Reference genomes have great benefits for medicine: they allow the discovery of the molecular mechanisms responsible for many diseases and facilitate the diagnosis and development of more specific therapies. Knowing the genomic map of cancer cells can provide us with useful information to understand how they work. In some types of cancer, we do not know if mutations in the sequence compared to the normal genome are the cause or the effect of the cancer itself.
Through the game we will analyze the genome of the cancer cells in parts and in a collaborative way: first we will do a chromosome by chromosome analysis and then we will compare pairs of chromosomes with pairs of chromosomes. Always taking into account the known genome of cells without cancer, we will look in the genome of the cancer cells for the presence of modified or moved fragments or the absence of known sequences.
Analysing breast cancer, we will put a lot of attention looking for information about certains genes that science know are particularly relevant in this type of cancer.
These are the chromosomes we are analyzing in the order we have released to the players
Chromosome 17. (Launched on January 27th) This chromosome contains a high number of breast cancer related genes. Some of them are tumor suppressor genes like TP53 or BRCA1. Tumor suppressor genes are genes that regulate a cell growth and division. Thus, if they are mutated it might result in the development of cancer. For example, a reduction of the function of BRCA1 has been associated with about 40% of inherited breast cancer. Other associated genes are oncogenes like MAP2K4 or BCAS3. Oncogenes are genes that, when mutated or overexpressed, can cause cells to survive and proliferate, instead of undergo a programmed cell death (apoptosis). ERBB2 is an important oncogene, since its overexpression is associated with 20% of invasive breast carcinomas. Finally, an interesting chr17 located gene is RAD51C. It’s localized in a region where amplification occurs frequently in breast tumors, suggesting a role in tumor progression.
Chromosome 10. (Launched on February 1st) This chromosome contains interesting internal rearrangements, like translocations (portion of a chromosome that breaks and jumps to a different location) or duplications (production of one or more copies of a gene or region of a chromosome). Moreover, it encloses breast cancer related genes. Some of them (PTEN or FGFR2) are linked with an important pathway that regulates the cell cycle, playing a role in functions like metabolism, growth, proliferation or cell survival (the PI3K/AKT pathway). Therefore, an aberrant activation of this pathway will lead to the survival/proliferation of tumour cells. PTEN is a gene that functions as a tumour suppressor, acting as a negative regulator of the PI3K/AKT pathway. Mutations in this gene will lead to overexpression of the pathway, increasing the risk of cancer. FGFR2 can activate the PI3K/AKT pathway, and participates in cell maturity or bone maintaining. An erroneous increment in the number of copies of this gene have been observed in breast cancer. Other interesting genes localized in chromosome 10 are KIF5B or SUFU. The first one functions as a motor protein, and have been observed to be highly expressed in breast cancer. SUFU plays a role in the hedgehog pathway, which is a signalling pathway that participates in human development, and is mostly inactive in the adult organism. Thus, an aberrant hedgehog signalling has been linked with various cancer types.
Chromosome 7. (Launched on Febrary 4th) This chromosome contains some internal rearrangements, like an interesting translocation. It encloses breast cancer related genes. We can find BRAF or KMT2C, two of the most commonly mutated genes in this type of cancer. BRAF is an oncogene that participates in cell division and differentiation. KMT2C participates in the modification of histones (proteins that protect DNA). This gene has a mutation frequency of 8% in breast cancer. We can find other important genes like EGFR, an epidermal growth factor receptor, that leads to cell proliferation. Amplifications and mutations of this gene have been shown to be the detonating factors in many cancer types.
Chromosome 16. (Launched on Febrary 4th) This chromosome contains small rearrangements and some breast cancer related genes. We can find tumour suppressor genes like PALB2, BRD7 or CTCF. PALB2 helps to repair DNA breaks, and BRD7 has an important role by interacting with the oncogene p53 and preventing tumour growth. CTCF regulates gene expression and is involved in the 3D structure of the genome. It is commonly mutated in breast cancer cell lines and breast tumours. Moreover, chromosome 16 contains CDH1, which is a gene that encodes a protein involved in the adhesion of proteins. Mutations in this gene are related with a variety of cancers, since its loss of function is thought to contribute to cancer progression.
Chromosome 1. (Launched on Febrary 11th)This chromosome is the largest human chromosome. It contains some important breast cancer related genes such as MTOR, involved in the PI3K/AKT pathway with an essential role in cell growth, proliferation, apoptosis and angiogenesis. Deregulation of MTOR has been observed in many cancer types. BCAS2, also in chr1, has been associated with breast cancer since it increases the activity of oestrogen receptor (ER), and might promote carcinogenic processes in breast cancer cells. Moreover, tumour suppressor genes like SPEN are located in chr1.
Chromosome 13. (Launched on Febrary 11th) This chromosome contains an important breast cancer gene, BRCA2. This gene is involved in DNA double strand break repair. Mutations in this gene have become a hallmark for hereditary breast and ovarian cancers. Moreover, it contains RB1, a gene that regulates negatively the cell cycle, and was the first tumor suppressor gene found.
Chromosome 2. (Launched on Febrary 18th) This chromosome contains some breast cancer related genes like BARD1, DNMT3A or SF3B1. The first gene, BARD1, encodes a protein that interacts with other breast cancer gene, BRCA1 (chr17). Their interaction promotes tumour suppression functions, since they participate in double strand break repair and apoptosis. DNMT3A participates in methylation processes, and its downregulation has been related with breast cancer. On the other hand, SF3B1 is involved in RNA splicing. Mutations in this gene have been described in breast cancer.
Chromosome 3. (Launched on Febrary 18th) This chromosome conteinsan important oncogene, PIK3CA.This gene has the highest mutation frequency in breast cancer, being an important focus on cancer studies in the last decade. It has a role on diverse cell functions, including proliferation and survival. Other gene located in this chromosome is SETD2, involved in histone modifications. Its mutations have been commonly found in cancers, and has a high frequency mutation rate in phyllopodes tumour of the breast (PT). This type of tumours can be really aggressive.
Chromosome 4. (Launched on Febrary 25th) This chromosome contains some breast cancer related genes like REST, FGF2 or FBXW7. REST acts as a transcriptional repressor of neuronal genes in non-neuronal tissues. Interestingly, can act as an oncogene or a tumour suppressor depending on the context. FGF2 is a member of the fibroblast growth factor family (FGF). It participates in wound healing or tumour growth among other functions. FBXW7 participates in the ubiquitination of proteins. Is a critical tumour suppressor gene and mutations in this gene have been detected in ovarian and cancer cell lines.
Chromosome 5. (Launched on Febrary 25th) This chromosome conteins tumour suppressor genes like APC or IRF1. APC encodes a tumour suppressor protein that acts as an antagonist of cell surface signaling pathways. Is involved in cell migration or apoptosis among other functions. IRF1 acts as a transcriptional regulator and tumour suppressor. It activates the transcription of genes involved in immune response. Defects in this gene have been associated with some cancer types. Other interesting gene located in chromosome 5 is TERT, which encodes a protein that maintains telomere ends in the chromosomes. Deregulation of this protein may be involved in oncogenesis.
Chromosome 21. (Launched on March 4th) This chromosome contains an interesting breast cancer related gene, RUNX1. This gene controls the expression of genes essential for cell development. A bad regulation in this gene is associated with many cancers, including breast.
Chromosome 22. (Launched on March 4th) This chromosome is one of the smaller chromosomes, it contains three breast cancer related genes. One of them is PRODH which encodes a mitochondrial protein that is involved in processes that produce ATP or reactive oxygen species, having a role in cell survival or death. CHEK2 is another gene involved in cell cycle checkpoints and is a tumour suppressor. It stabilizes tumour suppressor protein p53, leading to cell cycle arrest. Moreover, it interacts with BRCA1 (located in chromosome 17), thus is involved in cell survival after DNA damage. Mutations on CHEK2 confer predisposition to breast cancer, sarcomas or brain tumours among others. Finally, APOBEC3A is a gen that encodes a protein involved in immunity. Mutagenesis in this gene are one of the major sources in breast cancer.
Chromosome 6. (Launched on March 11th) This chromosome contains a huge variety of breast cancer related genes. Like TRIM27, a transcription repressor involved in cell senescence. It has a role in the development of cancer, since is highly expressed in cancer cells, leading to cell dysregulation, tumour cell proliferation and migration. It has the potential to serve as a biomarker for cancer patients. MAPK14 is a member of the MAP kinase family. They act as integration point for multiple biochemical signals and are involved in a wide variety of cellular processes. This gene has an essential role in cell migration in breast cancer cells. HSP90AB1 encodes a protein that belong to the family of HSP (heat shock proteins), which are involved in cell survival, signal transduction or protein folding among other processes. They have been related with tumour formation and cancer cell proliferation, and are being studied as new therapeutic approaches in cancer treatment. Finally, FOXO3 functions as a trigger for apoptosis through expression of genes necessary for cell death. Is an important tumour suppressor gene in a variety of human cancers.
Chromosome 20. (Launched on March 11th) This chromosome contains BCAS4 and BCAS1, two genes located in the region 20q13.2, a region that undergo amplification, overexpression and fusion in breast cancer. Amplification of this region is associated with more aggressive tumour phenotypes. Other breast cancer related gene located in this chromosome is CD40. This gene is a receptor on antigen-presenting cells of the immune system, which mediates a broad variety of immune inflammatory responses. Is a member of the tumour necrosis factor receptor (TNR) family, which are proteins that develop antitumour responses against cancer cells. CD40 is broadly expressed on the surface of immune cells and in diverse cancer types, including breast.
Chromosome 19. (Launched on March 25th) This chromosome contains one tumour suppressor gene like STK1, which regulates cell polarity and is involved in the cell cycle and is altered in almost 3% of cancers with lung adenocarcinoma or breast invasive ductal carcinoma. Moreover, we can find other genes like CCNE1 or KCNN4. Overexpression of CCNE1 has been observed in many tumors, which results in chromosome instability and may contribute to tumorigenesis. KCNN4 encodes a protein that participates in the formation of potassium channels in the cell membrane. It has been seen that this gene is a modulator of progression and drug resistance in breast cancer. Targeting this gene might serve as a therapeutic strategy.
Chromosome 8. (Launched on March 25th) This chromosome encloses some cancer related genes like LOXL2, MYC or NDRG1. LOXL2 encodes a protein essential for biogenesis of connective tissue. Moreover allows the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of metastases. Is of particular interest in cancer biology since is highly expressed in some tumors, and affects proliferation of breast cancer cells. Amplification of MYC is observed in numerous human cancers. Moreover, is highly expressed in triple-negative breast cancer type, the most aggressive breast cancer subtype. Finally, NDRG1 encodes a cytoplasmic protein involved in stress responses, cell growth and differentiation. It drives tumor progression and brain metastasis in aggressive breast cancers, thus it may serve as a therapeutic target and prognostic biomarker.
Chromosome 9. (Launched on 1 April) This chromosome contains the NOTCH1 gene, an important gene as it is part of a signalling pathway involved in processes related to cell fate specification, differentiation and proliferation. Increased Notch receptors have been observed in several types of cancer, including breast cancer. In addition, chromosome 9 contains the SMC5 gene, which is involved in DNA recombination, cellular senescence and DNA double-strand breaks. Changes in the expression of this gene have been observed in breast cancer patients.
Chromosome 11. (Launched on April 8th). This chromosome contains the gene ATM that encodes a protein which is an important cell cycle checkpoint. It regulates a wide variety of proteins, including p53 or BRCA1, two important tumor suppressors. Mutations on the ATM gene are associated with an increased risk on breast cancer development and a worse prognosis.
Chromosome 12. (Launched on April 8th). This chromosome contains three interesting breast cancer genes. CD9 encodes a cell surface glycoprotein. It participates in differentiation, adhesion and signal transduction. Expression of this gene plays a critical role in suppression of cancer cell motility and metastasis. The ETV6 gene is involved in protein-protein interactions. Rearrangements of this gene have been seen in secretory breast carcinoma patients, which is an uncommon type of breast cancer which usually has a favorable outcome. Other gene is MDM2. This gene encodes an ubiquitin ligase. It can promote tumor formation by targeting tumor suppressor proteins, such as p53. Thus, overexpression of this gene is detected in a variety of different cancers.
Chromosome 14: (Launched on April 22h). This chromosome contains the DICER1 gene. It encodes a miRNA processing protein that regulates gene expression. The processing of miRNA have been related with a broad range of cancer types, thus, mutations in DICER1 have been related with cancer development. Is also known as a strong antiviral agent with activity against RNA viruses like SARS-CoV-2. Other gene contained is TEP1. It encodes a protein that catalyzes the addition of new telomeres on the chromosome ends. Since telomere length has been related with breast cancer, is a really interesting gene understudy. Gene AKT1 is also present in this chromosome: it is a known oncogene that plays a role in cell survival, angiogenesis and tumor formation.
Chromosome 15: (Launched on April 22h). This chromosome encloses some cancer related genes like SMAD3, a tumour suppressor gene. It transmits signals from the cell surface to the nucleus, regulating gene activity and cell proliferation. NTRK3 encodes a protein that acts as a membrane-bound receptor. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. this chromosome also contains IGF1R gene, which binds to the insulin-like growth factor. Ii is highly overexpressed in malignant tissues by enhancing cell survival.
Chromosome 18: (Launched on April 22h). This chromosome contains the gene SMAD4, which encodes a signal transduction protein. A low expression of this gene have been related with the development of breast cancer. This is because SMAD4 is activated by the growth factor TFG-beta, which usually is altered in various tumor types. Another gene present in this chromosome is BCL2. This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, is thought to be the cause of follicular lymphoma, a cancer type that affects white blood cells, lymphocytes.
Chromosome X: (Launched on April 22h). This chromosome contains the gene KDM6A, which encodes UTX, a histone demethylase involved in embrionic development. Mutations on this gene has been described in a wide range of cancers, like breast cancer. Other enclosed gene is XIST, which participates in the X chromosome silencing process in mammalian females, to provide dosage equivalence between males and females, since males have only one X chromosome. XIST is expressed exclusively in the X chromosome that is inactivated. Expression of this gene has been found to be dysregulated in a variety of human cancers when compared to normal cells.