Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing

Kovaleva, Valentina; Geissler, Anna Lena; Lutz, Lisa; Fritsch, Ralph; Makowiec, Frank; Wiesemann, Sebastian; Hopt, Ulrich T.; Passlick, Bernward; Werner, Martin; Laßmann, Silke

doi:10.1186/s12943-016-0549-8

Cited by 43 publications

(47 citation statements)

References 34 publications

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“…Previous sequencing studies of cancer-associated genes revealed that TP53 , PTEN , KRAS and SMAD4 were among the genes most frequently affected by mutations restricted to the metastasis (11, 12, 41, 42). Although TP53 , PTEN and KRAS mutations were not found to be restricted to or enriched in the metastases in this study, we have identified a likely pathogenic SMAD4 mutation associated with LOH, along with likely pathogenic mutations affecting other EMT-related genes, such as TCF7L2 and TCF4 ( ITF2 ), restricted to or enriched in the metastases.…”

Section: Discussionmentioning

confidence: 99%

“…EMT, a phenomenon by which epithelial cells acquire invasive and migratory properties, has been shown to be key to the metastatic process (43). SMAD4 loss has been implicated in the metastatic spread of breast cancer in preclinical models (44), and SMAD4 mutations restricted to metastases have been reported in three breast cancers (11, 12) and in two colorectal cancers with synchronous liver metastasis (42). TCF7L2 loss-of-function mutations have been shown to activate Wnt pathway (45), which plays pivotal roles in EMT, and knock-down of TCF4 (ITF2) deregulates TGF-β signaling, EMT and apoptosis (46).…”

Section: Discussionmentioning

confidence: 99%

“…Our analyses also resulted in the identification of metastasis-specific secondary LOH events associated with likely pathogenic mutations affecting JAK3 and FLT4 . Alterations in both genes have previously been described as metastasis-specific, with a JAK3 mutation restricted to the liver metastasis of a colorectal cancer (42) and a FLT4 mutation restricted to the liver metastasis of a breast cancer (47). We did not observe specific patterns in terms of the number of private mutations in the metastases, likely pathogenic mutations enriched in the metastases or mutational signature in the five liver metastases or the two bone metastases, or any significant associations between the number of mutations and histopathologic parameters, such as histologic grade, tubule formation, nuclear pleomorphism and mitotic index (Supplementary Table S1).…”

Section: Discussionmentioning

confidence: 99%

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Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Bidard

Piscuoglio

et al. 2017

Clinical Cancer Research

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Purpose Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies or both. We sought to define the repertoire of genetic alterations in breast cancer patients with de novo metastatic disease who had not received local or systemic therapy. Experimental Design Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Results Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%–95%) of shared somatic mutations. Whilst mutations in known driver genes including TP53, PIK3CA and GATA3 were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intra-tumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including SMAD4, TCF7L2 and TCF4 (ITF2), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Conclusion Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intra-tumor genetic heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Bidard

Piscuoglio

et al. 2017

Clinical Cancer Research

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“…The third BRAF positive case in our study exhibited G442D point mutation. This mutation has earlier been reported in colon cancers 25 and proven to be the causative factor. 26,27 Additionally, we also observed BRAF polymorphism in 14.4% cases.…”

Section: Discussionmentioning

confidence: 54%

Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India

Singh

Guleria

Malik

et al. 2019

Current Problems in Cancer

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Mitogen-Activated Protein (MAP) Kinase pathway involves several oncogenic genes which can serve as potential targets for therapy. Therefore, aim of the present study is to analyze mutations in the MAP Kinase pathway in pulmonary adenocarcinoma (ADCA) of Indian patients along with clinico-pathologic correlation and determination of the survival status in patients receiving therapy. Blocks and slides of 125 pulmonary ADCA of last 5 years were retrieved. Histo-morphology and tumor content were determined. EGFR, KRAS, BRAF and MEK1 genes were analyzed using Sanger sequencing and Real-time polymerase chain reaction (PCR). Clinico-pathologic correlation and survival analysis were performed. Fifty-eight (46.4%) patients harbored genetic mutations of which 49 had single somatic mutations, 5 had multiple exonic and 4 showed coexisting EGFR and KRAS mutations. EGFR mutations were seen in 24.8%, KRAS in 19.2% and BRAF (non-V600E) in 2.4% cases. There was no difference in progression-free survival of wild- type/single mutations when compared with multiple/ coexisting mutations (P = 0.09). However, the P value may indicate borderline correlation. To conclude, EGFR and KRAS mutations may coexist in the same patient in lung ADCA. Multiple exonic mutations of KRAS gene formed substantial percentage of our cohort, requiring further exploration. Lung ADCA harbouring BRAF mutations are commonly non-V600E. Testing of all major genetic driver mutations of lung ADCA irrespective of histology and other demographic characteristics is necessary.

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“…As reported by us before [69], DNA quality was measured using FFPE QC kit and libraries were prepared using the TruSeq Amplicon Cancer Panel (48 cancer related genes) (both Illumina). Quantity and quality of libraries were examined using the Bioanalyzer 2100 system (Agilent Technologies) and DNAs were pooled for sequencing on the MiSeq (Illumina).…”

Section: Methodsmentioning

confidence: 99%

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

et al. 2017

Self Cite

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EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.

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Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing

Cited by 43 publications

References 34 publications

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Genetic Heterogeneity in Therapy-Naïve Synchronous Primary Breast Cancers and Their Metastases

Epidermal growth factor receptor (EGFR), KRAS, and BRAF mutations in lung adenocarcinomas: A study from India

ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

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