Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer

Ishaque, Naveed; Abba, Mohammed; Hauser, Christine; Patil, Nagamma; Paramasivam, Nagarajan; Huebschmann, Daniel; Leupold, Jörg Hendrik; Balasubramanian, Gnana Prakash; Kleinheinz, Kortine; Toprak, Umut; Hutter, Barbara; Benner, Axel; Shavinskaya, Anna; Zhou, Chan; Gu, Zuguang; Kerssemakers, Jules N. A.; Marx, Alexander; Moniuszko, Marcin; Kozłowski, Mirosław; Reszeć, Joanna; Nikliński, Jacek; Eils, Jürgen; Schlesner, Matthias; Eils, Roland; Brors, Benedikt; Allgayer, Heike

doi:10.1038/s41467-018-07041-z

Cited by 108 publications

(123 citation statements)

References 70 publications

(75 reference statements)

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“…Furthermore, other suitable agents for the treatment of both primary HGSOC tumours and metastases in our cohort may include immune checkpoint and PARP inhibitors, due to the sustained involvement of defective DNA repair pathways over both tumour types. 31 Metastatic-specific events, in three patients (OVA_048, OVA_365 and OVA_378) converging at the Wnt/β-catenin signalling pathway, also indicate the potential use of targeted therapies, such as oral retinoids, e.g., acitretin, Src-tyrosine kinase inhibitors, e.g., bosutinib and smoothened inhibitors or hedgehog pathway antagonists, such as vismodegib, for the treatment of metastatic lesions in these patients. RARA, SRC and SMO can also potentially be used as diagnostic, prognostic and/ or therapy-response biomarkers in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, immune checkpoint inhibitors and poly ADP-ribose polymerase (PARP) inhibitors may be suitable for the treatment of both primary HGSOC tumours and metastases in our cohort, via antitumour synthetic lethality, due to the sustained involvement of defective DNA repair pathways over both tumour types. 31,32 Subclonal events can further inform the clinician about potential prognostic or diagnostic factors, and/or resistance to certain therapies, increasingly so in patients exhibiting parallel metastatic progression, where the primary tumour varies considerably from the metastasis. Using the TARGET database (v3), we were able to establish potentially clinically actionable events for individual cases in our metastatic HGSOC cohort.…”

Section: Analysis Of Pathways Associated With the Hgsoc Metastatic Prmentioning

confidence: 99%

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Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases

Masoodi

Siraj

et al. 2020

Br J Cancer

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BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian carcinoma, associated with poor clinical outcome and metastatic disease. Although metastatic processes are becoming more understandable, the genomic landscape and metastatic progression in HGSOC has not been elucidated. METHODS: Multi-region whole-exome sequencing was performed on HGSOC primary tumours and their metastases (n = 33 tumour regions) from six patients. The resulting somatic variants were analysed to delineate tumour evolution and metastatic dissemination, and to compare the repertoire of events between primary HGSOC and metastasis. RESULTS: All cases presented branching evolution patterns in primary HGSOC, with three cases further showing parallel evolution in which different mutations on separate branches of a phylogenetic tree converge on the same gene. Furthermore, linear metastatic progression was observed in 67% of cases with late dissemination, in which the metastatic tumour mostly acquires the same mutational process active in primary tumour, and parallel metastatic progression, with early dissemination in the remaining 33.3% of cases. Metastatic-specific SNVs were further confirmed as late dissemination events. We also found the involvement of metastatic-specific driver events in the Wnt/β-catenin pathway, and identified potential clinically actionable events in individual patients of the metastatic HGSOC cohort. CONCLUSIONS: This study provides deeper insights into clonal evolution and mutational processes that can pave the way to new therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Pathways Associated With the Hgsoc Metastatic Prmentioning

confidence: 99%

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases

Masoodi

Siraj

et al. 2020

Br J Cancer

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“…Loss of MTAP activity has been hypothesized to play a role in malignant melanoma [ 32 , 33 ]. Unfortunately, very little is known in CRC where it appears overexpressed compared to normal mucosa and positively related to aggressiveness of CRC cells [ 34 , 35 ]. Another important ancillary observation of our study is the alterations of some genes correlated to the homing of metastases to the liver.…”

Section: Discussionmentioning

confidence: 99%

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Ottaiano

Caraglia

Mauro

et al. 2020

Cancers

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Genetic dynamics underlying cancer progression are largely unknown and several genes involved in highly prevalent illnesses (e.g., hypertension, obesity, and diabetes) strongly concur to cancer phenotype heterogeneity. To study genotype-phenotype relationships contributing to the mutational evolution of colorectal cancer (CRC) with a focus on liver metastases, we performed genome profiling on tumor tissues of CRC patients with liver metastatic disease and no co-morbidities. We studied 523 cancer-related genes and tumor-immune microenvironment characteristics in primary and matched metastatic tissues. We observed a loss of KRAS and SMAD4 alterations and a high granzyme-B+ T-cell infiltration when the disease did not progress. Conversely, gain in KRAS, PIK3CA and SMAD4 alterations and scarce granzyme-B+ T-cells infiltration were observed when the tumor evolved towards a poly-metastatic spread. These findings provide novel insights into the identification of tumor oligo-metastatic status, indicating that some genes are on a boundary line between these two clinical settings (oligo- vs. poly-metastatic CRC). We speculate that the identification of these genes and modification of their evolution could be a new approach for anti-cancer therapeutic strategies.

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“…Isaque and coworkers have performed a comprehensive whole-genome analysis of differences between metastatic lesions and their corresponding primary tumors in 12 MSS CRC patients [ 42 ]. This detailed analysis showed that 65% (range from 36% to 92%) of all mutation events were shared between primary tumors and corresponding metastases, suggesting the existence of a common truncal clone; 15% (range from 1% to 29%) were tumor-specific and 19% (ranging from 3 to 42%) were metastasis-specific; recurrent driver mutations were equally present in primary tumors and their matched metastases, with the exception of only metastatic TP53 mutation, absent in the corresponding primary tumor; a number of metastasis-specific mutations were identified, including non-silent mutations of FAT1 , FGF1 , BRCA2 , TP53 , and KDR , splice site mutations of JAK2 and 3′-UTR mutations in KDR , PDGFRA , and AKT2 genes [ 42 ].…”

Section: Comparative Analysis Of the Genetic Abnormalities Of Primmentioning

confidence: 99%

Genetic Alterations of Metastatic Colorectal Cancer

Testa

Castelli

2020

Biomedicines

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Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stability (MSS), microsatellite-instability-high (MSI-H), and hypermutation. Most of these studies characterized primary tumors. Only recent studies have addressed the characterization of the genetic and clinical heterogeneity of metastatic CRC. Metastatic CRC genomes were found to be not fundamentally different from primary CRCs in terms of the mutational landscape or of genes that drive tumorigenesis, and a genomic heterogeneity associated with tumor location of primary tumors helps to define different clinical behaviors of metastatic CRCs. Although CRC metastatic spreading was traditionally seen as a late-occurring event, growing evidence suggests that this process can begin early during tumor development and the clonal architecture of these tumors is consistently influenced by cancer treatment. Although the survival rate of patients with metastatic CRC patients improved in the last years, the response to current treatments and prognosis of many of these patients remain still poor, indicating the need to discover new improvements for therapeutic vulnerabilities and to formulate a rational prospective of personalized therapies.

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Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer

Cited by 108 publications

References 70 publications

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases

Genetic heterogeneity and evolutionary history of high-grade ovarian carcinoma and matched distant metastases

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Genetic Alterations of Metastatic Colorectal Cancer

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