The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use ...plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.
Solid pseudopapillary neoplasms (SPNs) are rare and relatively indolent tumors of the pancreas. While primary SPNs can be surgically resected, there are currently no therapies available for patients ...with advanced stage disease. Given that these tumors frequently carry CTNNB1 hotspot (recurrently mutated loci in a gene) mutations resulting in β‐catenin nuclear accumulation, it has been speculated that the Wnt pathway may be a driver in this disease. Here, we present a comprehensive “multi‐omics” study where the genome, transcriptome, and methylome of SPNs were analyzed. We found that SPNs are characterized by a low‐complexity genome where somatic mutations in CTNNB1, present in 100% of the cases, are the only actionable genomic lesions. Compared to more common subtypes of pancreatic tumors (adenocarcinomas and pancreatic neuroendocrine tumors), SPNs show high expression levels of genes belonging to the Wnt pathway. Their methylome was consistent with an epithelial cell origin and a general upregulation of Wnt pathway genes. Clinical studies to evaluate the exquisite sensitivity of SPNs to inhibitors of the Wnt pathway are warranted.
Solid pseudopapillary neoplasms of the pancreas are governed by the presence of mutations of β‐catenin that, in turn, induce transcriptional rewiring, which converges in the activation of the Wnt pathway and proliferation of tumor cells.
Current clinical management of breast cancer relies on the availability of robust clinicopathological variables and few well-defined biological markers. Recent microarray-based expression profiling ...studies have emphasised the importance of the molecular portraits of breast cancer and the possibility of classifying breast cancer into biologically and molecularly distinct groups. Subsequent large scale immunohistochemical studies have demonstrated that the added value of studying the molecular biomarker expression in combination rather than individually. Oestrogen (ER) and progesterone (PR) receptors and HER2 are currently used in routine pathological assessment of breast cancer. Additional biomarkers such as proliferation markers and ‘basal’ markers are likely to be included in the future. A better understanding of the prognostic and predictive value of combinatorial assessment of biomarker expression could lead to improved breast cancer management in routine clinical practice and would add to our knowledge concerning the variation in behaviour and response to therapy. Here, we review the evidence on the value of assessing biomarker expression in breast cancer individually and in combination and its relation to the recent molecular classification of breast cancer.
Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER+) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot ...mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third β strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.
Display omitted
•FOXA1 mutations are enriched in metastatic tumors•FOXA1 mutations are associated with worse outcome to aromatase inhibitors•Wing2 mutations promote an enhanced estrogen response upon estrogen•SY242CS induces alternative chromatin states by binding to a non-canonical motif
Arruabarrena-Aristorena et al. determine that mutations in the pioneer transcription factor FOXA1 lower the therapeutic response to aromatase inhibitors in ER+ breast cancer. Mechanistically, two phenotypic groups are established: hypermorphic Wing2 mutants that augment estrogen response, and a neomorphic SY242CS mutant that promotes an alternative pioneering, and cistromic and transcriptomic function.
Uterine adenosarcomas are mesenchymal neoplasms Piscuoglio, Salvatore; Burke, Kathleen A; Ng, Charlotte KY ...
Journal of pathology,
February 2016, Letnik:
238, Številka:
3
Journal Article
Molecular analyses of circulating tumor DNA (ctDNA) in plasma from cancer patients have the potential to deliver minimally invasive diagnostic and disease-monitoring biomarkers. Drawing from ...experience gained through the translation of circulating tumor cell detection to clinical tests, we discuss ctDNA as a source of tumor material for biomarker development.
Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic type of breast cancer, predominantly of triple-negative phenotype, and characterized by the presence of malignant cells showing ...squamous and/or mesenchymal differentiation. We sought to define the repertoire of somatic genetic alterations and the mutational signatures of MBCs.
Whole-exome sequencing was performed in 35 MBCs, with 16, 10, and 9 classified as harboring chondroid, spindle, and squamous metaplasia as the predominant metaplastic component. The genomic landscape of MBCs was compared with that of triple-negative invasive ductal carcinomas of no special type (IDC-NST) from The Cancer Genome Atlas. Wnt and PI3K/AKT/mTOR pathway activity was assessed using a qPCR assay.
MBCs harbored complex genomes with frequent
(69%) mutations. In contrast to triple-negative IDC-NSTs, MBCs more frequently harbored mutations in
(29%),
(11%),
(11%),
(11%), and
(11%).
mutations were not found in MBCs with chondroid metaplasia. Compared with triple-negative IDC-NSTs, MBCs significantly more frequently harbored mutations in PI3K/AKT/mTOR pathway-related (57% vs. 22%) and canonical Wnt pathway-related (51% vs. 28%) genes. MBCs with somatic mutations in PI3K/AKT/mTOR or Wnt pathway-related genes displayed increased activity of the respective pathway.
MBCs are genetically complex and heterogeneous, and are driven by a repertoire of somatic mutations distinct from that of triple-negative IDC-NSTs. Our study highlights the genetic basis and the importance of PI3K/AKT/mTOR and Wnt pathway dysregulation in MBCs and provides a rationale for the metaplastic phenotype and the reported responses to PI3K/AKT/mTOR inhibitors in these tumors.
.
Breast cancer intra-tumor heterogeneity Martelotto, Luciano G; Ng, Charlotte K Y; Piscuoglio, Salvatore ...
Breast cancer research,
05/2014, Letnik:
16, Številka:
3
Journal Article
Recenzirano
Odprti dostop
In recent years it has become clear that cancer cells within a single tumor can display striking morphological, genetic and behavioral variability. Burgeoning genetic, epigenetic and phenomenological ...data support the existence of intra-tumor genetic heterogeneity in breast cancers; however, its basis is yet to be fully defined. Two of the most widely evoked concepts to explain the origin of heterogeneity within tumors are the cancer stem cell hypothesis and the clonal evolution model. Although the cancer stem cell model appeared to provide an explanation for the variability among the neoplastic cells within a given cancer, advances in massively parallel sequencing have provided several lines of evidence to suggest that intra-tumor genetic heterogeneity likely plays a fundamental role in the phenotypic heterogeneity observed in cancers. Many challenges remain, however, in the interpretation of the next generation sequencing results obtained so far. Here we review the models that explain tumor heterogeneity, the causes of intra-tumor genetic diversity and their impact on our understanding and management of breast cancer, methods to study intra-tumor heterogeneity and the assessment of intra-tumor genetic heterogeneity in the clinic.
PDF
