Education

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

Never Too Young for Colorectal Cancer

Never Too Young for Colorectal Cancer

NTY Coalition_final logo Colorectal cancer no longer discriminates on age. While colorectal cancer incidences and mortality rates in Canadians aged 50+ have been declining in recent years due to increased screening and surveillance programs, the opposite is unfortunately being reported for our younger population.

In the last few years, Canadian doctors have observed a rapid increase in the number of patients under age 50 with colorectal cancer. What makes it even more concerning is that they cannot explain why.

The study also found that younger patients are getting diagnoses at later stages making them harder to treat and leading to increasing fatalities. These shocking statistics reveal that there is more work to be done in terms of prevention and treatment of colorectal cancer in Canada – especially for young adults.


In the last year, the CCAC has partnered with the Never Too Young (“N2Y”) Coalition, an organization united to take action on young onset of colorectal cancer through action, education, and research. The Coalition includes medical professionals, patient advocacy organizations, cancer survivors and caregivers working to educate the public about this growing issue and to reduce the number of late stage young-onset colorectal cancer cases.

Together with the N2Y coalition, the CCAC provides support and information to young patients in Canada who have experienced early onset of the disease.

Young patients may not always understand the signs and symptoms of colorectal cancer, which may delay their seeking medical attention. Symptoms of CRC can vary from blood in the stool, abdominal discomfort, constipation and much more.

According to the Canadian Cancer Society, men are more at risk than women for the disease. Eating processed and red meats, a lack of dietary fiber, a lack of physical exercise, obesity, alcohol, smoking, diabetes and genetics are also identified as risk factors.

Younger patients should consider the following when speaking to their doctors about their inherited risk or symptoms for colorectal cancer:

Family Tree

About 10% of the population has a first degree relative with colon or rectal cancer. If it is evident in your family tree, it is recommended to start screening as early as the age of 25.

Lynch Syndrome

Changes in certain genes increase your risk of colon cancer.
Lynch Syndrome is the most common type of inherited colon cancer, accounting for about 2% of all colon cancer cases. Lynch syndrome is a mutation of a gene that is responsible for fixing errors in your DNA. Lynch Syndrome, also known as hereditary nonpolyposis colon cancer (HNPCC), is an hereditary disorder caused by a genetic mutation in which affected individuals have a higher than normal chance of developing colorectal cancer, endometrial cancer, and various other types of aggressive cancers, often at a young age. To prevent colorectal cancer, people with Lynch Syndrome should undergo a colonoscopy every 1-2 years, starting in their twenties. Doing this will reduce the risk of colorectal cancer by 77%.

References:
http://www.ctvnews.ca/health/rapid-increase-in-colorectal-cancers-among-young-canadians-study-finds-1.2919527

March Colorectal Cancer Awareness Month

March Awareness_FB TW BANNER (1)This March, join Canadians across the country to honor all those affected by colorectal cancer during Colorectal Cancer Awareness Month. Last year alone, an estimated 26,100 Canadians were diagnosed with colorectal cancer. One in 12 men and one in 14 women are expected to develop colorectal cancer during their lifetime.

Despite the fact that colorectal cancer is Preventable, Treatable, and Beatable, it remains the second leading cancer killer in our nation. It does not discriminate against sex nor age. In past generations it was a disease more commonly found in individuals 50 years and over. However, statistics now show that more young people are being diagnosed, particularly those with Lynch syndrome.

Awareness, education and prevention through timely screening and healthy lifestyles are key to survival. Consequently, the Colorectal Cancer Association of Canada (CCAC) programs and campaigns are designed with this goal in mind, particularly to our younger population through our Never Too Young (N2Y) campaign.

butt picOn March 3rd, you can help support the CCAC and our patients by organizing a “Dress in Blue” Day at your work place. By dressing in Blue and raising funds for important CCAC programs, you will be spreading awareness of the disease, supporting patients and their families. It’s a simple and fun way to help us help you! For more information and to register your workplace, see: http://ccac.donordrive.com/event/515.

During awareness month, we are also celebrating the success of our Foods That Fight Cancer (FTFC) program under the direction of Dr. Richard Béliveau. FTFC’s goal is to help Canadians make the right food choices that will not only help prevent cancer, but also increase the chances of survival.
By supporting the CCAC, not only are you becoming part of the fight against cancer, you are helping to develop important programs and support for patients across the country who struggle to meet the challenges of this disease. “Patients now have more options to treat this disease than ever before. New treatments may completely change the manner in which we treat this disease. I am more optimistic than ever before that we can prolong lives longer and ultimately find a cure”, said Barry D. Stein, president of the CCAC.

We need your help to get the word out to save a life! Please donate to help us help you!
Together we can make a difference!

Visit our website or follow us on social media for a full list of our upcoming March Awareness Month events.

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Foods That Fight Cancer

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

Kent Nagano and the Montreal Symphony Orchestra

The Montreal Symphony Orchestra’s annual summer concert at the Olympic Park has become a tradition. Led my maestro Kent Nagano, it always attracts a crowd of music lovers. This year on August 10th, the MSO put together a concert to celebrate the Olympic Park’s 40th anniversary. A truly musical celebration to mark an important event and pay tribute to the athletes who competed here in 1976!

In coloboration with the Montréal East Island Integrated University Health and Social Services Center, the Colorectal Cancer Association of Canada had the opportunity to greet the concert goers and inform them about colorectal cancer screening.

4 Things You Need to Take Away From ASCO’s Annual Meeting

4 Things You Need to Take Away From ASCO’s Annual Meeting

Guest Blogger – Marc-Aurèle Chay

ASCO 2016 - image 2 The American Society of Clinical Oncology (ASCO) 2016 annual meeting took place June 3rd to 7th in Chicago, Illinois. Being the largest cancer conference in the world, it gathered doctors, researchers and biopharma giants to discuss the latest trends in cancer research. On the topic of colorectal cancer, you will find the four most promising advances that were presented at the conference below.

Combining Nivolumab and Ipilimumab to treat MSI-H mCRC: The CheckMate-142 trial
CheckMate-142, an ongoing phase II clinical trial, is testing the efficacy of combining Nivolumab with Ipilimumab for treatment of mCRC. The two drugs are hypothesized to enhance T cell antitumor activity through complementary mechanisms, and are promising for the targeting of MSI-H (microsatellite instability high) mCRC especially. With an overall response rate (ORR) of up to 33% (9/27 MSI-H patients on combination therapy having a partial remission), this combination therapy shows good potential and appears to be tolerated by most patients, although the effects seem to be more effective for MSI-H mCRC only.

A new promising combination therapy for the treatment of KRAS-mutated, non-MSI-High CRC.
A phase Ib study is investigating the combination potential of Cobimetinib (a MEK inhibitor) and Atezolizumab (an anti-PDL1 antibody) for the treatment of advanced solid tumors. Using a predefined expansion cohort of KRAS-mutated mCRC, the combination treatment achieved an ORR of 20%, with treatment related grade 3 adverse event occurring in 35% of the patients. This is a step forward in the treatment of non MSI-H mCRC, and evaluation of the combination treatment effectiveness will be continued.

More is not always better when treating CRC with chemotherapy.
STAR-01, a randomized phase III clinical trial, investigated the effects of increasing the aggressiveness of chemotherapy for the treatment of resectable locally advanced rectal cancer. They compared a standard regimen of 5FU-based chemoradiation with the same regimen + oxaliplatin. The more aggressive chemotherapy regimen did not result in improved pathological complete response or 5 year overall survival rate, but was unfortunately associated with increased toxicity.

Right-side vs left-side colorectal cancers, differences in prognosis and response to treatment.
A lot of attention was brought to the debate of the differences between left and right side colorectal cancer. A retrospective analysis of the CALGB/SWOG 80405 study showed that patients with primary tumors on the right side of the colon have a 55% higher risk for death compared with patients with primary tumors located on the left side. This finding is especially important for the designing of new drugs and drug trials, and need to be taken into account when doing randomization for studies.

And there you have it, the most promising studies presented at this year’s ASCO relating to colorectal cancer.

Becoming a volunteer for the CCAC can help us save lives. Maybe even yours.

Becoming a volunteer for the CCAC can help us save lives. Maybe even yours.

b8b5b063f881516dcc09c7cf26ed1d55 While it’s true that people with firsthand colorectal cancer experience are more inclined to join the fight against the disease, anyone can play a role in and impact the battle that the CCAC continues to fight daily.

Whether you are a cancer survivor or care about someone living with cancer, you have valuable knowledge and experience that can help shape the experience of others with compassion and understanding. By becoming a CCAC volunteer, you can use your cancer experience in a positive way. Not only will it impact someone else’s life, it will positively affect your own.

Why volunteer?

• Build relationships – Your experience can help others deal with their journey
• To create hope and inspire patients and caregivers in their fight against cancer
• Widen your support network – It’s a great way to deal with your own cancer through shared experiences
• Your involvement can help save lives

Ways to volunteer

We offer a flexible range of ways to become involved, no matter how much time or the skills you have to share. Our volunteer opportunities include assisting with fundraising activities, healthy living education/promotion, creating awareness about prevention, patient or family support or office work assistance if you are in the Montreal area.

Cancer support groups

Trained volunteer facilitators lead support groups for people with colorectal cancer and their families. Our programs offer critical information on the disease and its management, as well as emotional and practical support to patients and their families to help them find ways to cope while undergoing the journey.
Awareness and education.

Spreading the word about symptoms and prevention is key to early detection and survival, particularly with the growing rates of those under 50 being diagnosed. We constantly need people to help raise awareness about colorectal cancer and to provide education about prevention and screening. Whether it be at CCAC organized events (table tops or at a Giant Colon Tour stop), hosting your own event or via social media, it’s easy and all are welcome.

Fundraising

Like most non-profit organizations, we rely on donations and money collected from fundraising events to maintain the services and programs we offer for patients and their families. There are organized CCAC events scheduled throughout the year that you can participate in or like many of our supporters have done in the past you can create your own within your own community. The CCAC will support you with any promotional or educational materials that you require. Previous volunteer hosted events include; golf/baseball tournaments, luncheons, dinners, concerts, fashion shows, movie nights, art exhibitions and auctions.

Testimonial

13413841_10154115661646422_686387621_n“Having colorectal cancer running in my family, I wished to help raise awareness of this life taking disease, and did so by being a volunteer for the CCAC for quite a few years now. With the equal participation and support of my boyfriend, we have taken part of many events hosted by the association to bring awareness to one of the most preventable diseases, if caught early. It has been one of the most fulfilling experiences of our lives and we can only hope that we have brought and will continue bringing awareness to people. Early screening can save your life, so literally, go get your butt checked.” Tam & Max

For more volunteer information please contact Frank Pitman at frankp@colorectal-cancer.ca.

Young Survivor’s Week – Bravery comes in many forms, thank you Jamie Mead for your story!

Young Survivor’s Week – Bravery comes in many forms, thank you Jamie Mead for your story!

jamie 2 It was a day I will never forget. Two weeks shy of my 28th birthday I was awoken after my colonoscopy and told I have stage four colon cancer. My heart sunk. How is this possible? Just two months ago I was at the walk-in clinic complaining of acid reflex and now I have cancer?

I was quickly introduced to a surgeon who informed me that my liver was riddled with tumours and unfortunately I was inoperable. I quickly kicked everyone out of the room as I felt myself running out of air. Five minutes later he came back in and I sat up from the fetal position and said, “No. I believe you will operate. I challenge that you will see the inside of my body within 1 or 2 years.” After four rounds of chemotherapy, to my surprise, I was right. I underwent two operations that year and since then I have had five, with my sixth coming this June. jamie 1 I have been told not once, but twice that I am inoperable. I have had my surgeon admit that he never thought he would see me again after our first meeting. But with determination, a positive attitude and the will to keep on living – I have proved everyone wrong. I know this is not the end of my battle against colon cancer. I will be fighting this for the rest of my life, but that is ok. I am not thankful for cancer – that would be crazy – I am thankful for other things it has given me. I have a greater appreciation for all those who surround my life. It has made me into a person I didn’t know existed.

For my own therapeutic reasons I started a blog to help drain the chaos that exists in my brain. It is found at www.youngfemalecancer.com. I openly share my experiences and thoughts – and welcome anyone to interact with me through there.

Keep on fighting!

“It Happened to Me” – Young Survivor Story – Elan Freedy

“It Happened to Me” – Young Survivor Story – Elan Freedy

graphic with logo On December 2, 2014, I went for my annual physical. I was feeling to be in perfect health, no issues whatsoever. During the exam my doctor found microscopic traces of blood after doing a rectal exam to check my prostate, which all men over 40 dread. The doctor said the finding was probably nothing but referred me to a GI doctor for further investigation.

I blew off making the follow up appointment for a few weeks until I just happened to stumble across the paper with the GI doc’s info on my generally messy office desk where it could have easily gotten lost and the referral forgotten. I went to see the GI doc in early January, he concurred with my primary care doctor’s opinion that it was probably nothing based on my young age but recommended we schedule a colonoscopy just in case.

A few weeks later (5 days after my 42nd birthday), I got scoped… when I awoke from anesthesia the doctor informed me that he found a 2.5cm tumor in my rectum. Obviously, this news hit me and my wife like a ton of bricks. The day of the diagnosis still seems likes a dream in my memory. I remember feeling like it can’t be real. Although a CT scan I had later that day revealed an enlarged lymph node, it showed no spread to my vital organs. My diagnosis was classified as Stage IIIB rectal cancer.

The anticipation of treatment came with a lot of fear and uncertainty. I worried not only about how it would affect me, but I had concerns for how my family would handle it. My kids were 4 and 7 at the time, and while we felt it was important for them to know the truth, their daddy had cancer; we wanted to be careful not to scare them. I worried about how my business would function without me, as I run a small software company and play a large role in the day-to-day management responsibilities.

Treatment itself was challenging, but I suffered no complications and managed to deal with the side effects of chemotherapy relatively well. I was lucky that I had a great response to chemotherapy and was therefore able to avoid radiation. I never really felt like a cancer patient except for maybe on a handful of days.
Surgery brought some adjustments to the new anatomical structure of my GI tract, but again I was lucky to avoid needing “a bag” and for the most part function returned to normal.

Looking back on my cancer journey I don’t consider myself to have been unlucky for having developed this disease, but rather I consider myself very fortunate for having found it relatively early, for having responded well to treatment and for being on the road to full recovery.
I was lucky to have such supportive and loving family and wife who took amazing care of me through all stages of my treatment. I also feel lucky to have made some amazing friends who are my peers in this journey and have greatly enriched my life. I think everyone who goes through the journey comes out stronger and with a better perspective on life than when they went into it.