Highlight HEALTH

Here’s another reason to enjoy your coffee. A recent study in the July edition of the Journal Hepatology found a significant inverse association (meaning opposingly related; an increase in one variable results in a decrease in another) between coffee drinking and the risk of primary liver cancer [1]. The study also found that serum levels of an antioxidant enzyme, elevated in people with low coffee consumption, were associated with an increased risk of developing the disease.

photo credit: Marcelo Alves

Primary liver and bile duct cancers are the sixth most common cause of cancer death in men and the tenth most common cause of cancer death in women [2]. Hepatitis B and C viral infections have been identified as causative factors in greater than 75% of liver cancers worldwide [3]. Interestingly, incidence rates are low in most developed countries except for Japan, where coffee drinking is relatively uncommon. Several studies have also identified an inverse association between coffee consumption and serum levels of gamma-glutamyltransferase (GGT), an enzyme involved in glutathione metabolism [4-5]. Glutathione plays important roles in antioxidant defense, nutrient defense and regulation of a variety of cellular events [6].

Residents of Finland consume more coffee per capita than the Japanese, Americans, Italians and other Europeans. University of Helsinki researchers examined the associations between coffee consumption and serum GGT levels in 60,323 Finnish participants between the ages of 25 and 74 who were cancer-free at the beginning of the study.

Participants were mailed a questionnaire about their medical history, socioeconomic factors, smoking habits and dietary habits. A subset of participants (n = 37,842) had clinical data available, including alcohol consumption and serum levels of GGT. Study participants were divided into five categories based on their response to the question “How many cups of coffee do you drink daily?”:

• Category 1:   0 — 1 cup
• Category 2:   2 — 3 cups
• Category 3:   4 — 5 cups
• Category 4:   6 — 7 cups
• Category 5:   8 or more cups per day

During a median follow-up period of 19.3 years, 128 participants were diagnosed with primary liver cancer.

The researchers observed that the cumulative incidence curve of liver cancer decreased with increasing amounts of daily coffee consumption (graph). When the analysis was restricted to surveys from participants that had clinical data available, a statistically positive association was found between serum GGT level and liver cancer risk. Joint association of coffee consumption and serum GGT level with liver cancer showed that participants who drank 0 — 1 cups of coffee and were in the top 25% of subjects sampled with respect to serum GGT had about 9.2 times increased risk for liver cancer compared to participants who drank at least 6 cups of coffee daily and were in the bottom 75% of subjects sampled with respect to serum GGT.

The study results are consistent with two meta-analyses published last year demonstrating an inverse relation between coffee consumption and liver cancer [7-8]. While a previous investigation found an inverse association between coffee consumption and serum GGT level, this study is the first large prospective study to suggest that a high level of serum GGT is a risk factor for primary liver cancer. The authors discuss a mechanism for the association between coffee drinking and serum GGT on liver cancer risk [1]:

Several other putative mechanisms behind the association of coffee drinking and serum GGT on liver cancer risk have also been proposed. Coffee contains many compounds, such as chlorogenic acid, which may have the potential to influence glucose metabolism processes to prevent hyperglycemia, and consequently oxidative stress.

Indeed, chlorogenic acid, a chemical largely responsible for coffee’s bitterness, may also be responsible for coffee’s effect on serum GGT level and, ultimately, coffee’s health benefits.

More information and support for patients with “Liver cancer” can be found at Organized Wisdom and MDJunction. Additionally, the American Liver Foundation, the nation’s leading nonprofit organization promoting liver disease prevention and liver wellness, provides research, education and advocacy for those affected by liver-related diseases.

References

1. Hu et al. Joint effects of coffee consumption and serum gamma-glutamyltransferase on the risk of liver cancer. Hepatology. 2008 Jul;48(1):129-36. DOI: 10.1002/hep.22320
   View abstract

2. A Snapshot of Liver and Bile Duct Cancers. American Cancer Society. Atlanta, Ga. 2007.
3. Ferlay et al. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5. version 2.0. Lyon, France: International Agency for Cancer Research; 2004.
4. Casiglia et al. Unexpected effects of coffee consumption on liver enzymes. Eur J Epidemiol 1993;9:293-297.
   View abstract
5. Tanaka et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol 1998;27:438-443.24.
   View abstract
6. Wu et al. Glutathione metabolism and its implications for health. J Nutr. 2004 Mar;134(3):489-92.
   View abstract
7. Larsson and Wolk. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007 May;132(5):1740-5. Epub 2007 Mar 24.
   View abstract
8. Bravi et al. Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology. 2007 Aug;46(2):430-5.
   View abstract

Bookmark or Share

The 2008 NF Conference was held last weekend (June 6 — 10) in Bonita Springs, Florida. The preeminent annual meeting provides a forum for basic and clinical neurofibromatosis (NF) investigators to present their research (pronounced noor-oh-fahy-broh-muh-toh-sis). The conference was attended by over 200 researchers from around the world

This year’s theme — Genes to Complications to Treatments — highlighted the progress being made in NF research and clinical care, as well as the research programs of the Children’s Tumor Foundation. Last year’s NF Conference focused on models, mechanisms and therapeutic targets.

The neurofibromatoses are familial cancer syndromes that predispose individuals to the development of a variety of benign and malignant tumors in the central and peripheral nervious systems. The disorders cause tumors to grow along various types of nerves and can also affect the development of bones and skin. Neurofibromatosis has been classified into three distinct types:

• Neurofibromatosis type 1 (NF1) occurs in 1:3,500 births and is caused by a mutation of the NF1 gene on chromosome 17q11.2. NF1 diagnostic criteria (two or more) include cafe-au-lait macules, freckling, optic glioma, Lisch nodules, bony abnormalities, a first-degree relative with NF1, two or more benign nerve sheath tumors (neurofibromas) of any type, or at least one plexiform neurofibroma [1-2].
  At least 95% of NF1 patients develop benign tumors called neurofibromas [3], which may be disfiguring or associated with pain and neurological defect. As there is no cure for neurofibromatosis, the only therapy is surgical removal of the tumor and associated nerve. Approximately 6 — 13% of NF1 patients will progress and develop a malignant peripheral nerve sheath tumor (MPNST), an aggressive sarcoma that has a high mortality rate (~ 50%) [4].

• Neurofibromatosis type 2 (NF2) occurs in 1:25,000 births and is caused by a mutation of the NF2 gene on chromosome 22q12. Ninety percent of NF2 patients develop bilateral vestibular schwannomas and/or spinal schwannomas. Enlarging schwannomas can compress adjacent structures, resulting in deafness or other neurologic deficits depending on their location. Surgical removal of these tumors is difficult, often resulting in patient morbidity. Although 95% of schwannomas occur sporadically, multiple schwannomas are the hallmark of inherited NF2 [5].

• Schwannomatosis occurs in 1:40,000 patients and, in contrast to NF2, develop multiple peripheral schwannomas, but not schwannomas of the vestibular nerve. Schwannomas in schwannomatosis patients are often associated with severe, intractable neuropathic pain and sometimes numbness, tingling and weakness. It was believed that a germline mutation in an unidentified gene predisposes patients to NF2 mutation [6]. Recently, the INI1 gene was identified as a possible schwannomatosis gene [7-8].

Both NF1 and NF2 are tumor suppressor genes.

The Children’s Tumor Foundation (CTF) is dedicated to ending neurofibromatosis through research. The CTF has funded NF research for over 25 years with the goal of identifying NF drug therapies and improving the lives of those living with the disorder. The Foundation also endeavors to increase public awareness of NF and provides resources for NF patients and their families.

For more information on NF, visit the Children’s Tumor Foundation and Neurofibromatosis Cafe.

CTF medical podcasts are also available.

References

1. Riccardi VM. The prenatal diagnosis of NF-1 and NF-2. J Dermatol. 1992 Nov;19(11):885-91.
   View abstract
2. Gutmann et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997 Jul 2;278(1):51-7.
   View abstract
3. Rasmussen and Friedman. NF1 gene and neurofibromatosis 1. Am J Epidemiol. 2000 Jan 1;151(1):33-40.
   View abstract
4. Evans et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4.
   View abstract
5. Evans et al. A genetic study of type 2 neurofibromatosis in the United Kingdom. I. Prevalence, mutation rate, fitness, and confirmation of maternal transmission effect on severity. J Med Genet. 1992 Dec;29(12):841-6.
   View abstract
6. Jacoby et al. Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet. 1997 Dec;61(6):1293-302.
   View abstract
7. Hulsebos et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet. 2007 Apr;80(4):805-10. Epub 2007 Feb 16.
   View abstract
8. Hadfield et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet. 2008 Jun;45(6):332-9. Epub 2008 Feb 19.
   View abstract

Bookmark or Share

At the annual meeting of the American Association for Cancer Research (AACR) last month, researchers from GeneNews Corp. reported that the probability of colorectal cancer (CRC) in asymptomatic patients can be accurately stratified by RNA expression profiling of six genes in whole blood [1]. The company focuses on developing blood-based biomarker tests for the early detection of diseases and personalized health management.

Stratification is a statistical method of sampling from a population, whereby members are grouped into subgroups that display a consistent feature. In the current study, the six-gene panel was able to stratify a population with average risk for CRC into three groups:

• Increased probability (18% had a 3-fold increased probability of currently having CRC)
• Average probability (20% had an average probability of currently having CRC)
• Decreased probability (62% had a 4-fold decreased probability of currently having CRC)

The study comes after publication of their approach to detecting blood biomarker sets earlier this year in the journal Clinical Cancer Research [2]. The study evaluated blood RNA samples from an Asian population and identified five genes in patients with CRC that could be differentiated from controls.

photo credit: DimsumDarren

In the study, researchers screened 31 whole blood samples from patients without CRC (n = 15) or patients with CRC (n = 16) by DNA microarray, a technology that enables scientists to examine how active thousands of genes are at a given time. They identified 37 genes unrelated to age or gender that were significantly different between controls and patients with CRC. The 37 genes were then tested with a large training set of 115 samples (57 controls, 58 CRC) using real-time PCR. 17 of the 37 genes were validated as differentially expressed. Five of the 37 validated genes were selected for logistic regression analysis.

Logistic regression is a statistical model used for prediction of the probability of occurrence of an event, using predictor variables that may be either numerical or categorical.

The predictive power of the five genes was then validated with a third independent set of 92 samples (49 controls, 43 CRC). The validation correctly identified 88% of CRC samples and 64% of non-CRC samples.

In their most recent study, GeneNews examined more samples than previously analyzed, this time in a heterogeneous North American population. Researchers screened a training set of 243 whole blood samples from patients without CRC (n = 127) or patients with CRC (n = 116) by DNA microarray. Six genes whose expression could meaningfully discriminate between the two groups were identified [3]:

• Annexin A3 (ANXA3), which plays a role in the regulation of cellular growth and in signal transduction pathways.
• C-type lectin domain family 4, member D (CLEC4D), which has diverse functions, such as cell adhesion, cell-cell signalling, glycoprotein turnover, and roles in inflammation and immune response.
• Lamin B1 (LMNB1), which is thought to be involved in nuclear stability, chromatin structure and gene expression.
• Proline rich Gla (G-carboxyglutamic acid) 4 (PRRG4), function unknown.
• Vanin 1 (VNN1), involved in the recycling of pantothenic acid (vitamin B5).
• Interleukin 2 receptor, beta (IL2RB), which is involved in T cell-mediated immune responses.

The predictive power of the six genes was then validated in a blinded, independent set of 337 samples (171 controls, 166 CRC). The combined training/blind set had an average accuracy of 70.8%. GeneNews has announced plans to develop a laboratory test later this year based on the six-gene panel called ColonSentry [4]. Similar blood screening tests are under investigation by the GeneNews for prostate, breast and ovarian cancer.

Why is this important? Colorectal cancer (CRC) is the third most common cancer in both men and women with an estimated 49,960 deaths expected to occur in 2008, accounting for 9% of all cancer deaths [5]. A simple, noninvasive test that can classify average risk patients into more defined groups would help to assess an individual’s risk for CRC. Since CRC can often be treated if caught early enough, those having an increased probability could be screened more frequently. Screening can result in the detection and removal of colorectal polyps before they become cancerous. Additionally, screening can help to detect CRC that is at an early stage.

Consider these statistics: when CRC is detected early, the 5-year survival rate is 90%. If the cancer has spread locally, the 5-year survival rate decreases to 68%. For patients with advanced CRC that has metastasized, the 5-year survival rate is 10% [5].

The American Cancer Society (ACS) has published guidelines for the early detection of cancer. Beginning at age 50, men and women at average risk for developing CRC should be screened with one of the following tests:

Tests that find polyps and cancer

• Flexible sigmoidoscopy every 5 years
• Colonoscopy every 10 years
• Double contrast barium enema every 5 years
• CT colonography (virtual colonoscopy) every 5 years

Tests that mainly find cancer

• Fecal occult blood test (FOBT) every year
• Fecal immunochemical test (FIT) every year
• Stool DNA test (sDNA), interval uncertain

Don’t underestimate the importance of regular cancer screening. One of the reasons for a decline in CRC incidence rates since 1998 is increased surveillance. If you’re at risk, get checked.

References

1. Stratification of colorectal cancer probability using six genes from whole blood. American Association for Cancer Research (AACR) annual meeting abstract, Clinical Research. 2008 Apr 15.
2. Han et al. Novel blood-based, five-gene biomarker set for the detection of colorectal cancer. Clin Cancer Res. 2008 Jan 15;14(2):455-60. Epub 2008 Jan 18.
   View abstract
3. Six-Gene Cluster Stratifies Which Patients Most Need Colonoscopy. OncologySTAT. 2008 Apr 29.
4. GeneNews Reports Positive Results From Validation Study of Colorectal Cancer Biomarkers in Late Breaking Abstract at AACR. Biomarkers form basis of blood-based ColonSentry test. GeneNews Press Release. 2008 Apr 14.
5. Cancer Facts & Figures 2008. American Cancer Society. Atlanta, Ga. 2008.

Bookmark or Share