Research in Genetic Epidemiology and Risk Assessment (GERA) is bringing scientists closer to the day of 'personalized medicine' when physicians will routinely order genetic profiles to determine treatment and to even recommend prevention strategies for patients based on this information.
A brief overview of selected advances in GERA research is listed below. Other research activities are described in Ongoing Research.
Prostate Cancer Gene Discovery
Susceptibility Genes in Colon Cancer
Minnesota Breast Cancer Family Study
Tissue Markers: Benign Breast Disease
Dr. Weinshilboum's lab resequenced CYP19 through the Pharmacogenetic Research Network, providing data on 88 SNPs (Ma et al., 2005). CYP19 encodes aromatase, which is a major pathway for conversion of androgens to estrogens, and a strong candidate gene for breast cancer. Haplotype and tagSNPs were selected and genotyped, but none of the individual SNPs were associated with breast cancer (Olson et al., 2007) or mammographic breast density (Olson et al., 2007b). In prostate cancer, 46 polymorphisms from the estrogen and androgen metabolic pathways were evaluated in familial (N=438 from 178 high-risk families), sporadic (N= 499 with no family history), and screen-negative controls (N=493). Suggestive findings were found with AKR1C3, HSD17B1, NQO1, and GSTT1, although none were significant after adjustment for multiple comparisons (Cunningham et al., 2007). Further, in the process of genotyping SULT1A1 in the prostate cancer study, suspicious genotyping results across platforms lead to further study of the gene and the finding that copy number variation is very common, and that variability in the level of enzyme activity was best explained by gene number differences when all sources of genetic variability were considered (copy number, deletions, haplotypes) (P<0.0001) (Hebbring et al., 2007). This has led to the need to reassess findings for this important gene in drug and hormone metabolism.
Medical History and Patient Record Advances
An automated system for assigning diagnosis codes to patient encounters was developed and implemented, resulting in a reduction in staff engaged in manual coding from 34 coders to seven verifiers (Pakhomov et al., 2006).
On the same note, Dr. Schaid derived analytic methods to determine sample size and power to test the association of haplotypes with either a quantitative trait or disease status (e.g., a case-control study design), assuming that all subjects are unrelated. These derivations covered both phase-known and phase-unknown haplotypes, allowing evaluation of the loss of efficiency due to unknown phase, and included an extension to when a subset of tag-SNPs is chosen, allowing investigators to explore the impact of tag-SNPs on power. Dr. Schaid has also developed an exact stratified test of Hardy-Weinberg equilibrium (HWE) for diallelic markers and an exact test for homogeneity of HWE, which is particularly useful for samples composed of multiple ethnic groups (Schaid et al., 2006). These various methods have been made widely available through the internet-based Mayo SPLUS/R library, including haplo.stats, haplo.glm and haplo.power.
In another development, researchers determined multi-locus association analyses, including haplotype-based analyses, can sometimes provide greater power than single locus analyses for detecting disease susceptibility loci. Drs.Yu and Schaid presented a sequential haplotype scan method to search for combinations of adjacent markers that are jointly associated with disease status. When evaluating each marker, markers are added close to each other in a sequential manner: a marker is added if its contribution to the haplotype association with disease is warranted, conditional on current haplotypes. The proposed sequential haplotype scan algorithm is more powerful than single-locus method and it is more computationally efficient than sliding window methods.
Microarray and Proteomics Analysis
Changing Clinical Practice -- Familial Colorectal Cancer Type X
The American Cancer Society reports that colorectal cancer is diagnosed in nearly 154,000 people each year in the United States. A highly-preventable cancer if found early, colorectal cancer is the focus of many researchers at Mayo Clinic Cancer Center, who are searching for better ways to screen for this disease, thus enabling earlier intervention/prevention.
One of the primary ways to improve screening is to better identify individuals at higher risk to develop colorectal cancer. Through collection and analysis of environmental and genetic information of large groups of people, risk estimates can be developed across populations.
Dr. Lindor and her colleagues took this type of research to the next level. Reported in The Journal of the American Medical Association in 2006, risks were refined for a sub-group of individuals who meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HPNCC), resulting in a higher risk of developing colorectal cancer than the general population. Families meeting AC-I criteria have heretofore been diagnosed with HPNCC-Lynch syndrome; however, pedigree-defined families comprise two entities.
It has long been known that about 60 percent of people that meet the AC-I have an inherited abnormality in a DNA mismatch repair gene. This entity may be called Lynch Syndrome. The cancer risks associated with the hereditary disorder are well defined and significantly greater than in the general population. Dr. Lindor and her inter-institutional team of investigators sought to determine if remaining families that fulfilled the AC-I criteria but did NOT have this genetic abnormality have the same risks as those with true Lynch Syndrome. After analysis of of 161 families that all fit the AC-I critieria, they reported that those without evidence of DNA mismatch repair gene defect had lower risks for colorectal cancer than did the Lynch Syndrome families. In addition, risks for non colonic cancers were not appreciably increased. Lastly, those with no DNA mismatch repair deficiency has older ages of diagnosis of colorectal cancer than did the Lynch Syndrome families (60.7 vs 48.7 years).
These findings negate the common practice of applying the HPNCC-Lynch syndrome diagnosis across the board for AC-I families. Instead, Dr. Lindor and colleagues recommended the use of a new term to describe the cancers of individual families without the abnormality -- Familial Colorectal Cancer Type X, reserving the HNPCC-Lynch Syndrome diagnosis for those families with the DNA mismatch repair deficiency.
More research needs to be done, but the research appears to indicate that this DNA abnormality is related not only to colorectal cancer, but also to uterine, stomach, urinary tract (including kidney), ovary and small intestine cancer. There is some evidence of increased risk for these families of pancreatic and liver cancer as well, whereas for the other AC-I families, only colorectal cancer risk is elevated beyond that of the general population.
Dr. Lindor is also the primary investigator of the Mayo site of the Colon Cancer Family Registry (CFR), which is a National Cancer Institute (NCI)-supported consortium of six centers initiated in 1997 to establish a comprehensive collaborative infrastructure to facilitate interdisciplinary studies of the genetics and epidemiology of colorectal cancer. The Colon CFR has been the basis for multiple studies.
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