Genomics|Update|Current: Genomics in the Scientific Literature - CANCER

Genomics in the Scientific Literature
Topics in the Scientific Literature

Cancer
1. Architecture of inherited susceptibility to common cancer
Fletcher O & Houlston RS
Nat Rev Cancer 2010 May;10(5):353-61

Nat Rev Cancer. 2010 May;10(5):353-61.

Architecture of inherited susceptibility to common cancer.
Fletcher O, Houlston RS.

Olivia Fletcher is at the Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, UK.

Abstract
This Timeline article looks back at 40 years of research into the inherited genetic basis of cancer and the insights these studies have yielded. Early epidemiological research provided evidence for the 'two-hit' model of cancer predisposition. During the 1980s and 1990s linkage and positional cloning analyses led to the identification of high-penetrance cancer susceptibility genes. The past decade has seen a shift from models of predisposition based on single-gene causative mutations to multigenic models. These models suggest that a high proportion of cancers may arise in a genetically susceptible minority as a consequence of the combined effects of common low-penetrance alleles and rare disease-causing variants that confer moderate cancer risks.

PMID: 20414203 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20414203?dopt=Abstract


2. Candidate gene association studies: successes and failures
Pasche B & Yi N
Curr Opin Genet Dev 2010 Apr

Curr Opin Genet Dev. 2010 Apr 21. [Epub ahead of print]

Candidate gene association studies: successes and failures.
Pasche B, Yi N.

Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham and UAB Comprehensive Cancer Center, 1802 6th Avenue South, NP 2566, Birmingham, AL 35294-3300, United States.

Abstract
Epidemiologic studies of twins indicate that 20-40% of common tumors such as breast, colorectal, and prostate cancers are inherited. However, the effect of high penetrance tumor susceptibility genes such as APC, BRCA1, BRAC2, MSH1, MLH2 and MSH6 only accounts for a small fraction of these cancers. Low to moderate penetrance tumor susceptibility genes likely account for the large remaining proportion of familial cancer risk. Candidate tumor susceptibility genes have been identified based on the discovery of tumor-specific mutations, in vitro experiments, as well as animal models of cancer. Translational studies based on in vitro and in vivo discoveries have led to the identification of novel phenotypes and genotypes associated with cancer in humans. Case-control studies followed by validation studies and meta-analyses have unveiled several novel tumor susceptibility genes, several of which belong to genes encoding metabolizing enzymes and genes from the TGF-beta signaling pathway. Together with genome-wide association studies, candidate gene approaches are likely to fill a large gap in our knowledge of the genetic basis of cancer within the next decade. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20417090 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20417090?dopt=Abstract


3. Common variants associated with breast cancer in genome wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers
Wang X, et al.
Hum Mol Genet 2010 Apr

Hum Mol Genet. 2010 Apr 23. [Epub ahead of print]

Common variants associated with breast cancer in genome wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers.
Wang X, Pankratz VS, Fredericksen Z, Tarrell R, Karaus M, McGuffog L, Pharaoh PD, Ponder BA, Dunning AM, Peock S, Cook M, Oliver C, Frost D; EMBRACE, Sinilnikova OM, Stoppa-Lyonnet D, Mazoyer S, Houdayer C; GEMO, Hogervorst FB, Hooning MJ, Ligtenberg MJ; HEBON, Spurdle A, Chenevix-Trench G; kConFab, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Domchek SM, Nathanson KL, Rebbeck TR, Singer CF, Gschwantler-Kaulich D, Dressler C, Fink A, Szabo CI, Zikan M, Foretova L, Claes K, Thomas G, Hoover RN, Hunter DJ, Chanock SJ, Easton DF, Antoniou AC, Couch FJ.

Department of Laboratory Medicine and Pathology, and.

Abstract
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWAS), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (p<1x10(-3)) in two breast cancer GWAS studies were genotyped in 3,451 BRCA1 and 2,006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (P(trend)<0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR=0.78, 95%CI:0.69-0.90, P(trend)=3.6x10(-4) and HR=1.25, 95%CI:1.10-1.41, P(trend)=4.2x10(-4)), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the stongest associations in BRCA2 carriers (HR=1.55, 95%CI:1.25-1.92, P(trend)=6x10(-5) and HR=1.37, 95%CI:1.16-1.62, P(trend)=1.7x10(-4)). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.

PMID: 20418484 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20418484?dopt=Abstract


4. From "omics" to complex disease: a systems biology approach to gene-environment interactions in cancer
Knox SS
Cancer Cell Int 2010 Apr;10(1):11

Cancer Cell Int. 2010 Apr 26;10(1):11. [Epub ahead of print]

From "omics" to complex disease: a systems biology approach to gene-environment interactions in cancer.
Knox SS.

Abstract
ABSTRACT: BACKGROUND: Cancer is a complex disease that involves a sequence of gene-environment interactions in a progressive process that cannot occur without dysfunction in multiple systems, including DNA repair, apoptotic and immune functions. Epigenetic mechanisms, responding to numerous internal and external cues in a dynamic ongoing exchange, play a key role in mediating environmental influences on gene expression and tumor development. Hypothesis: The hypothesis put forth in this paper addresses the limited success of treatment outcomes in clinical oncology. It states that improvement in treatment efficacy requires a new paradigm that focuses on reversing systemic dysfunction and tailoring treatments to specific stages in the process. It requires moving from a reductionist framework of seeking to destroy aberrant cells and pathways to a transdisciplinary systems biology approach aimed at reversing multiple levels of dysfunction. CONCLUSION: Because there are many biological pathways and multiple epigenetic influences working simultaneously in the expression of cancer phenotypes, studying individual components in isolation does not allow an adequate understanding of phenotypic expression. A systems biology approach using new modeling techniques and nonlinear mathematics is needed to investigate gene-environment interactions and improve treatment efficacy. A broader array of study designs will also be required, including prospective molecular epidemiology, immune competent animal models and in vitro / in vivo translational research that more accurately reflects the complex process of tumor initiation and progression.

PMID: 20420667 [PubMed - as supplied by publisher]Free Article
http://www.ncbi.nlm.nih.gov/pubmed/20420667?dopt=Abstract


5. Hereditary and familial colon cancer
Jasperson KW, et al.
Gastroenterology 2010 Jun;138(6):2044-58

Gastroenterology. 2010 Jun;138(6):2044-58.

Hereditary and familial colon cancer.
Jasperson KW, Tuohy TM, Neklason DW, Burt RW.

Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.

Abstract
Between 2% to 5% of all colon cancers arise in the setting of well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and certain hamartomatous polyposis conditions. Each is associated with a high risk of colon cancer. In addition to the syndromes, up to one-third of colon cancers exhibit increased familial risk, likely related to inheritance. A number of less penetrant, but possibly more frequent susceptibility genes have been identified for this level of inheritance. Clarification of predisposing genes allows for accurate risk assessment and more precise screening approaches. This review examines the colon cancer syndromes, their genetics and management, and also the common familial colon cancers with current genetic advances and screening guidelines.

PMID: 20420945 [PubMed - in process]
http://www.ncbi.nlm.nih.gov/pubmed/20420945?dopt=Abstract


6.Molecular biology from bench-to-bedside - Which colorectal cancer patients should be referred for genetic counselling and risk assessment
Jensen LH, et al.
Eur J Cancer 2010 Apr

Eur J Cancer. 2010 Apr 21. [Epub ahead of print]

Molecular biology from bench-to-bedside - Which colorectal cancer patients should be referred for genetic counselling and risk assessment.
Jensen LH, Dysager L, Lindebjerg J, Kølvrå S, Byriel L, Crüger DG.

Danish Colorectal Cancer Group South, University of Southern Denmark, Vejle Hospital, Denmark.

Abstract
Lynch syndrome is associated with deficiency of the mismatch repair genes MLH1, MSH2, MSH6 or PMS2. However, most MLH1 deficient tumours are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 gene promoter. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumours were tested for MLH1, PMS2, MSH2 and MSH6 protein expression with immunohistochemistry. DNA from MLH1 negative tumours was sequenced for BRAF mutations. If BRAF was wild-type, MLH1 promoter was subsequently analyzed for promoter hypermethylation. Most tumours, 251 (88%), stained positive for all four proteins. Six (2%) had negative MSH2 and one (<1%) isolated loss of MSH6. MLH1 and PMS2 were negative in 29 cases (10%). DNA quality allowed BRAF analysis in 27 of these with 14 mutations and 13 wild-type. DNA quality allowed methylation analysis in 11 of the 13 BRAF wild-type, and all but one were methylated. Subsequently, Lynch syndrome could not be ruled out in 12 patients. A follow-up at 8-10years revealed four definite cases of Lynch syndrome and three highly suspicious. An easy and clinically applicable step-wise approach with immunohistochemistry (100%), BRAF sequencing (10%) and methylation analysis (5%) identified several patients with hereditary cancer. It is feasible to perform a molecular screening to select patients for genetic counselling. Copyright © 2010 Elsevier Ltd. All rights reserved.

PMID: 20417091 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20417091?dopt=Abstract