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Using Epigenetics as Biomarkers for Colorectal Cancer

Using Epigenetics as Biomarkers for Colorectal Cancer

By Marc Aurèle Chay

http://www.genengnews.com/gen-news-highlights/pan-cancer-epigenetic-signature-readable-in-circulating-tumor-dna/81252334

http://www.genengnews.com/gen-news-highlights/pan-cancer-epigenetic-signature-readable-in-circulating-tumor-dna/81252334

In Canada, screening for colorectal cancer can be done using the FOBT or FIT tests. These currently have suboptimal diagnostic accuracy, which is why researchers are investigating other avenues for non-invasive detection of early CRC. Scientists have found that in many early-stage cancers, including CRC, epigenetic alterations are present in much higher frequency than genetic mutations. As such, DNA methylation, ncRNAs, histone modifications are being investigated for potential diagnostic and prognostic markers of CRC.

DNA Methylation Biomarkers

Blood, stool, saliva and urine are being examined by the research community for these markers. DNA methylation in particular is being studied extensively, and some groups have reported sensitivities of 90-95% with specificity ranges of 85-94% for certain biomarkers in CRC. Some genes have risen to be the most promising markers, including the tumor specific M2 isoform of pyruvate kinase (PKM2), tissue inhibitor of matrix metalloproteinase 1 (TIMP1), vimentin (VIM) and septin 9 (SEPT9). DNA methylation is also being investigated for prognostic biomarkers and predictive markers for response to treatment. In particular, CpG island methylator phenotype (CIMP) positive cancers are found to correlate strongly with overall unfavorable prognosis, but seem to benefit from 5-FU based adjuvant chemotherapy. Hypermethylated Transcription Factor AP-2 Epsilon (TFAP2E) seems to also predict response to 5-FU based chemotherapy.

Histone Modification Biomarkers

Diagnostic and prognostic biomarkers using histone modifications have been much less studied, partly due to technical limitations of assays that are used to characterize the chromatin landscape. Some studies show acetylation of H3 lysine 56 and di- or tri-methylation of H3 lysine 9 and 27 have potential to be prognostic markers in CRC. These results are still currently preliminary and are expected to be further explored with the new bioinformatic tools and next-generation sequencing technologies that are being optimized.

Non-Coding RNA Biomarkers

On the other hand, non-coding RNAs, and in particular miRNAs, have triggered a substantial interest from the scientific community. Blood and stool based biomarkers have been investigated, and multiple candidates such as miR-21, miR-92a, miR17-3p or miR-106a have come up as potential diagnostic markers. MiR-21 has also been associated with poor patient survival, and several other miRNAs have been proposed as prognostic markers. As research evolves, scientists hope to engineer a panel of biomarkers that will be able to accurately identify and predict prognosis for early stage CRCs.

Epigenetics has offered us new tools to understand the complex etiology of colorectal cancer. As the scientific community further elucidates the mechanisms at play, epigenetic biomarkers to diagnose, classify and predict prognosis of CRC are also uncovered. Further research on these biomarkers may provide us with high performance assays that can be used to prevent and better manage patients with CRC.

References

Mitchell, S.M., Ho, T., Brown, G.S., Baker, R.T., Thomas, M.L., McEvoy, A., Xu, Z.-Z., Ross, J.P., Lockett, T.J., Young, G.P., LaPointe, L.C., Pedersen, S.K., Molloy, P.L., 2016. Evaluation of Methylation Biomarkers for Detection of Circulating Tumor DNA and Application to Colorectal Cancer. Genes (Basel) 7. doi:10.3390/genes7120125

Okugawa, Y., Grady, W.M., Goel, A., 2015. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 149, 1204–1225.e12. doi:10.1053/j.gastro.2015.07.011

Rozalski, R., Gackowski, D., Siomek-Gorecka, A., Banaszkiewicz, Z., Olinski, R., 2016. Urinary Measurement of Epigenetic DNA Modifications: A Non-Invasive Assessment of the Whole-Body Epigenetic Status in Healthy Subjects and Colorectal Cancer Patients. ChemistryOpen 5, 550–553. doi:10.1002/open.201600103

Sameer, A.S., Nissar, S., 2016. Epigenetics in diagnosis of colorectal cancer. Mol Biol Res Commun 5, 49–57.

Sazanov, A.A., Kiselyova, E.V., Zakharenko, A.A., Romanov, M.N., Zaraysky, M.I., 2016. Plasma and saliva miR-21 expression in colorectal cancer patients. J. Appl. Genet. doi:10.1007/s13353-016-0379-9

Understanding What Epigenetic Means in Colorectal Cancer

Understanding What Epigenetic Means in Colorectal Cancer

By Marc Aurèle Chay

Vaiopoulos, A.G., Athanasoula, K.C., Papavassiliou, A.G., 2014. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1842, 971–980. doi:10.1016/j.bbadis.2014.02.006

Vaiopoulos, A.G., Athanasoula, K.C., Papavassiliou, A.G., 2014. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1842, 971–980. doi:10.1016/j.bbadis.2014.02.006

Consider the genome as words in a book, and epigenetics as the punctuation and accents that dictate the way each sentence is read. Epigenetic regulation refers to the heritable and reversible mechanisms that alter gene expression without affecting the underlying DNA sequence. Epigenetic mechanisms, among others, include DNA methylation, non-coding RNAs, chromatin remodelers and histone post-translational modifications. They play a crucial role in the proper functioning of a cell. In cancer, genetic and epigenetic alterations are linked together and can both contribute to the activation of oncogenes and/or the silencing of tumor suppressors. In colorectal cancer (CRC), understanding the epigenetic mechanisms driving pathogenesis have been a focus of the scientific community since the early 2000s. Many potential driver aberrations have been found, but as with genetic mutations, there isn’t a single mechanism that can explain CRC development.

DNA Methylation in CRC

DNA methylation refers to the addition of a methyl group to a nucleotide, usually a cytosine in a CG context. When present at CpG islands, it correlates strongly with repression of the nearest gene. Researchers have found global genomic hypomethylation, especially in CIN CRCs, as well as hypermethylation in promoter regions of specific genes such as APC, Cadherin-1 (CDH1), runt-related transcription factor 3 (RUNX3), mutL homolog 1 (MLH1), O-6-methylguanine-DNA methyltransferase (MGMT), cyclin-dependent kinase inhibitor 2A (CDKN2A), and RASSF1A.

Histone Modifications in CRC

Other than DNA methylation are histone post-translational modifications. These are the addition of methyl/acetyl/ubiquityl/phosphate groups to the proteins that make up nucleosomes. The modifications regulate the way DNA is compacted in the nucleus, and recruit various proteins involved in activation or repression of gene expression. In CRC, many genes encoding of proteins responsible for these histone modifications are dysregulated, thus changing the epigenomic landscape of the cell. For example, histone deacetylase 2(HDAC2) is upregulated in the early steps of CRC. HDAC1-3, 5 and 7 have also been reported to be upregulated in CRC. Dysregulation of Lysine specific demethylase 1 (LSD1), which interacts with tumor suppressor p53, seems also to increase the proliferation, invasion and metastatic potential of CRC cells.

Non-Coding RNAs in CRC

Another type of epigenetic mechanism which can modulate gene expression in CRC is the non-coding RNAs which include the micro-RNAs (miRNA), and long-non-coding RNAs (lncRNA). For example, the miR-200 family are known to be implicated in cancer invasion and migration; the hox transcript antisense intergenic RNA (HOTAIR) is correlated to advanced CRC and enhanced metastatic potential of cancer cells.

Epigenetics is still a relatively new field of research. As scientists strive to elucidate the etiology of colorectal cancer, they discover new potential mechanisms at play. Understanding the epigenetic basis of CRC may open the door for new drugs and biomarkers, so be on the lookout!







References:

Bardhan, K., Liu, K., 2013. Epigenetics and Colorectal Cancer Pathogenesis. Cancers (Basel) 5, 676–713. doi:10.3390/cancers5020676

Sameer, A.S., Nissar, S., 2016. Epigenetics in diagnosis of colorectal cancer. Mol Biol Res Commun 5, 49–57.

Sazanov, A.A., Kiselyova, E.V., Zakharenko, A.A., Romanov, M.N., Zaraysky, M.I., 2016. Plasma and saliva miR-21 expression in colorectal cancer patients. J. Appl. Genet. doi:10.1007/s13353-016-0379-9

Vaiopoulos, A.G., Athanasoula, K.C., Papavassiliou, A.G., 2014. Epigenetic modifications in colorectal cancer: Molecular insights and therapeutic challenges. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1842, 971–980. doi:10.1016/j.bbadis.2014.02.006

Together we can conquer cancer!

Together we can conquer cancer!

February 4th is World Cancer Day

World Cancer Day is an annual global event taking place every year on 4 February that unites the world’s population in the fight against cancer. Its goal is to save millions of preventable deaths each year.

On this day and throughout the month of February, the month of love, hundreds of cities and organizations around the world link together as one under the sole purpose of raising awareness and education about the disease and pressing governments to take action.

The theme for Cancer Day this year until 2018 is “We Can, I Can,” highlighting how everyone – as a collective or as individuals – can do their part to reduce the global burden of cancer.
Currently, 8.2 million people die from cancer worldwide every year, out of which, 4 million people die prematurely (aged 30 to 69 years).

World Cancer Day is the ideal opportunity to spread the word and raise the profile of cancer in people’s minds.
We encourage you to visit the World Cancer Day website and check out the local events in your area.

#WorldCancerDay #WeCanICan

WCD2017_Infographic-fact-sheet_FA_Full

March Awareness Month Comes to a Close – Words From Ministers Around the Country

March Awareness Month Comes to a Close – Words From Ministers Around the Country

As March awareness month comes to a close, we would like to reflect upon our reach and the impact these campaigns have on the lives of Canadians throughout the country. More than ever this year, the international and national community has come together to bring more awareness to colorectal cancer everywhere. We thank all of our supporters/followers for helping to spread the word and hope that you will continue to do – There is still work to be done. Continue to follow us and the social media platforms of our partners: N2Y & Foods That Fight. And continue to share, not only our content but also that of your own. Please send us private messages on any news stories that you have or survivor stories of your own. You are not alone, WE are in this fight together and will one day be able proudly say that WE BEAT THIS DISEASE TOGETHER!

INFOGRAPHIC Ministers of Health 2016 FINAL

Giant Colon Tour at Pen Centre in St. Catharines Ontario

Giant Colon Tour at Pen Centre in St. Catharines Ontario

PenCentre4Niagara Health System’s (NHS) Colorectal Screening Program, in partnership with Juravinski Cancer Centre in Hamilton, brought the Giant Colon Tour to the Pen Centre in St. Catharines Ontario as part of Colorectal Cancer Awareness Month.
Colorectal Cancer Association of Canada’s (CCAC) pink inflatable walk-through reproduction of the human colon is 40 feet long and eight feet high. The exhibit attracted over 2,300 visitors on Friday March 4th and Saturday March 5th, 2016.
The NHS partnered with The Giant Colon Tour, an educational exhibit part of the CCAC campaign that seeks to educate Canadians that this disease is preventable, treatable and beatable.
A team of registered nurses and health promotion specialists from Niagara Health System’s Endoscopy department were on hand to offer information about screening and prevention. Dr. Meghan Davis, CCO Regional Primary Care Lead and Dr. Pierre Major, the Chair of the CCAC’s Medical Advisory Board were also on hand to speak to the numerous visitors from the Niagara Region.
The message on prevention and screening reached thousands more in the region due to the extensive media coverage that was orchestrated by NHS Communications Specialist Steven Gallagher. Below are the links to some of the coverage:

CHCH TV story/video
TV Cogeco story/video
Niagara This Week story

A special thanks to Ruth Peters (NHS) and Andi Sinclair (Brock University), who were instrumental in bringing The Giant Colon Tour to the region for the second time since 2010.

More photos:

VØID Cancer Makes 1st Donation to CCAC

VOIDI am proud to say that on Sunday, December 28th, I made my first donation on behalf of VØID Cancer (www.voidcancer.com) to The Colorectal Cancer Association of Canada for $948.65 using proceeds collected from the purchase of my Rockstar Mind guitar training products.

The donation will be used to continue to educate and support patients and caregivers much like the CCAC has done for my father and my family.

Without them, I’m not sure where my father would be right now.

So thank you again to everyone who contributed and asked me to help them achieve their dream of playing guitar.

We did it….together!

And in 2015, I plan to raise the stakes, expand the company, and donate even more money to this great cause!

In short, even though I end the year by giving, I am really the one who is left with a feeling of gratitude.

And I think it’s fitting to take a page from my band The Envy and say “I Never Wanna Lose This Feeling”.

With that said, I would like to share an unreleased music video for a track with the same name.

CLICK HERE TO WATCH

Happy New Year and all the best to you and your family in 2015!

Steve (aka VØID)

From Rockstar To Fundraiser

For Steve Mastroianni (aka VØID), 2013 was a year he won’t soon forget.

After touring all over the world with top Rock Bands such as KISS, Our Lady Peace, and Finger Eleven, Steve’s life took a devastating turn for the worse when his father, Anthony Mastroianni, told him that he’s just been diagnosed with Stage 4 Colon Cancer.

“When my father was diagnosed last Spring, I knew right away that I would put my music career on hold and stop at nothing to get him back to 100% and onto the golf course. I didn’t know exactly how we would do it, but I knew that his passion would be a KEY component to his recovery.” said Steve.

Shortly after the diagnosis, the Mastroianni family was approached by Fil from the Colorectal Cancer Association of Canada (CCAC), offering to coach everyone involved through the difficult time.

“Fil answered EVERY single one of our questions about the upcoming process, educated us about how Colorectal Cancer functions in the body, and connected us with all the people who helped my father fully recover and return to the golf course.” said Steve.

Despite the emotional rollercoaster ride that was 2013-2014, after two surgeries, countless visits to the hospital, and the horrors of spending more time in the emergency room than his previous 28 years combined, Steve is proud to say that they achieved their goal on July 22nd, 2014, just over one year after the diagnosis.

Photo: Steve Matroianni (aka VØID) and father Anthony Mastroianni

Photo: Steve Matroianni (aka VØID) and father Anthony Mastroianni

Photo: “The path that Fil and the CCAC set out for us in 2013 was the crucial element that ensured my Dad spent this summer out of the hospital and on the golf course. I may have toured with KISS, but Fil is the real Rockstar here!” said Steve.

So WHY VØID Cancer?

After traveling the world for 10 years with a guitar on his back, Steve is no stranger to communicating his message to large crowds.

However, it was his experience with his father this past year that would help to put everything in perspective and inspire him to use his guitar to make an even bigger impact in the world.

His goal is to Teach and Inspire new Guitar Players around the world, while donating proceeds to the CCAC to further Cancer Research and introduce new programs for those who are suffering from this horrible disease.

He calls this movement VØID Cancer and his mission is to Eliminate Cancer: One Note at a Time.

He plans to accomplish this by selling his online coaching platform & digital products as well as through LIVE workshops for patients, caregivers, and anyone else who would like to learn how to create beautiful music and lasting change.

If you or someone you love has always dreamed of playing guitar, or just wants to give it a try, then there is no better time to learn than now.

“I can’t think of any better incentive to practice than knowing that proceeds will be going to further Cancer research.” said Steve.

Even his Rockstar mentor Gene Simmons approves of his new venture: “VØID is a special guy and what he is doing with VØID Cancer is admirable.” – Gene Simmons

Photo: Gene Simmons from KISS and Steve Mastroainni (aka VØID) We couldn’t agree more.

Photo: Gene Simmons from KISS and Steve Mastroainni (aka VØID) We couldn’t agree more.

Please click the link below and sign up to find out how you can get started today.

www.voidcancer.com

New molecular features of colorectal cancer and five colon cancer subtypes are identified with proteomics

Researchers report first large-scale integrated proteomic and genomic analysis of a human cancer: Identification of new molecular features of colorectal cancer

Investigators who analyzed 95 human colorectal tumor samples have determined how gene alterations identified in previous analyses of the same samples are expressed at the protein level. The integration of proteomic and genomic data, or proteogenomics, provides a more comprehensive view of the biological features that drive cancer than genomic analysis alone and may help identify the most important targets for cancer detection and intervention. The results of this study appeared online July 20, 2014, in Nature.

The colorectal study produced several key findings:

  • Measurements of messenger RNA abundance did not reliably predict protein abundance. The investigators were not surprised by this discordance, because many regulatory controls lie between RNA and protein expression. However, it did demonstrate that RNA analyses do not necessarily give a correct indication of protein levels.
  • Most of the focal amplifications (increased amounts of certain chromosome segments) observed in the earlier genomic analyses of the same tumors did not result in corresponding elevations in protein level. Proteomic analyses identified a few amplifications that had dramatic effects on protein levels and may represent potentially important targets for diagnosis or therapeutic intervention.
  • Proteomics identified five colon cancer subtypes, including classifications that could not be derived from genomic data. Protein expression signatures for one of the subtypes indicated molecular characteristics associated with highly aggressive tumors with poor clinical outcome.

These findings, by Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigators, including Henry Rodriguez, Ph.D., director of the Office of Cancer Clinical Proteomics Research, NCI, and Daniel C. Liebler, Ph.D., Vanderbilt University School of Medicine, Nashville, were made possible because of genomic analyses that were done on the same tumors in 2012 by The Cancer Genome Atlas (TCGA) Research Network. The CPTAC study provided a clear demonstration of how proteomics can be used to help understand how genomic abnormalities drive cancer.

Ottawa Hospital hopes diagnosis lab will aid cancer treatment: This is the future for target therapy

The Ottawa Hospital is hoping a new diagnostic centre for identifying cancers that could be treated through less invasive means will be open by the fall.

 

The hospital says it has raised half the $3 million it needs to open its own Molecular Oncology Diagnostics Laboratory.

 

Currently cancer patients in Ottawa who want to know if their particular disease could be treated with a targeted therapy instead of a one-size-fits all treatment like chemotherapy have to wait months before their samples can be assessed at labs in Toronto.

 

The Ottawa Hospital, which treated 24,000 cancer patients last year, said having a lab here in the city could cut the wait time for results to days instead of months.

 

The head of the new lab, Dr. Bryan Lo, said targeted treatments, if available, are far preferable to other options.

 

“When a cancer is discovered we’ll really be characterizing genetically this cancer to try to determine if we can apply some of these newer targeted therapies. Therapies that are much less toxic and with fewer side effects,” said Lo.

 

Jenn Miriguay, 37, has been living with cancer for five years and has gone through an arsenal of treatments, including chemotherapy, and lived through the side effects.

 

“It’s an all-hazards approach, you throw everything at it that you can and hope and pray that it works,” she said.

 

Dr. Brian Lo, Ottawa HospitalDr. Brian Lo said targeted treatments can be less toxic than broad-spectrum treatments such as chemotherapy. (CBC)

She said the new diagnosis centre has raised her hopes there will be an alternative way to treat her disease.

 

“The kids aren’t going to have a grumpy mommy all the time, my husband’s going to have a wife who wants to actively participate in life,” she said.

 

The clinic, when it opens, will focus on analyzing samples from patients with breast, lung, melanoma and colorectal cancers, the four most common types of cancers for which targeted therapies are available.

The hospital hopes within a year of opening it will then be able to accept samples from all cancer patients.

“CANCER AND CULTURE: A DIFFERENT APPROACH” Symposium

On May 15, 2013 The Colorectal Cancer Association of Canada participated in the symposium titled “CANCER AND CULTURE: A DIFFERENT APPROACH” sponsored by la Coalition Priorité Cancer au Québec and l’Alliance des communautés culturelles pour l’égalité dans la santé et les services sociaux (ACCÉSSS). The symposium discussed the various differences of ethnocultural clients, patient-caregiver relationships in the intercultural context, focusing in particular on ways to improve the understanding and participation of patients and their families in public health programs for prevention and screening, and cancer treatment.

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