Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

Shah, Sohrab P.; Morin, Ryan D.; Khattra, Jaswinder; Prentice, Leah M; Pugh, Trevor J.; Burleigh, Angela; Delaney, Allen; Gelmon, Karen A.; Guliany, Ryan; Senz, Janine; Steidl, Christian; Holt, Robert A.; Jones, Steven J.M.; Sun, Mark; Leung, Gillian; Moore, Richard A.; Severson, Tesa; Taylor, Greg; Teschendorff, Andrew E.; Tse, Kane; Turashvili, Gulisa; Varhol, Richard; Warren, René L.; Watson, Peter H.; Zhao, Yongjun; Caldas, Carlos; Huntsman, David G.; Hirst, Martin; Marra, Marco A.; Aparicio, Samuel

doi:10.1038/nature08489

Cited by 983 publications

(788 citation statements)

References 19 publications

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“…In addition, the imbalances of SNP allele frequencies were used to correctly predict an LOH on chromosome 3 in only a subset of the tumour samples. Recent studies found genomic heterogeneity in breast cancer 10,24 , pancreatic cancer 25,26 , and B-cell chronic lymphocytic leukemia 9 , as well as mosaic amplifications of tyrosine kinase receptor genes in glioblastoma 27 . Together, these findings provide compelling evidence for clonal evolution as a general mechanism in cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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

et al. 2012

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According to the clonal evolution model, tumour growth is driven by competing subclones in somatically evolving cancer cell populations, which gives rise to genetically heterogeneous tumours. Here we present a comparative targeted deep-sequencing approach combined with a customised statistical algorithm, called deepsnV, for detecting and quantifying subclonal single-nucleotide variants in mixed populations. We show in a rigorous experimental assessment that our approach is capable of detecting variants with frequencies as low as 1/10,000 alleles. In selected genomic loci of the TP53 and VHL genes isolated from matched tumour and normal samples of four renal cell carcinoma patients, we detect 24 variants at allele frequencies ranging from 0.0002 to 0.34. moreover, we demonstrate how the allele frequencies of known single-nucleotide polymorphisms can be exploited to detect loss of heterozygosity. our findings demonstrate that genomic diversity is common in renal cell carcinomas and provide quantitative evidence for the clonal evolution model.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

et al. 2012

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“…500 ng was used for Illumina library construction as previously described. 48 The library then underwent a selected gene capture step consisting of 15 genes that included BRCA1 and BRCA2 using cDNA as the capture probe. The select gene capture data were first aligned to the whole genome using the BWA (LD09) 49 aligner, and the alignment results were converted to bam files (LHW þ 09).…”

Section: Brca1 and Brca2 Somatic Mutation Testingmentioning

confidence: 99%

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

et al. 2012

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We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P ¼ 0.0008). Among high-grade serous carcinomas, there were no differences between groups 1-3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P ¼ 0.034, 0.027). TP53 expression differed between groups (Po0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (Po0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.

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“…Interestingly, recent genomic profiling studies 24, 25, 26, 27, 28, 29, 30, 31 suggested a substantial degree of intra‐ and inter‐tumour heterogeneity fuelling selection processes during evolution of breast cancer 32, 33, which may complicate prognostication as well as prediction and impede cancer precision medicine approaches 34. In this context, it is worth recalling that just as the molecular phenotype, the morphological phenotype of the tumour, including tumour grade and tumour size is essentially a result of accumulated genetic aberrations over time, thereby reflecting tumour evolution at the phenotypic level.…”

Section: Introductionmentioning

confidence: 99%

Classical pathology and mutational load of breast cancer – integration of two worlds

Budczies

Bockmayr

Denkert

et al. 2015

The Journal of Pathology CR

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Breast cancer is a complex molecular disease comprising several biological subtypes. However, daily routine diagnosis is still based on a small set of well‐characterized clinico‐pathological variables. Here, we try to link the two worlds of surgical pathology and multilayered molecular profiling by analyzing the relationships between clinico‐pathological phenotypes and mutational loads of breast cancer. We evaluated the number of mutated genes with somatic non‐silent mutations in different subgroups of breast cancer based on clinico‐pathological, including immunohistochemical and tumour characteristics. The analysis was performed for a cohort of 687 primary breast cancer patients with mutational profiling, gene expression and clinico‐pathological data available from The Cancer Genome Atlas (TCGA) project. The number of mutated genes was strongly positively associated with higher tumour grade (p = 1.4e−14) and with the different immunohistochemical and PAM50 molecular subtypes of breast cancer (p = 1.4e−10 and p = 4.3e−10, respectively). We observed significant associations (|R| > 0.4) between the abundance of mutated genes and expression levels of genes related to proliferation in the overall cohort and hormone receptor positive cohort, including the Recurrence Score gene signature (e.g., MYBL2 and BIRC5). Specific mutated genes (TP53, NCOR1, NF1, PTPRD and RB1) were highly significantly associated with high loads of mutated genes. Multivariate analysis for overall survival (OS) revealed a worse survival for patients with high numbers of mutated genes (hazard ratio = 4.6, 95% CI: 1.0 – 20.0, p = 0.044). Here, we report a strong association of the number of mutated genes with immunohistochemical and PAM50 subtypes and tumour grade in breast cancer. We provide evidence that specific levels of the mutational load underlie different morphological and biological phenotypes, which collectively constitute the current basis of pathological diagnosis. Our study is a step towards genomics‐informed breast pathology and will provide a basis for future studies in this field bridging the gap between morphology, tumour biology and medical oncology.

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Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

Cited by 983 publications

References 19 publications

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

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

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

Classical pathology and mutational load of breast cancer – integration of two worlds

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