Enhanced Expression of Radiation-induced Leukocyte CDKN1A mRNA in Multiple Primary Breast Cancer Patients: Potential New Marker of Cancer Susceptibility

This study was designed to discover blood biomarkers of cancer susceptibility using invasive multiple (n = 21), single primary breast cancer (n = 21), and control subjects (n = 20). Heparinized whole blood was incubated at 37 °C for 2 hours after 0–10 Gy of radiation, then cell cycle arrest marker CDKN1A and apoptosis marker BBC3 mRNA were quantified. This epidemiological study was practically feasible because radiation-induced mRNA was preserved for at least 1 day whenever blood was stored at 4 °C (r2 = 0.901). Moreover, blood could be stored frozen after radiation treatment (r2 = 0.797). Radiation-induced CDKN1A and BBC3 mRNA were dose dependent, and the degree of induction of CDKN1A was correlated with that of BBC3 (r2 = 0.679). Interestingly, multiple primary cases showed higher induction of CDKN1A mRNA than single primary and control groups, whereas BBC3 did not show such differences. The results suggested that cancer susceptibility represented by the multiple primary breast cancer cases was related to over-reaction of CDKN1A mRNA, not BBC3. The study also suggests that ex vivo gene expression analysis could potentially be used as a new tool in epidemiological studies for cancer and radiation sensitivity research

Extending Mendelian Risk Prediction Models to Handle Misreported Family History

Mendelian risk prediction models calculate the probability of a proband being a mutation carrier based on family history and known mutation prevalence and penetrance. Family history in this setting, is self-reported and is often reported with error. Various studies in the literature have evaluated misreporting of family history. Using a validation data set which includes both error-prone self-reported family history and error-free validated family history, we propose a method to adjust for misreporting of family history. We estimate the measurement error process in a validation data set (from University of California at Irvine (UCI)) using nonparametric smoothed Kaplan-Meier estimators, and use Monte Carlo integration to implement the adjustment. In this paper, we extend BRCAPRO, a Mendelian risk prediction model for breast and ovarian cancers, to adjust for misreporting in family history. We apply the extended model to data from the Cancer Genetics Network (CGN)

Socioeconomic Impacts on Survival Differ by Race/Ethnicity among Adolescents and Young Adults with Non-Hodgkin's Lymphoma

Shorter survival has been associated with low socioeconomic status (SES) among elderly non-Hodgkin's lymphoma (NHL) patients; however it remains unknown whether the same relationship holds for younger patients. We explored the California Cancer Registry (CCR), to investigate this relationship in adolescent and young adult (AYA) NHL patients diagnosed from 1996 to 2005. A case-only survival analysis was conducted to examine demographic and clinical variables hypothesized to be related to survival. Included in the final analysis were 3,489 incident NHL cases. In the multivariate analyses, all-cause mortality (ACM) was higher in individuals who had later stage at diagnosis (P < .05) or did not receive first-course chemotherapy (P < .05). There was also a significant gradient decrease in survival, with higher ACM at each decreasing quintile of SES (P < .001). Overall results were similar for lymphoma-specific mortality. In the race/ethnicity stratified analyses, only non-Hispanic Whites (NHWs) had a significant SES-ACM trend (P < .001). Reduced overall and lymphoma-specific survival was associated with lower SES in AYAs with NHL, although a significant trend was only observed for NHWs

Kids, Adolescents, and Young Adult Cancer Study—A Methodologic Approach in Cancer Epidemiology Research

Advances have been made in treatment and outcomes for pediatric cancer. However adolescents and young adults (AYAs) with cancer have not experienced similar relative improvements. We undertook a study to develop the methodology necessary for epidemiologic cancer research in these age groups. Our goal was to create the Kids, Adolescents, and Young Adults Cancer (KAYAC) project to create a resource to address research questions relevant to this population. We used a combination of clinic and population-based ascertainment to enroll 111 cases aged 0–39 for this methodology development study. The largest groups of cancer types enrolled include: breast cancer, leukemia, lymphoma, and melanoma. The overall participation rate is 69.8% and varies by age and tumor type. The study included patients, mothers, and fathers. The methods used to establish this resource are described, and the values of the resource in studies of childhood and young adult cancer are outlined

A Targeted Genetic Association Study of Epithelial Ovarian Cancer Susceptibility

BACKGROUND: Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. RESULTS: At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p \u3c5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p\u3c 3x10-6). METHODS: A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. CONCLUSION: Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance

Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis

A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis

Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44�1.33, p=0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are diferences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants

Quality of life, characteristics and survival of patients with HIV and lymphoma

We sought to compare the quality of life (QOL), characteristics, and survival of patients with non-Hodgkin lymphoma (NHL) with and without human immunodeficiency virus (HIV) infection. Using the population-based cancer registry for Orange and San Diego Counties, We recruited 50 patients with HIV and systemic NHL (cases) and 50 age, sex and race-matched NHL patients without HIV (controls) diagnosed with NHL during 2002–2006. Patients completed a medical history survey and QOL instrument, the Functional Assessment of Human Immunodeficiency Virus Infection (FAHI) for cases and Functional Assessment of Cancer Therapy-General (FACT G) for controls. HIV-infected patients had worse overall QOL and survival than uninfected patients. QOL differences were more marked in the areas of functional, physical and social well-being than in the area of emotional well-being. HIV-infected patients had lower income and were less likely to have private insurance and more likely to have diffuse large B cell histology than uninfected patients. HIV-infected NHL patients had worse QOL and survival than uninfected patients, due to a combination of co-morbidity, aggressive histology and lack of social support. However, their emotional well-being was comparable to that of uninfected NHL patients and better than historical norms for the HIV-infected

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in nonbreast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer

A design for cancer case–control studies using only incident cases: experience with the GEM study of melanoma

BACKGROUND: The population-based case-control study is not suited to the evaluation of rare genetic (or environmental) factors. The use of a novel case-control design in which cases have second primaries and controls are cancer survivors has been proposed for this purpose. METHODS: We report results from an international study of melanoma that involved population-based ascertainment of incident cases of second or subsequent primary melanoma as the 'case' group and incident cases of first primary melanoma as the 'control' group. We evaluate the validity of the study design by comparing the results obtained for phenotypic factors that have been shown consistently to be associated with melanoma in previous conventional studies with the results from a conventional case-control study conducted in Connecticut and from literature reviews. RESULTS: All but one of the known risk factors for melanoma were shown to be significantly associated with melanoma in our study, though the individual odds ratios appear to be somewhat attenuated relative to the magnitudes typically observed in the literature. CONCLUSIONS: Patients with a second or subsequent primary cancer of a single type represent a potentially valuable and under-utilized resource for the study of cancer aetiology