, United States of America.
2
Division of Biostatistics, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, United States of America.
3
Department of Medicine, University of California San Diego, La Jolla, CA, United States of America.
4
Department of Pediatrics, University of California San Diego, La Jolla, CA, United States of America.
5
Department of Psychiatry, University of California San Diego, La Jolla, CA, United States of America.
6
Department of Pathology, University of California San Diego, La Jolla, CA, United States of America.
7
Department of Surgery, University of California San Diego, La Jolla, CA, United States of America.

Abstract

BACKGROUND:

Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations).

METHODS:

Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas.

RESULTS:

We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value <0.01), across renal cell, testicular, and colorectal cancer. The CLS test correctly classified all validation samples but one, which it appears may have been incorrectly classified in the published data. As proof-of-concept we then applied the CLS test to two new cases of invasive synchronous bilateral breast cancer at our institution, each with one hormone receptor positive (ER+/PR+/HER2-) lobular and one triple negative ductal carcinoma. High confidence mutations were identified by exome sequencing and results were validated using deep targeted sequencing. The first tumor pair had CLS of 81% (p-value < 10-15), supporting clonality. In the second pair, no common mutations of 184 variants were validated (p-value >0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair.

CONCLUSION:

We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.

PMID:
26554380
PMCID:
PMC4640562
DOI:
10.1371/journal.pone.0142487
[Indexed for MEDLINE]
Free PMC Article

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