Sue A. Ingles

Multiple regions within 8q24 independently affect risk for prostate cancer

After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 × 10−19 for the strongest association, and P < 1.5 × 10−4 for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.

Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men

A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) = 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 × 10−9) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it.

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.

Ecuadorians who have a genetic mutation in the growth hormone receptor almost never die of cancer or diabetes complications, possibly because of high resistance to oxidative damage and low circulating insulin. Clues to a Cancer- and Diabetes-Free Life In the 1958 film Live Fast and Die Young, two reckless sisters threaten to burn out early. Similarly, one theory of aging predicts that a faster metabolism leads to a shorter life. Does this trade-off also apply to age-related disease? A new study by Guevara-Aguirre et al. offers clues that address this seminal question. The authors’ findings stem from studies of a unique group of Ecuadorian people who have a mutation in the growth hormone receptor (GHR) gene and a resulting insulin-like growth factor–1 (IGF-1) deficiency, which stunts their growth. These descendants of Spanish conversos, Jews who converted to Christianity to avoid the Inquisition, almost never get diabetes or cancer as a result, the authors postulate, of the privileged metabolic status that arises from their altered hormonal state. Relative to controls, these subjects show lower insulin concentrations and higher insulin sensitivity, and when stressed, their cells tend to self-destruct rather than accumulate mutations and DNA damage—all features that are known to promote cell protection in model organisms. For 22 years, this group of 99 related Ecuadorians—most of whom are homozygous for an A-to-G splice site mutation at position 180 in exon 6 of the GHR gene—has been monitored extensively, so that their health details are well documented. From this reservoir of data, plus information about the diseases of family members as well as causes of death of those relatives who have died, the authors deciphered that the Ecuadorian subjects who carried the GHR mutation had an abnormally low incidence of cancer and diabetes. The group showed only one case of nonlethal cancer and no cases of diabetes, whereas the controls—unaffected relatives—developed cancer (17%) and diabetes (5%) at rates similar to those of the Ecuadorian population as a whole. To illuminate the underlying reason for the subjects’ freedom from these diseases, the authors focused on the components carried in their blood. In experiments on cultured human epithelial cells, Guevara-Aguirre et al. found that low concentrations of one of these, IGF-1, was responsible for preventing oxidative DNA damage when the cells were exposed to the oxidizing agent H2O2 and for promoting cell death when stress-related DNA damage did occur, a checkpoint that averts cancer-promoting behavior by abnormal cells. Analysis of the participating cell signaling pathways identified activation of the transcription factor FoxO under conditions of low IGF-1 as a likely mediator of these effects. Further, the lower blood insulin concentrations and higher insulin sensitivity in these subjects likely account for the absence of diabetes in this population. Although it is difficult to prove that alterations in IGF-1 amounts are responsible for the cancer- and diabetes-free lives of these Ecuadorian people, genetic work from several model organisms suggests that this is so. In yeast, mutations in genes that encode components of a growth-promoting pathway protect against age-dependent genomic instability, and mutations in the insulin/IGF-1–like signaling pathway increase life span and reduce abnormal cellular proliferation in worms. Mice with defects in GH and IGF-1 live exceptionally long lives, with delayed appearance of age-dependent mutations and cancer. The Ecuadorians do not live longer-than-normal lives compared with their compatriots, but rather die in due course from causes of death other than cancer and diabetes complications. Thus, the metabolic inverse of “live fast and die young”—a slowed metabolism yields a longer life—is not supported by the current findings. But a life free from two dreaded diseases may be considered a desirable trade-off. Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor–1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 μU/ml versus 4.4 μU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment–insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

Detectable clonal mosaicism from birth to old age and its relationship to cancer

We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5–10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2–3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6–18).

Late Physical and Functional Effects of Osteoporotic Fracture in Women: The Rancho Bernardo Study

OBJECTIVE: To examine the associations between osteoporotic fractures and difficulty performing selected physical and functional activities.

The landscape of recombination in African Americans

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10−245). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10−13). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)

Vitamin D receptor genotype and breast cancer in Latinas (United States)

Objective: Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk.Methods: Polymorphisms in the 5′ and 3′ ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls.Results: Both the BsmI and poly-A polymorphisms in the 3′ end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0–2.3) and 3.2 (1.5–6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1–2.5) and 2.2 (1.0–4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk.Conclusion: These results suggest that polymorphic variation in or near the 3′ end of the VDR gene influences breast cancer risk in Latina women.

Human islet isolation in 104 consecutive cases : factors affecting isolation success

One of the major steps toward successful islet transplantation for the treatment of type diabetes is to obtain islets of sufficient number and viability. Using a standardized method of isolating islets, the goal of this study was to analyze the factors influencing the outcome of islet isolation. A total of 104 cadaveric human pancreata were processed for islets by the same team. Data from the islet-processing charts were reviewed retrospectively. The two endpoints were the recovery of islets, viable after 2 days of culture (group V = viable, group NV = nonviable) and the islet yield. Viable islets were recovered in 61% of cases (n = 63). Minimal blood glucose recorded during hospitalization was very significantly lower in group V (124 +/- 5 vs. 148 +/- 9, P = 0.01). Lack of significant medical history in the donor was associated with better viability as compared with various donor predispositions (chi-2 4.21, P = 0.04). Cold ischemia time (8.1 +/- 0.5 hr in group V vs. 9.8 +/- 0.9 hr in group NV, P = 0.07) and collagenase lot (5 lots tested, chi-2 13.1, P = 0.01) also affected the recovery of viable islets. Hospital time was shorter in group V (65.3 +/- 6.8 vs. 80.9 +/- 17.9 hr, P = 0.35). Multivariate logistic regression analyses of viable islet recovery identified minimal blood glucose (P = 0.03) and collagenase lot (P = 0.06) as the most significant risk factors. However, the best multivariate predictive model--which includes blood glucose, collagenase lot, donor age and surgical procurement team--correctly predicted 66.2% of cases only. Multivariate analysis of final islet yield designed hospitalization length, cardiorespiratory arrest, surgical procurement team, and collagenase lot as the best predictors. These data obtained in a large series of pancreata emphasized several donor and technical factors that should target the attention of islet transplant researchers in order to improve islet yield and viability.