Genome remodelling in a basal-like breast cancer metastasis and xenograft

Abstract

Massively parallel DNA sequencing technologies provide an unprecedented ability to screen entire genomes for genetic changes associated with tumor progression. Here we describe the genomic analyses of four DNA samples from an African-American patient with basal-like breast cancer: peripheral blood, the primary tumor, a brain metastasis, and a xenograft derived from the primary tumor. The metastasis contained two de novo mutations and a large deletion not present in the primary tumor, and was significantly enriched for 20 shared mutations. The xenograft retained all primary tumor mutations, and displayed a mutation enrichment pattern that paralleled the metastasis (16 of 20 genes). Two overlapping large deletions, encompassing CTNNA1, were present in all three tumor samples. The differential mutation frequencies and structural variation patterns in metastasis and xenograft compared to the primary tumor suggest that secondary tumors may arise from a minority of cells within the primary.

Exome sequencing of contralateral breast cancer identifies metastatic disease

“…Exome sequencing has proved useful to identify somatic mutations and investigate the clonal relationship between primary tumors and various forms of recurrences in a wide range of cancers, including breast cancer [8][9][10][11]. Taken together, the results from exome sequencing in the field of oncology show a large genetic diversity between tumors from different patients, with only few positions in the genome being mutated in 10% or more of cancer cases.…”

Reliable detection of subclonal single-nucleotide variants in tumour cell populations

“…They enable direct sequencing of mixed samples, such as virus populations 6,7 , bacterial communities 8 , tumours [9][10][11] and pooled samples 12,13 , and the reconstruction of their genomic composition. However, single-nucleotide errors resulting from target enrichment, library preparation and base calling are frequent on all current sequencing platforms 5 , and they are difficult to separate from true lowfrequency single-nucleotide variants (SNVs).…”

Contribution au développement de nouvelles thérapies contre le cancer colorectal

“…Cependant, l'apparition de quelques altérations de novo, absentes dans les tumeurs d'origine, pourrait s'expliquer par l'expansion clonale d'une population minoritaire et/ou par la poursuite dans la xénogreffe du processus de mutation qui avait commencé dans la tumeur issue du patient. Cette même évolution a récemment été rapportée dans un modèle de cancer du sein de type triple-négatif : la xénogreffe correspondante présentait les mêmes mutations que la tumeur d'origine, mais en exprimait également d'autres, et ce panel enrichi de mutations était similaire à celui de la métastase cérébrale synchrone qui avait été prélevée chez le patient [8].…”