Significance of TP53 mutations determined by next-generation “deep” sequencing in prognosis of estrogen receptor-positive breast cancer

Uji, Kumiko; Naoi, Yasuto; Kagara, Naofumi; Shimoda, Masafumi; Shimomura, Atsushi; Maruyama, Naomi; Shimazu, Kenzo; Kim, Seung Jin; Noguchi, Shinzaburo

doi:10.1016/j.canlet.2013.08.028

Cited by 25 publications

(23 citation statements)

References 27 publications

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“…Among others, we observed a correlation between HR+ and PIK3CA mutations, triple-negative tumors and TP53 mutations, PIK3CA and low Ki67 proliferative index, tumor grade and TP53 mutations. Many of the findings were expected and recapitulated scattered reports within other publications 18,21,22 ; however, this is the first report aimed at breast cancer to comprehensively correlate these measures with molecular characteristics and to do so specifically within clinical samples. It is critically important to examine the pathologic features and receptor status in concert with the molecular genetic profile; afterall, genetic variants ultimately manifest in cancer phenotype-including microscopic appearance and biological behavior.…”

Section: Discussionsupporting

confidence: 56%

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer

Gurda

Ambros

Nikiforova

et al. 2017

Applied Immunohistochemistry &Amp; Molecular Morphology

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Women with advanced breast carcinomas have few therapeutic options. Recent advances in genomic profiling represent a new paradigm of cancer classification and treatment, but experience with genomic testing in a clinical setting remains limited. We retrospectively determined the genomic variants and correlate these with histology [histomorphologic subtype, nuclear grade, standard immunohistochemistry (IHC)] and clinical utilization (ordering, turnaround time, report review, and targeted therapy). Among 48 patients, 2 showed no genetic alterations, 11 (23%) showed variants of unclear significance only and 35 (73%) showed variant(s) affecting function (VaF) and/or variants of unclear significance. Overall, 119 variants were observed in 20 of 50 tested genes. Each patient had a unique molecular profile, with numerous (n=58) variants not previously reported in breast cancer. VaF detected in more than 2 patients included: TP53 (n=21), PIK3CA (n=20), and FGFR1 (n=3). VaF comprised 46 single nucleotide variants (79%), 7 amplifications (12%), 3 frameshifts (5%), 1 insertion (2%), and 1 deletion (2%). The tested samples had very high Ki67 index (average 57%±23%) and approximately half were hormone receptor and HER2 negative (25/46, 54%). Metastatic breast carcinomas showed a higher average VaF versus breast-localized tumors (1.3±0.99 vs. 0.18±0.60, P<0.05). Next-generation sequencing reports were promptly reported and reviewed (average 1 to 2 d) and 7 (∼25%) of potentially eligible patients received targeted therapy. Advanced breast cancers show unique landscapes of genetic variants. Most testing was done in late disease, often in metastatic and receptor-negative carcinomas. Next-generation sequencing results were promptly reported and reviewed, but the utilization of targeted therapies was limited.

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Section: Discussionsupporting

confidence: 56%

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer

Gurda

Ambros

Nikiforova

et al. 2017

Applied Immunohistochemistry &Amp; Molecular Morphology

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“…Furthermore, the clinical impact of TP53 mutations in subclones resulting in rather low allelic frequencies, which can only be detected by NGS but not by Sanger sequencing is doubtful. Matching these considerations, a recent study comparing Sanger with NGS in breast cancer showed that the additional TP53 mutations detected by NGS had no additional impact on the clinical information that was already provided by Sanger sequencing [22]. …”

Section: Discussionmentioning

confidence: 99%

Role ofTP53mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

et al. 2016

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BackgroundTP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial.Methods450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup.ResultsOf 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019).ConclusionsOur study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.

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“…The GS Junior system (Roche Diagnostics, Basel, Switzerland) was used for the NGS methylation assay for region X (Fig. 1A) in accordance with the manufacturer's protocol, and data were analyzed using GS Amplicon Variant Analyzer software (version 2.7; Roche Diagnostics) (11). The LATS2 gene sequence was obtained from the University of California Santa Cruz browser (NM_014572, December 2013; GRCh38/hg38; https://genome.ucsc.edu).…”

Section: Introductionmentioning

confidence: 99%

LATS2 promoter hypermethylation and its effect on gene expression in human breast cancer

et al. 2017

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Abstract. Tumor-specific promoter hypermethylation of large tumor suppressor, homolog 2 (LATS2), a tumor suppressor gene, has been investigated using methylation-specific polymerase chain reaction (MSP) assays in different types of human cancer producing conflicting results. The aim of the present study was to evaluate the methylation status of the LATS2 promoter region using bisulfite sequencing with a next generation sequencer for breast cancer. In the 11 patients enrolled in the present study, the LATS2 promoter methylation index (MI) was uniformly high in tumor and normal tissues of the breast (median, 84.0 and 87.4%, respectively). The presence of LATS2 promoter hypermethylation was confirmed in isolated tumor cells and normal epithelial cells using the magnetic-activated cell sorting method. In situ hybridization for LATS2 messenger RNA (mRNA) revealed that the mRNA expression of LATS2 was higher in normal epithelial cells, compared with tumor cells, however, it was not significantly associated with LATS2 MI. In 12 breast cancer cell (BCC) lines and two normal breast cell lines, the LATS2 promoter was uniformly hypermethylated with no correlation between the mRNA expression of LATS2 and the LATS2 MI. In addition, treatment of the BCC lines with a demethylating reagent had minimal effect on the mRNA expression of LATS2 in any of these cell lines. These results demonstrated that LATS2 hypermethylation was not involved in silencing the mRNA expression of LATS2 mRNA. The lower mRNA expression level of LATS2 in tumor cells, compared with normal epithelial cells, suggested the possible involvement of downregulation in the mRNA expression of LATS2 in the pathogenesis of breast cancer. Therefore, the conflicting results previously reported for LATS2 promoter methylation in different types of cancer, detected using MSP assays may be attributable to the low fidelity of the MSP assay. IntroductionLarge tumor suppressor, homolog 2 (LATS2), is a tumor suppressor gene implicated in the regulation of cell proliferation, migration and apoptosis via several cell signaling pathways, particularly the Hippo, p53 and LATS-LIM domain kinase-actin pathways (1). Classically, a tumor suppressor gene is inactivated by a somatic mutation or promoter hypermethylation. Previous human cancer genome projects have revealed the presence of LATS2 mutations in several types of human cancer, including breast cancer, however, its frequency is low at ~1% (2,3). Therefore, LATS2 mutations are unlikely to be important in the pathogenesis of the majority of breast cancer cases. By contrast, hypermethylation of the LATS2 promoter has been reported in a higher proportion of breast cancer (50%) (4), acute lymphoblastic leukemia (ALL) (24%) (5), astrocytoma (71.5%) (6), lung cancer (78.8%) (7), and nasopharyngeal cancer (36.7%) (8) cases, and the absence of LATS2 hypermethylation has been confirmed in normal breast tissues (4) and normal brain tissues (6). In addition, the association between LATS2 promoter hypermethylation and reduced messenger RNA ...

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Significance of TP53 mutations determined by next-generation “deep” sequencing in prognosis of estrogen receptor-positive breast cancer

Cited by 25 publications

References 27 publications

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer

Characterizing Molecular Variants and Clinical Utilization of Next-generation Sequencing in Advanced Breast Cancer

Role ofTP53mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

LATS2 promoter hypermethylation and its effect on gene expression in human breast cancer

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