• Medicine
  • Spirituality
  • Astronomy
  • Sociology
  • Technology
  • History
  • Open Access
  • News

Metastatic Brain Tumours – The Molecular Genomics To Better Understand It

Despite significant breakthroughs in treating primary malignancies, metastatic brain tumours remain an intractable therapeutic challenge.

It is expected that 30–40% of individuals with breast and lung cancer may develop brain metastases. Because there are presently no diagnostics that can predict which individuals will be affected, brain lesions are often not detected until patients display neurological symptoms.

Current chemotherapies are ineffective against brain metastases, and despite surgical resection and radiation, the prognosis for these patients remains bleak, with an average life of just 6–9 months.

Because cancer is essentially a genetic illness involving both patient genetics and aberrant tumor genomes, determining why or how brain metastases develop necessitates an examination of the accompanying somatic mutations.

Metastatic Process Stages

Metastatic biological mechanisms, including the involvement of the microenvironment and cancer cells' capacity to cross the blood-brain barrier (BBB), have been thoroughly addressed elsewhere.

Local invasion, survival in the circulation, intravasation, extravasation, micrometastasis development, and metastatic colonization are the phases of metastasis in chronological sequence of occurrence.

Invasion is dependent on an epithelial to mesenchymal transition (EMT), in which epithelial cell qualities are inhibited, and mesenchymal cell traits are activated, resulting in the loss of cell polarity and cell-cell adhesion.

Underlying EMT is a gene expression pattern governed by epigenetic alterations across the genome and abnormal expression of critical transcription factors and microRNAs. New data suggests reversing the EMT pathway is essential for colonized metastatic cells to proliferate.

This potential phenotypic flexibility aligns with epigenetic principles inherent in the hierarchically structured cancer stem cell concept, in which cancer stem cells undergo irreversible epigenetic modifications to form phenotypically different cancer cells.

Additional research suggests that cancer cells acquire stem cell-like characteristics throughout the EMT process. The cancer stem cells are a small group of cells inside a tumor. They can self-renew indefinitely, may seed new tumors, and are a possible cell type from the initial tumor that develops a metastatic lesion.

Male medical figure with front of the brain highlighted
Male medical figure with front of the brain highlighted

Oncogenes And Tumor Suppressors

Decades of studies have discovered that carcinogenesis is regulated by oncogene activation and tumor suppressor gene inactivation.

Oncogenes are activated by various processes, including gain-of-function sequence mutations, overexpression owing to genomic amplification or unregulated epigenetics, and genomic rearrangements.

Tumor suppressors, which generally restrict normal cell proliferation or promote tissue differentiation, are inactivated by genomic lesions, resulting in loss of function.

Thus, the reasons for illness onset and progression may be located within the tumor genome. Significant clinical advancements in primary cancer therapy may be credited to molecularly focused medications that target active oncogenes such as HER2, EGFR, MET, and BRAF.

Their abnormal presence in the original tumor genome serves as a biomarker for the success of the targeted therapy.

Furthermore, oncogenic factors often have kinase or ligand-binding functions and 'druggable' protein motifs. The advantages of targeted therapies over standard chemotherapy are apparent, with improved effectiveness and less devastating side effects.

The Pattern Of Genomic Mutations In Metastatic Brain Tumours

Early research suggests that molecularly targeted treatments such as small-molecule kinase inhibitors and monoclonal antibodies against activated oncogenes might elicit a response and lower metastatic recurrence rates.

The inefficiency of targeted medication transfer over the BBB, on the other hand, has been linked to an increased incidence of metastatic brain tumours in patients with managed primary malignancy and peripheral metastasis.

Although further research is needed, each of these findings suggests that an oncogene mechanistically connected to the underlying malignancy is also involved in increasing the occurrence of metastatic brain tumours. This situation might apply to altered BRAF oncogene expression in melanoma metastases, abnormal levels of HER2 oncogene in breast cancer brain metastases, and mutated EGFR oncogene in lung cancer brain metastases.

Based on information on their driver oncogene status and frequency of mutation in the linked original tumor, the potential relevance of BRAF, HER2, and EGFR for brain metastasis was discovered.

Their precise oncogenic function and mutation frequency in metastatic brain tumours are unknown.

Furthermore, it is uncertain if, for a particular oncogene, certain kinds of activating mutations are more often found in brain metastases, as preliminary data suggests. Investigating these unknowns will help to understand why brain metastases emerge when systemic illness is treated with targeted medicines and why treating metastatic brain tumours has had minor impacts with no influence on therapeutic choices.

Comprehensive genomic characterization of metastatic brain tumours compared to their parent malignancies, especially the well-characterized molecular breast and lung cancer subtypes, is a helpful starting point.

Despite the vast number of individuals affected, research on significant cancer-linked genomic copy number aberrations, rearrangements, and sequence changes in metastatic brain tumours is still in its early stages.

Mutations In Gene Coding

Most research on somatic DNA coding mutations in metastatic brain tumours has been oriented toward activating mutations in oncogenes or tumor suppressors previously linked to the underlying malignancy.

A small study that included DNA from ten melanoma metastases measured a panel of BRAF, NRAS, AKT, PIK3CA, and KIT activating mutations using a highly sensitive primer extension and mass spectrometry BRAF activating mutations were the most common, followed by NRAS, as in primary melanoma.

A further investigation employing Sanger sequencing found BRAF and NRAS mutations in primary melanoma and matching brain metastases from 44 patients with 80% consistency.

Another research used high-resolution DNA melting analysis to detect mutations in 19 oncogenes, including BRAF, KRAS, NRAS, and PIK3CA, in specimens from matched brain metastases and original colorectal cancer.

The investigation confirmed that KRAS mutations were more prevalent in colorectal cancer and that 9 of 10 matched brain metastases were 100% concordant with mutations found in the source tumor.

A breast cancer investigation utilizing primer extension mass spectrometry examined mutations in EGFR, HRAS, KRAS, NRAS, and PIK3CA in 39 matched pairs of original breast tumours and brain metastases.

NRAS and PIK3CA mutations were found independently in samples from two individuals, both primary and metastatic. An EGFR mutation was found in a single patient's breast carcinoma but not in the matching metastasis.

Whether a driver is involved in discovering an oncogene in both primary and metastatic cancer or just in brain metastases is a significant difference that justifies altering targeted therapies or generating predictive biomarkers for metastatic brain tumors.

Ding et al. used massively parallel DNA sequencing methods to analyze three related specimens: a primary triple-negative basal-like breast cancer, a tumor derived from a mouse xenograft model, and matched metastatic brain tumor that developed within eight months of primary diagnosis.

They directly investigated whether processes leading to macrometastases are driven by mutations that pre-exist in primary tumor cells or arise at a distant site.

Regarding coding mutations, 48 of 50 verified somatic gene mutations were found in DNA isolated from all three tumor samples, indicating that coding mutations are consistent in primary and metastatic cancer.

The allelic frequency of 26 of these variants was considerably raised in metastases or xenograft specimens, whereas the allelic frequency of two mutations was reduced. The observed degrees of enrichment and decrease of enrichment (but still detectable) for particular coding mutations in metastasis and xenograft specimens might imply that a fraction of primary tumor cells bearing the array of mutations in the primary, rather than a single clone, was contributing.

Unlike coding mutations, copy number aberrations were seen in metastatic and xenograft specimens, with 19% and 39% distinct from the source malignancy, respectively. A similar study that used massively parallel sequencing to explore an estrogen receptor alpha-positive breast tumor yielded a different result. In this case, the metastasis was discovered nine years after the original diagnosis[88].

Variations Somatic Copy Number

Ding et al. discover that the incidence of copy number changes is higher in metastatic and xenograft specimens lend itself to the re-interpretation of previous investigations.

Low-resolution arrayed comparative genomic hybridization (aCGH) investigations, for example, have shown recurrent, wide copy number variation in primary tumours that generate brain metastases, implying that the particular loci constitute functional risk markers.

More research is needed to determine if the broad areas include actual driving lesions or whether they indicate more genomic instability underlying other structural abnormalities that have a role in metastasis.

Nonetheless, studies demonstrate a high frequency of copy number variations in recognized cancer genes in brain metastases. Two investigations of breast cancer brain metastasis, one utilizing aCGH techniques and the other fluorescence in situ hybridization (FISH), reveal that increases in the EGFR oncogene and loss of the PTEN tumor suppressor are more common in metastases.

Two more studies on the FISH analysis of lung cancer brain metastases reveal a modestly greater frequency of EGFR copy number gain (through amplification or polysomy) in brain metastases compared to the matched original malignancy.

Whole-Genome Expression Research

A range of structural and coding defects and epigenetic dysregulation provide the groundwork for aberrant gene expression, which serves as the biomolecular connection between the aberrant genome and changed cancer cell function.

Whole-genome and transcriptome analyses of primary tumours are used to discover genes or transcripts with considerable cancer-specific expression.

They are precious in elucidating cancer cell-specific systems and pathway-level malfunction. Furthermore, gene expression signature-based diagnostics help predict lymph node metastases and improve patient outcomes.

Recent gene expression data show pathways behind brain metastasis as well. Da Silva et al. used microarrays to assess 15 matched primary triple-negative basal breast tumours and their matched brain metastatic tumours to 512 cancer-linked genes.

Twenty-seven genes changed considerably, including HIF1A and HER3, both highly upregulated. This shows that the epidermal growth factor receptor family may have a role in even the triple-negative triple breast cancer subtype.

Furthermore, the HIF1A transcription factor activates genes encoding glucose transporters and glycolytic pathway genes.

An essential part of HIF1A is supported by independent research showing more frequent overexpression in inpatient brain metastases compared to primary breast cancer tissues and enhanced aerobic glycolysis in cells migrating to or implanted in the brain versus parent cells in mouse models of human cancer cell line xenografts.

Bos et al. identified upregulated expression of an EGFR ligand HBEGF and cyclooxygenase PTGS2 and ectopic expression of the brain-specific gene 2,6-sialyltransferase ST6GALNAC5 in breast cancer cells as factors contributing to their ability to cross the BBB in multiple lines of whole-genome investigation in cell lines and patient specimens.

Increased PTGS2 expression has also been linked to brain metastasizing melanoma.

People Also Ask

Is Metastatic Brain Cancer A Terminal?

Metastatic brain cancer is often fatal. While some individuals live longer than others, and a few live considerably longer than average, most people have months to live when diagnosed.

What Is The Average Survival For Patients With Brain Metastasis?

Brain metastases are associated with considerable morbidity, death, and a poor prognosis. The median survival duration ranges from 4 to 16 months, depending on the initial cancer location.

How Long Can You Live With Metastasized Brain Cancer?

People diagnosed with brain metastasis lived on average for fewer than six months a decade and a half ago. Treatments have improved throughout the years, and patients with brain metastases now enjoy longer lives than ever before.


Many concerns remain unanswered due to the present lack of understanding of brain metastases, including whether or not the initial cancer drivers are also the drivers of associated metastatic brain tumors. Early evidence shows that distinct factors may be responsible for developing metastatic brain cancers, generating new challenges. Does the accumulation of mutations at the metastatic location result in the emergence of a novel driver? Do cells produced from a small subclone in the initial tumor harbor lesions capable of evading primary adjuvant treatment and seeding the metastatic occurrence? More study is required to bridge the gap and address these essential concerns.

People suffering from metastatic brain tumors urgently need more effective treatments, and professionals want predictive laboratory tests to detect patients at risk of acquiring metastatic brain tumors. A hitherto imagined extensive investigation of metastatic brain tumor genomes is required to address these demands. Furthermore, without a better understanding of the genetic abnormalities that drive metastatic brain cancers, diagnostics and molecularly targeted therapeutics will remain stuck, and patient outcomes will stay poor.

About The Authors

Suleman Shah

Suleman Shah - Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences. Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA). Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.

Recent Articles

  • Stone Age Humans Conducted Surgical Amputation, A New Study Finds Evidence

    Stone Age Humans Conducted Surgical Amputation, A New Study Finds Evidence

    Scientific investigation in Borneo has unearthed the world's first documented instance that stone age humans conducted surgical amputation. This discovery represents a significant achievement in the annals of human prehistory.

  • 180 Tips - Best Website For Football Prediction And Tips

    180 Tips - Best Website For Football Prediction And Tips

    How can you beat the best odds at the most well-known online bookmakers when betting on soccer matches? Today's 180 Tips forecasts from Betwinner360 include a record of winning methods. 180 tips provides in-depth research of more than 50 different football leagues, betting tactics organized by market, and expert predictions for each match.

  • Virgo And Sagittarius Compatibility - Great Conversations

    Virgo And Sagittarius Compatibility - Great Conversations

    Virgo and Sagittarius's compatibility is such that they are attracted to one another right away. They base their first interactions on how well they get along in conversation, which comes naturally to them both. These changeable signs will enjoy every minute of talking to each other to death! They engage in frenzied arguments, lengthy philosophical discussions, and fast banter.

  • Pisces And Aquarius Compatibility - Creative Brilliance

    Pisces And Aquarius Compatibility - Creative Brilliance

    Pisces and Aquarius compatibility is such that these two are masters of manifestation while working together. When Aquarians let go of their rigid views, they become natural alchemists who are capable of creating with their creative brilliance. Because of their more flexible and understanding nature, Pisces may assist them in becoming less stuck and releasing their boundless creative potential.

  • Pisces And Scorpio Compatibility - Best Match For Love

    Pisces And Scorpio Compatibility - Best Match For Love

    Pisces and Scorpio compatibility is that they have an innate knowledge of one another, even though they are frequently mysterious to others. These two are irresistibly attracted to each other because they feel like they understand each other but don't say it out loud. They seem to have a psychic connection because they can easily tune into one another's brains.

  • A Massive 7.6 Earthquake Rocks Papua New Guinea

    A Massive 7.6 Earthquake Rocks Papua New Guinea

    On Sunday, a massive 7.6 earthquake rocks Papua New Guinea, causing landslides, cracking roads, and damaging houses. It is currently unknown how extensive the damage is; however, there is debris scattered over the highways and fissures popping up in the roads. According to the United States Geological Survey, the epicenter of the earthquake was located at a depth of 90 kilometers, or around 56 miles, and was close to the town of Kainantu, which has a population of approximately 8,500 people.

  • Most Frequent Angel Numbers You Keep Seeing Is Luck Or Unlucky

    Most Frequent Angel Numbers You Keep Seeing Is Luck Or Unlucky

    The most frequent angel numbers you keep seeing are distinct from other forms of esoterica in that they have no connection to the date that you were born. In numerology, every number has a meaning. Nevertheless, certain number sequences are more prevalent than others. Because all of us have come across them, three-digit angel numbers are widespread.

  • Pisces And Leo Compatibility Is Quite Strong

    Pisces And Leo Compatibility Is Quite Strong

    Leo will inevitably rule Pisces in some aspect of life, Pisces and Leo compatibility whether it is in terms of work, friendship, or love. However, as Leos are kind and loving rulers who have no malice in their hearts, and since the fish don't mind being ruled if it's done with warmth and love, this isn't always a terrible thing.

  • Angel Number 6666 Meaning - A Sign That Your Heart Is Full Of Love

    Angel Number 6666 Meaning - A Sign That Your Heart Is Full Of Love

    If you keep seeing the same number in your life, it's not a coincidence. The angels use Angel Number 6666 meaning to send you an important message. If you can clearly interpret the message of angel number 6666, it will serve you well. This number appears in your life directly from the divine realm.