Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis

Genetic Variations in Stem Cell-Related Genes and Colorectal Cancer Prognosis:

Abstract

Background  

Many properties of cancer cells are reminiscent of those in normal stem cells. Genes important to stem cell development have been significantly implicated in the etiology and clinical outcome of colorectal cancer (CRC). However, the associations of genetic variations in these genes with CRC prognosis have not yet been elucidated.

Methods  

We analyzed the effects of eight potentially functional single nucleotide polymorphisms (SNPs) in six stem cell-related genes on the prognosis of a well-characterized population of 380 Chinese CRC patients diagnosed from February 2006 to January 2010.

Results 

The most significant finding was related to rs879882, a variant in the 5′ region of POU5F1 gene which encodes a protein essential for embryonic stem cell self-renewal and pluripotency, and induced pluripotent stem cell reprogramming. The variant-containing genotypes of rs879882 were associated with an increased risk of recurrence (hazard ratio [HR] = 2.10, 95 % confidence interval [CI] 1.17–3.76, P = 0.01). In chemotherapy-stratified analysis, the association remained borderline significant in patients receiving chemotherapy (HR = 1.97, 95 % CI 0.89–4.34, P = 0.09). In addition, a nonsynonymous SNP of APC gene was also significantly associated with recurrence risk in chemotherapy-treated patients (HR = 2.63, 95 % CI 1.14–6.06 P = 0.02). Further analyses showed a combined effect of the two SNPs in predicting CRC recurrence in patients receiving chemotherapy (P = 0.04) but not in those without chemotherapy (P = 0.43). Moreover, an exploratory multivariate assessment model indicated that these two variants enhanced the power to predict recurrence after chemotherapy.

Conclusion 

We presented one of the first epidemiologic studies showing that stem cell-related genetic variants may impact CRC clinical outcomes, especially in chemotherapy-treated patients.

• Journal Journal of Gastrointestinal Cancer

Reuters: Myriad gene patent ruling sent back to lower court

 Reuters: Myriad gene patent ruling sent back to lower court

"The move is expected to delay a verdict in the Myriad case by as much as several years."

open access: Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine - Wiley Online Library

Resolving the variable genome and epigenome in human disease - Knight - 2012 - Journal of Internal Medicine

pdf file

Conclusions

There is no doubt that recent advances in genomics, currently driven by new high-throughput sequencing techniques, are taking us to remarkable new levels in our understanding of the human genome, and the genetic and epigenetic variation that exists, with important implications for our understanding of human disease. As this knowledge grows, our appreciation of the complexity with which we are faced is also underlined. For common multifactorial traits, GWAs have been very informative but leave much heritable risk unresolved. Rarer variants may prove important but in general, more integrated approaches are needed in which environmental risk factors are considered and combined with functional genomic analyses. Moreover, we need to derive functional genomic data in a disease-relevant setting as the consequences of underlying genetic and epigenetic diversity are increasingly recognized to be highly context specific.

Current technologies that can interrogate the whole genome carry with them significant caveats: these tools are new, and successful application to important biological problems requires careful experimental design and consideration of the limitations inherent in such approaches. The data sets involved are highly complex, and analysis remains extremely challenging with significant risks of false positive and negative results until the field matures. High-throughput sequencing is not a panacea but a critical tool in current genomics.  

Used wisely, it is resolving the individual genome and epigenome, at a structural and functional level, and will radically advance our understanding of disease. For Mendelian traits (Wiki) , the impact is already being felt. For common multifactorial diseases, this may take a little longer.

US firm (Myriad) corners exclusive license for RAD51C (breast/ovarian)cancer gene : The Lancet Oncology

 abstract

Bryant Furlow

"Already facing a legal challenge to its BRCA1 and BRCA2 patents, Myriad Genetics (Salt Lake City, UT, USA) has secured an exclusive licence for another breast and ovarian cancer-associated gene, RAD51C , under agreement with the German Consortium for Hereditary Breast and Ovarian Cancers, which will share exclusivity in Germany. RAD51C will be used to test patients' hereditary breast and ovarian cancer risks.

“I think it is unfortunate for both the clinical and research communities”, Jim Evans (University ..."

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Researchers Find Ovarian Cancer Risk Related To Inherited Inflammation Genes - newswise

"... The authors noted that in 2011 there were an estimated 225,500 new cases of ovarian cancer worldwide. Although some women are at greatly elevated risks of ovarian cancer due to inherited mutations in the BRCA1 and BRCA2 genes (and Lynch Syndrome amongst other rarer syndomes), these are rare in the population and account for perhaps 10 percent of cases. However, a substantial portion of genetic influence on ovarian cancer risk has been “unexplained” and some of that may be due to common genetic variants. Sellers points out that “the Il1A variant that was most strongly protective is carried by 30 percent of women in the study, so the impact at the population level is not trivial.”




Blogger's Note: interleukins and therefore the interest in interleukin research noting the variables within (eg. IL2;IL3..) as an example:

(2009) Interleukin 2-mediated conversion of ovarian cancer-associated CD4+ regulatory T cells into proinflammatory interleukin 17-producing helper T cells.

Correspondence: Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas' (includes stats on serous/endometrioid/clear cell/mucinous)

Blogger's Note: without a subscription ($$$), the following is available for viewing:

Authors' response: 'Focusing on HER2 as a potential therapeutic target in primary ovarian mucinous carcinomas':
In a study involving a large series of epithelial ovarian carcinomas (EOCs), McCaughan et al1 reported human epidermal growth factor receptor 2 (HER2) protein overexpression and amplification in all major histological subtypes, an observation consistent with the literature.2 3 Specifically, they document HER2 gene amplification in 3.0% (7/259) of serous papillary carcinomas, 2.1% (2/92) of endometrioid carcinomas, 25.0% (3/12) of mucinous carcinomas, 4.0% (1/25) of clear cell carcinomas and 11.9% (7/60) of mixed type carcinomas. Although their number of mucinous carcinomas was low (n=12), the higher prevalence of HER2 gene amplification relative to the other histological subtypes is also consistent with the literature.4 5
We had previously reported similar findings of primary ovarian mucinous carcinomas having the highest prevalence of HER2 genomic amplification and protein overexpression among the various EOC histological subtypes and had proposed that ovarian mucinous carcinomas represent a...

Essential gene profiles in breast, pancreas and ovarian cancer cells

Secrets To Longevity: It's Not All About Broccoli : NPR (genes vs lifestyle)

Faulty Gene Helps Tumors Dodge Drugs (MCL1 and FBW7)

NIH Research Matters is on Facebook
 www.facebook.com/ResearchMatters,

Retrospective study of the impact of pharmacogenetic variants on paclitaxel toxicity and survival in patients with ovarian cancer.

PURPOSE: Paclitaxel has a broad spectrum of anti-tumor activity and is useful in the treatment of ovarian, breast, and lung cancer. Paclitaxel is metabolized in the liver by CYP2C8 and CYP3A4 and transported by P-glycoprotein. The dose-limiting toxicities are neuropathy and neutropenia, but the interindividual variability in toxicity and also survival is large. The main purpose of this study was to investigate the impact of genetic variants in CYP2C8 and ABCB1 on toxicity and survival.
METHODS: The 182 patients previously treated for ovarian cancer with carboplatin and paclitaxel in either the AGO-OVAR-9 or the NSGO-OC9804 trial in Denmark or Sweden were eligible for this study. Genotyping was carried out on formalin-fixed tissue. The patients' toxicity profiles and survival data were derived from retrospective data. CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T were chosen a priori for primary analysis; a host of other variants were entered into an exploratory analysis.
RESULTS: Clinical data and tissue were available from a total of 119 patients. Twenty-two single nucleotide polymorphisms (SNPs) in 10 genes were determined. Toxicity registration was available from 710 treatment cycles. In the primary analysis, no statistically significant correlation was found between CYP2C8*3, ABCB1 C1236T, G2677T/A, and C3435T and neutropenia, sensoric neuropathy, and overall survival.
CONCLUSION: CYP2C8*3 and the ABCB1 SNPs C1236T, G2677T/A, and C3435T were not statistically significantly correlated to overall survival, sensoric neuropathy, and neutropenia in 119 patients treated for ovarian cancer with paclitaxel/carboplatin.

Hereditary Colorectal Cancer: eMedicine Gastroenterology

Background

Hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal-dominant syndrome, accounts for 2-5% of all colorectal carcinomas. Colorectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) presents at an earlier age than in the general population and is characterized by an increased risk of other cancers, such as endometrial cancer and, to a lesser extent, cancers of the ovary, stomach, small intestine, hepatobiliary tract, pancreas, upper urinary tract, prostrate, brain, and skin.



Table 1. Seven different genes are known to be associated with HNPCC, 
and all of them are involved with DNA mismatch repair, identified with
the frequencies below.

Mismatch Excision Repaired MMR	Chromosome Location	Frequency of HNPCC Cases
MSH2	2p16	45-50%
MLH1	3p22.3/A>	20%
MSH6	2p16	10%
PMS2	7p22.1	1%
PMS1	2q32.2	Rare
MSH3	5q14.1	Rare
EXO1	1q43	Rare
Other genes not yet discovered Table 2. Incidence of different types of cancers between individuals with Lynch syndrome and those in the general population. Table Type of Cancer General Population Risk (by age 70 y) Lynch Syndrome Risk (by age 70 y)   Endometrial 1.5% 40-50% Ovarian 1% 9-12% Upper Urinary Tract Less than 1% 4-10% Stomach Less than 1% 13% (higher in Asians) Small Bowel Less than 1% 1-3% Brain Less than 1% 1-4% Biliary Tract Less than 1% 1-5%		20-25%

full free text: Targeted Epigenetic Therapies: The Next Frontier? — J. Natl. Cancer Inst. (includes discussion regarding clear cell/ARIDIa mutation

Targeted Epigenetic Therapies: The Next Frontier?

1. Rabiya S. Tuma

When researchers look for mutations associated with cancer, they often expect to come up with alterations in signaling molecules or transcription factors. But an increasing number of the mutations found are in genes that regulate the epigenome—a system that alters DNA structure and regulates gene activity without changing the nucleotide sequence itself.

On Sept. 8, investigators published two independent reports online—one in Science and one in the New England Journal of Medicine—showing that mutations in an epigenetic regulatory gene, ARID1a, were associated with approximately half of the ovarian clear-cell cancers tested.

health media: BRCA1 Breast Cancer Risk Linked To Other Genes

"...People who carry certain mutations of the BRCA1 gene are known to have a higher risk of developing breast cancer.

Couch told the media that their findings should be "useful in helping determine individual risk for breast cancer in BRCA1 carriers".

"It also provides insights into hormone-receptor-negative breast cancer in the general population," he added.

For the study, Couch and colleagues conducted four phases of genome-wide association studies (GWAS) that altogether involved 20 research centers in 10 North American and European countries and Israel.

For the first phase, to identify candidate gene variants, they scanned the genomes of 1,193 carriers of BRCA1 mutations who were under 40 and had invasive breast cancer and compared them to scans of about the same number of controls: BRCA1 carriers of similar age who did not have breast cancer.

In comparing the genomes from the two populations the researchers examined over half a million genetic alterations. They found 96 pieces of DNA called SNPs, or "snips", short for single nucleotide polymorphisms, that they thought would be likely candidates because they differed between the two populations...."cont'd

The rate of the predominant Jewish mutations in the BRCA1, BRCA2, MSH2 and MSH6 genes in unselected Jewish endometrial cancer patients (study number 289 patients)

Note: MSH2/MSH6 are 2 of the Lynch Syndrome genes

Objectives

The genes associated with familial Endometrial Cancer (EC) are largely unknown. While EC is an integral part of Hereditary Non-Polyposis Colon Cancer, there is an ongoing debate if EC is indeed overrepresented in hereditary breast/ovarian cancer families.

Conclusions

Our data do not support screening for BRCA1/2 mutations in consecutive EC patients.

Breast cancer classification algorithm to identify 20 gene signature developed using Microsoft Excel

"....The 10 most highly ranked genes predictive of poor prognosis and those 10 genes most highly predictive of good prognosis established a 20-gene expression based predictor, which was found to perform as well as two other models in the validation group. According to Hassell, "Our algorithm produces prediction models with comparable accuracy to other feature selection techniques while having generally better accessibility and useability for biological research scientists. We've begun using our algorithm to generate gene expression based prediction models of breast cancer cell sensitivity to commonly used anti-cancer therapies"....cont'd

Medical News: Ovarian Cancer Subtype Linked to Gene Mutations (re: clear cell ovarian cancer)

Note: easier to read article

NIH expands network focused on how genes affect drug responses, September 7, News Release - National Institutes of Health (NIH)

"...Spearheaded by the NIH's National Institute of General Medical Sciences (NIGMS) and launched in 2000, the PGRN has already identified gene variants linked to responses to medicines for different cancers, heart disease, asthma, nicotine addiction and other conditions...."cont'd

UK, China Research Teams Partner on $31M Epigenetics Study | GenomeWeb Daily News | GenomeWeb

"The study will harness King's College London's Twin Research and Genetic Epidemiology department and will involve 5,000 twins. The project initially will focus on obesity, diabetes, allergies, heart disease, osteoporosis, and longevity.

"Finding the crucial differences between twins will lead us to the key genes that are being turned on and off, and so to the cause of disease, with great potential to find key targets for drug treatments," Tim Spector, director of TwinsUK and leader of the Epitwin project, said in a statement."

Methylation profiles of hereditary and sporadic ovarian cancer - Histopathology - abstract

Conclusions: 

 CDH13, GSTP1 and RASSF1 are frequently methylated in both sporadic and BRCA1-associated ovarian cancers. Interestingly, methylation of BRCA1, while frequent in sporadic ovarian cancer, never occurred in the hereditary group. BRCA1-associated ovarian cancers mimic their sporadic counterparts in extent and pattern of promoter methylation of several common tumour suppressor genes. This finding could have implications for future chemotherapy regimens based on epigenetic changes

Genomics of Drug Sensitivity in Cancer - as per Libby's Hope blog reference mutations/ovarian cancer

Mutation Prevalence

Click here to download a spreadsheet (Excel) showing the prevalence of mutations in 52 cancer genes across tissue types.