Research

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

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.

RECENT STUDIES SHOW COLORECTAL CANCER DOES NOT AGE DISCRIMINATE. YOU’RE NEVER TOO YOUNG TO BE AWARE & PREPARED

RECENT STUDIES SHOW COLORECTAL CANCER DOES NOT AGE DISCRIMINATE. YOU’RE NEVER TOO YOUNG TO BE AWARE & PREPARED

butt pic Reports from across Canada show doctors are observing a new trend in colorectal cancer that cannot be ignored nor explained – a “rapid increase” in the number of patients being diagnosed under age 50.
A new study, led by doctors from the University of Toronto, looked at Canadian Cancer Registry data from 1997 to 2010 and found that incidences of colorectal cancer rose by:

• 0.8 per cent per year for people in their 40s,
• 2.4 per cent per year for people in their 30s, and
• 6.7 per cent per year for those between ages 15 and 29.

Thankfully awareness campaigns and advocacy to increase the accessibility of colorectal cancer screening has been responsible for declining rates in people over 50 in the last few years. However, these new reports are a reminder that there is still so much more work to be done.

This year, the CCAC was proud to join forces with the Never Too Young Coalition (N2Y), a branch of Colon Cancer Alliance. Their mandate, like ours, is to raise awareness about the disease, preventative screening and to provide much needed information to the younger Canadian population about the signs and symptoms of the disease, particularly how to avoid a misdiagnosis, which according to studies is occurring more frequently due to the age shift.

Although it is evident that more research is needed to determine the cause of this age shift, we are encouraging doctors and patients to become more vigilant and conscience as the signs and symptoms of colon cancer can often be mistaken for other, less serious issues. The longer it takes for a diagnosis the harder it is treat, which is key in survival.

Risk factors for colon cancer

The fact that incidence is rising only among younger people suggests “lifestyle” factors are at play, but the evidence of this is not concrete. Pay attention to your body and if you have any of these risk factors, talk to your doctor – take charge of your health!

• Family history of colon cancer or polyps: First and second degree relatives of a person with a history of colon cancer and polyps are more likely to develop this disease, especially if the relative had the cancer at a young age
• Genetic Alterations: Changes in certain genes increase your risk of colon cancer. Those with syndromes like hereditary nonployposis colon cancer (HNPCC or Lynch Syndrome) or Familial Adenomatous Polyposis (FAP) should be screened earlier than 50
• Ulcerative Colitis and Crohn’s disease
• African Americans should be screened starting at age 45, or sooner if you have other risk factors or symptoms
• Lifestyle factors, like eating processed and red meats, a lack of dietary fibre, a lack of physical exercise, obesity, alcohol, smoking, diabetes and genetics

June 5-11 will mark the second annual “Young Survivors Week,” connecting with patients, survivors, and caregivers to create buzz around young onset colon cancer. Join us and N2Y as we spread the word via social media by sharing stories and information to help others understand that IT can happen to anyone.

Partners in Prevention

The Giant Colon Tour greeted over 1,300 health and safety professionals at the Partners in Prevention 2015 Health and Safety Conference and Trade Show at the International Centre in Mississauga.

It is Canada’s health and safety industry’s largest and longest running conference and trade show, where over 4,000 health and safety professionals connected to do business.

Cancer, Fertility and Motherhood Survey

Every year, approximately 85,000 Canadian women are diagnosed with cancer; of these, over 4,000 women are between the reproductive age range of 20 and 39. Fertility and motherhood are important quality of life issues for young women with a history of cancer. However, very limited data are available to document how fertility matters are addressed when they receive cancer care in Canada.

The CCAC is proud to support a doctoral research study entitled, “Cancer, fertility and motherhood: Addressing the fertility needs of young women with cancer in times of stress, uncertainty, and time pressure”. The study aims to explore the retrospective views of female cancer survivors on fertility matters related to cancer care, and their perspectives on preserving fertility through assisted reproductive technologies.

Eligibility criteria

1.Female cancer survivor
2.received a cancer diagnosis after year 2000
3.between the age of 18 and 39 when diagnosed with cancer
4.received cancer treatment in Canada
5.have completed cancer treatment.

Should you meet the above criteria, please support this research by participating in this quick survey which takes approximately 30 to 45 minutes to complete. Survey respondents can participate in a draw to win a $50 Amazon gift certificate.

How to begin the web-based survey:
Visit the project website www.cancerandfertility.com for more information or access the e- survey directly at http://fluidsurveys.com/s/fertility.

CCAC Partners With Mt. Sinai

The CCAC is collaborating with Mt. Sinai’s bioethicist Dr. Kerry Bowman who is working on a research project involving the development of synthetic antibodies aimed at treating colorectal cancer and other cancer sites. We continue to deliver presentations on disease trajectory, ethical issues facing colorectal cancer patients and families resulting from drug costs and disease burden. The CCAC will continue to provide assistance and support in the project’s next phase by helping to recruit individuals who have had colorectal cancer to explore their lived experience in relation to contemporary drug costs. Stay tuned as the CCAC continues to partner with Mt. Sinai on this pivotal project.

2012 Colorectal Cancer Statistics Summary

Trends in Colorectal Cancer

Colorectal cancer incidence rates between 1983 and 2000 were relatively stable in men and declined slightly in females. In both sexes, the incidence rate has declined significantly (0.8% per year) since 2000.

Between 2001 and 2007 for males and between 1998 and 2007 for females, overall mortality rates declined significantly. The rates declined, on average, by at least 2% per year since 2003 in males. In men and women combined, colorectal cancer is the third most common cancer at 13%.

Mortality rates continue to decline in both sexes—by 2.6% per year in males since 2003 and 1.8% per year in females since 1998. Colorectal cancer has a significant impact on mortality for men and women combined, with 12% of all cancer deaths expected.

Screening for colorectal cancer can reduce both incidence (by identifying and removing precancerous polyps) and mortality. Screening has already been occurring in several provinces, which may partly account for the decline in mortality, though screening rates are low. All provinces have announced or have started implementing organized screening programs.

Canada Wide Statistics 2012

This year, an estimated 23,300 Canadians (13,000 men and 10,300 women) will be diagnosed with colorectal cancer and 9,200 (5,000 men and 4,200 women) will die from it.

On average, 448 Canadians will be diagnosed with colorectal cancer every week and 176 will die from the disease every week.

The highest colorectal cancer incidence rates among men and women occur in Newfoundland and Labrador. For women, high rates also occur in Prince Edward Island and Nova Scotia. The lowest rates for both sexes are in British Columbia.

Provincial Colorectal Cancer Statistics 2012

Alberta

1930 estimated new colorectal cancer cases (1100 men and 830 women)
720 estimated colorectal cancer deaths (390 men and 330 women)

British Columbia

2850 estimated new colorectal cancer cases (1600 men and 1250 women)
1150 estimated colorectal cancer deaths (630 men and 520 women)

Manitoba

870 estimated new colorectal cancer cases (490 men and 380 women)
330 estimated colorectal cancer deaths (180 men and 150 women)

New Brunswick

590 estimated new colorectal cancer cases (340 men and 250 women)
210 estimated colorectal cancer deaths (110 men and 100 women)

New Foundland

530 estimated new colorectal cancer cases (310 men and 220 women)
230 estimated colorectal cancer deaths (130 men and 100 women)

Nova Scotia

860 estimated new colorectal cancer cases (470 men and 390 women)
360 estimated colorectal cancer deaths (200 men and 160 women)

Ontario

8700 estimated new colorectal cancer cases (4800 men and 3900 women)
3450 estimated colorectal cancer deaths (1900 men and 1550 women)

PEI

115 estimated new colorectal cancer cases (60 men and 55 women)
45 estimated colorectal cancer deaths (25 men and 30 women)

Quebec

6200 estimated new colorectal cancer cases (3400 men and 2800 women)
2450 estimated colorectal cancer deaths (1300 men and 1150 women)

Saskatchewan

730 estimated new colorectal cancer cases (420 men and 310 women)
280 estimated colorectal cancer deaths (150 men and 130 women)

(Source: Canadian Cancer Statistics 2012- Canadian Cancer Society, Statistics Canada, Provincial/Territorial Cancer Registries, Public Health Agency of Canada)

Pan-Canadian Ostomy Supplies Reimbursement Policy Reform Meeting

Montreal – March 2nd, 2012

On March 2nd, 2012, the Colorectal Cancer Association of Canada (CCAC) hosted the Pan-Canadian Ostomy Supplies Reimbursement Policy Reform Meeting at the Montreal Airport Marriott Hotel.

In attendance were key healthcare professionals from across the country, contributing their expertise and experience towards the drafting of a consensus document for the reform of policies governing the reimbursement of ostomy supplies in Canada. Presentations throughout the day by colorectal surgeon Dr. Jean-Francois Latulippe, enterostomal therapy nurse (ETN) Joanne Hoeflok, psychosocial oncology specialist Dr. Mary Jane Esplen, economist Dr. Chris Longo, as well as our dedicated meeting chairs Gwen Turnbull and Louise Forest-Lalande (both ETNs), prepared the group with a comprehensive background on ostomies in Canada.

Issues such as the psychosocial impact of living with an ostomy, the psychosocial link between improved Quality of Life (QoL) and optimal reimbursement, the health care costs associated with ostomy-related complications resulting from suboptimal reimbursement of ostomy supplies, and the complex health care system within which the current reimbursement policies are embedded were explored. The meeting was a glowing success as the group reached consensus on all proposed statements.

Stay tuned as the CCAC endeavours to have the consensus document published in one of Canada’s prominent journals, which will then be subsequently utilized for advocacy purposes when addressing the various provincial policy makers overseeing the reimbursement of ostomy supplies.

Don’t Lose Sleep Over It!

Don’t Lose Sleep Over It!

Labelled as a society riddled by overindulgence time and time again, Westerners have succumb to being referred to as gluttons. We eat too much, drink too much and when we are not working ourselves to the bone, we entertain too much. Yet with all these guilty pleasures under our belt, it’s funny how so many of us seem to cast aside the most simple of them all – sleep!

Today, priorities have become conditioned by one’s lifestyle. For the business and social nomads, governed by busy daily schedules, the act of sleeping is considered a waste of time and only needed when extremely tired. However, as the number of health afflictions and disease risks linked to inadequate sleep are on the rise, perhaps this modern notion of sleep as a form of ‘surrender’ requires a re-examination.

Recent study links sleep sacrifice to increased risk of colorectal cancer

In a recent study published in the Feb. 15, 2011 issue of the journal Cancer, researchers from University Hospitals (UH) Case Medical Center and Case Western Reserve University School of Medicine, found that people who slept an average of six hours or less per night had an almost 50% increase in the risk of colorectal adenomas compared with individuals sleeping at least seven hours a night. Adenomas are precancerous polyps that, left untreated, can turn malignant.

“To our knowledge, this is the first study to report a significant association of sleep duration and colorectal adenomas,” Li Li, MD, PhD, the study’s principal investigator and Associate Professor of Family Medicine, Epidemiology and Biostatistics at Case Western Reserve University School of Medicine, said in a statement to the media. ‘A short amount of sleep can now be viewed as a new risk factor for the development of colon cancer.’
Conducted by phone, the study surveyed patients prior to their scheduled colonoscopies at the UH Case Medical Center. The questions were drawn from the Pittsburgh Sleep Quality Index (PSQI) and concerned sleep frequency, troubles falling asleep and most importantly, their average hours of sleep per night.

Of the 1,240 patients interviewed, 338 were diagnosed with colorectal adenomas at their colonoscopy. The majority of those diagnosed with precancerous polyps had reported sleeping less than six hours a night, compared to those patients without adenomas.  The association between less sleep and adenomas remained consistent despite adjustments made for family history, obesity and smoking.

Dr. Li’s report notes that the dramatic risk increase of insufficient sleep is comparable to genetic risk, having a first-degree relative who has had colon cancer, as well as the risk associated with eating a lot of red meat: “Short sleep duration is a public health hazard leading not only to obesity, diabetes and coronary heart disease, but also, as we now have shown in this study, colon adenomas…Effective intervention from www.health-canada-pharmacy.com/ambien.html to increase duration of sleep and improve quality of sleep could be an under-appreciated avenue for prevention of colorectal cancer,” Dr. Li concluded.

Sleep deprivation alters immune function, particularly the activity of the body’s killer cells. Keeping up with sleep has been proven to strengthen one’s immune system and consequently help the body battle against cancer. So, while those increasing the hours in their day by decreasing their nightly hours of sleep believe that they are maximizing the time available in their business and social agendas, they are really just aiding and abetting the risk of their lives’ maxing out!

For more information about Dr. Li’s study please consult the Journal Reference:

Cheryl L. Thompson, Emma K. Larkin, Sanjay Patel, Nathan A. Berger, Susan Redline, Li Li. Short duration of sleep increases risk of colorectal adenoma. Cancer, 2011; 117 (4): 841 DOI: 10.1002/cncr.25507