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Hereditary breast and ovarian cancer syndrome (HBOC) related to the breast cancer (BRCA) genes initially was identified in families with the use of genetic linkage analysis.1–3 Since then, over 5000 different mutations in these genes have been identified that are inherited in an autosomal-dominant fashion and are responsible for approximately 5% to 10% of breast cancer diagnoses.4 Carriers of this mutation have an elevated risk of developing both breast and/or ovarian cancer, and a meta-analysis estimate of the lifetime risk of breast cancer was 47% to 66% in BRCA1 carriers and 40% to 57% in the BRCA2 carriers, and the risk of developing ovarian cancer was 35% to 46% and 13% to 23%, respectively, in the same analysis.5 One of the major risk factors for HBOC is the development of breast cancer at a very young age, Thus, the National Comprehensive Cancer Network (NCCN) guidelines panel has recommend initiating screening at ages 20 to 25 years, or 5 to 10 years earlier than the youngest age at diagnosis in the family.6 Implementing screening techniques is meant to identify cancers at the earliest time possible; therefore, estimating the onset of disease is vital in timing the initiation of screening and interventions. Anticipation has been described as a phenomenon observed in inherited diseases such as Fragile X syndrome and Huntington disease, in which the disease occurs at younger ages or with increased severity of disease in subsequent generations.7,8 The cause of this anticipation has been identified as DNA instability, such as nucleotide repeats that change in length in subsequent generations, altering the phenotype of the disease. However, changes in disease phenotype in subsequent generations also have been identified in other disorders, such as in colon cancer, Alzheimer disease, and diabetes.9,10 With the increase in BRCA1 and BRCA2 testing, there also has been an increase in families being evaluated and screened for HBOC. There have been several reports of anticipation in breast cancer. To date, these reports have been based on very small cohorts; those studies indicated an earlier age at diagnosis and examined the absolute differences between matched pairs. Dagan and Gershoni-Baruch reported a statistically significant difference of approximately 4 years in BRCA2 mutation carriers and a statistically nonsignificant numerical difference in BRCA1 carriers.11 In addition, Peixoto et al and Paltiel et al also observed similar patterns of earlier age of diagnosis for subsequent generations in breast cancer registries.12,13 When discussing appropriate screening interventions for women with a known deleterious BRCA1 or BRCA2 mutation, potential interventions include clinical breast examination, magnetic resonance imaging, and mammography.14 Evaluating for patterns of inheritance like anticipation in families with known deleterious BRCA mutations may help promote understanding of these genes and provide further insight into the timing of screening initiation and starting other interventions. The objective of the current analysis was to evaluate any trends in age at diagnoses in families with known deleterious BRCA mutations at a single institution to add to the growing evidence of genetic anticipation in patients with HBOC. We evaluated families who were referred to the Clinical Cancer Genetic Program at our institution and analyzed age at diagnosis across 2 generations.

BACKGROUND: Overall, Latinas are more likely to be diagnosed with a more advanced stage of breast cancer and are 20% more likely to die of breast cancer than non-Hispanic white women. It is estimated that from 2003 to 2006, $82.0 billion in direct medical care expenditures, in addition to 100,000 lives annually, could be saved by eliminating health disparities experienced by Latinos and increasing the use of up to 5 preventive services in the United States. An additional 3700 lives could be saved if 90% of women aged ≥40 years were recently screened for breast cancer. METHODS: The authors examined the risk for breast cancer in a case-control, population-based sample of Mexican-origin women in Harris County, Texas (n = 714), where the rates of breast cancer mortality for Latina women have doubled since 1990. RESULTS: Half of breast cancer cases (n = 119) were diagnosed in women aged

BACKGROUND. The p53 tumor suppressor protein homolog p73 can be inactivated by oncoprotein E6 of human papillomavirus (HPV). Variation in p73 may alter the interaction between the E6 protein and p73 and, thus, alter the risk for HPV-associated carcinogenesis. It is believed that the p73 G4C14-to-A4T14 polymorphism affects p73 function by altering gene expression; however, whether that polymorphism also alters the risk of HPV type 16 (HPV-16)-associated squamous cell carcinoma of the oropharynx (SCCOP) is unknown. METHODS. The current case-control study included a case group of 188 non-Hispanic white patients with newly diagnosed SCCOP and a control group of 349 healthy individuals. Logistic regression analyses were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for cases and controls stratified by p73 genotype, age, sex, smoking status, alcohol use, and HPV-16 status. The effects of p73 genotypes on the risk of HPV-16-associated SCCOP were explored with further stratification by smoking and drinking status. RESULTS. HPV-16 seropositivity was associated with an increased risk of SCCOP (adjusted OR, 5.98; 95% CI, 3.89-9.20), especially among never smokers (adjusted OR, 13.8; 95% CI, 5.91-32.1), never drinkers (adjusted OR, 14.9; 95% CI, 5.24-42.4), and individuals with p73 variant genotypes (GC/AT and AT/AT; adjusted OR, 7.96; 95% CI, 3.83-16.5). Moreover, the risk of HPV-16-associated SCCOP for individuals who had p73 variant genotypes was particularly high in never smokers and never drinkers. CONCLUSIONS. The p73 G4C14-to-A4T14 polymorphism may modulate the risk of HPV-16-associated SCCOP, and the p73 variant genotypes may be markers of genetic susceptibility to HPV-16-associated SCCOP, particularly in never smokers and never drinkers. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND. The familial risk of bladder cancer (BC) is not well understood and, to date, little attention has been paid to the joint effect of smoking and family history in modifying the risk of BC. The authors investigated the role of family history in association with the risk of BC. METHODS. Case and control probands were identified as part of an on-going BC case–control study. The relative risk associated with a family history of BC was estimated. RESULTS. In total, 713 cases and 658 controls were included. In a case–control analysis, compared with individuals who never smoked and who had no family history of BC, probands who had smoked and who also had a positive family history were at 5.31-fold increased risk of BC (P for interaction = .04). The 713 case probands and the 658 controls reported 5160 and 4816 first-degree relatives, respectively. Compared with never-smoking relatives who had probands diagnosed with BC at an older age (age >65 years), ever-smoking relatives who had probands diagnosed at a younger age (ages 40–65 years) showed a 6.89-fold (95% confidence interval, from 2.25-fold to 21.12-fold) increased risk. Similar results were obtained for the joint effects of family history of BC and smoking. CONCLUSIONS. The current results indicated that a positive family history of BC may have interacted with smoking habits to increase the risk of BC in the study population. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND The objective of this study was to evaluate the effects of polymorphisms in 2 genes in the glutathione S-transferase (GST) family and the mutagen-sensitivity phenotype on the risk of second primary tumors (SPTs) in patients with previously diagnosed early-stage head and neck squamous cell carcinoma. Data were available for 303 patients who were enrolled in a placebo-controlled chemoprevention trial of low-dose 13-cis-retinoic acid to reduce the occurrence of SPTs. METHODS A Cox proportional hazards model and survival tree analysis were used to evaluate the association between specified genetic variations and the development of SPTs. The average number of bleomycin-induced chromatid breaks per cell was used to quantify mutagen sensitivity as an individual patient's degree of sensitivity to genotoxicity. RESULTS The GST-M1 null genotype was associated with an increased risk for any SPTs (hazard ratio [HR], 1.99; 95% confidence interval [95% CI], 1.11-3.56) and for tobacco-related SPTs (HR, 2.16; 95% CI, 1.01-4.62) after adjusting for covariates. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with a statistically significant increased risk for SPTs or tobacco-related SPTs after similar adjustment. Simultaneous nonnull status for both GST genotypes was associated with a decreased risk for any SPTs (HR, 0.52; 95% CI, 0.28-0.96) and tobacco-related SPTs (HR, 0.50; 95% CI, 0.22-1.11) compared with null status for GST-M1 accompanied by nonnull status for GST-T1. CONCLUSIONS An association was observed between the development of SPTs and the GST-M1 null genotype after successful treatment for early-stage head and neck squamous cell carcinoma. The GST-T1 null genotype and bleomycin-induced chromatid breaks were not associated with an increased risk, and no significant interactions were identified. Cancer 2006. © 2006 American Cancer Society.

BACKGROUND: Although the pathogenesis of Hodgkin disease (HD) remains unknown, the results of epidemiologic studies suggest that heritable factors are important in terms of susceptibility. Polymorphisms in DNA repair genes may contribute to individual susceptibility for development of different cancers. However, to the authors' knowledge, few studies to date have investigated the role of such polymorphisms as risk factors for development of HD. METHODS: The authors evaluated the relation between polymorphisms in 3 nucleotide excision repair pathway genes (XPD [Lys751Gln], XPC [Lys939Gln], and XPG [Asp1104His]), the base excision repair XRCC1 (Arg399Gln), and double-strand break repair XRCC3 (Thr241Met) in a population of 200 HD cases and 220 matched controls. Variants were investigated independently and in combination; odd ratios (OR) were calculated. RESULTS: A positive association was found for XRCC1 gene polymorphism Arg399Gln (OR, 1.77; 95% confidence interval [95% CI], 1.16-2.71) and risk of HD. The combined analysis demonstrated that XRCC1/XRCC3 and XRCC1/XPC polymorphisms were associated with a significant increase in HD risk. XRCC1 Arg/Arg and XRCC3 Thr/Met genotypes combined were associated with an OR of 2.38 (95% CI, 1.24-4.55). The XRCC1 Arg/Gln and XRCC3 Thr/Thr, Thr/Met, and Met/Met genotypes had ORs of 1.88 (95% CI, 1.02-4.10), 1.97 (95% CI, 1.05-3.73), and 4.13 (95% CI, 1.50-11.33), respectively. XRCC1 Gln/Gln and XRCC3 Thr/Thr variant led to a significant increase in risk, with ORs of 3.00 (95% CI, 1.15-7.80). Similarly, XRCC1 Arg/Gln together with XPC Lys/Lys was found to significantly increase the risk of HD (OR, 2.14; 95% CI, 1.09-4.23). CONCLUSIONS: These data suggest that genetic polymorphisms in DNA repair genes may modify the risk of HD, especially when interactions between the pathways are considered. Cancer 2009. © 2009 American Cancer Society.

BACKGROUND: The tumor protein p73 interacts with the human papillomavirus type 16 (HPV-16) oncoproteins E6 and E7, and p73 variation may modify the interaction between p73 protein and HPV-16 oncogenic proteins and contribute to cellular malignant transformation. METHODS: In this case-case comparison study, the authors analyzed HPV-16 status in tumor specimens and genotyped the p73 G4C14-to-A4T14 polymorphism using genomic DNA from blood of 202 non-Hispanic white patients with squamous cell carcinoma of the head and neck (SCCHN). Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated in univariate and multivariable logistic regression models to examine the association between the p73 polymorphism and HPV-16 status in SCCHN. RESULTS: Compared with the p73 GC/GC genotype, the AT/AT and combined GC/AT + AT/AT variant genotypes were associated significantly with HPV-16-positive tumor status among patients with SCCHN (adjusted OR, 5.32; 95% CI, 1.32-21.4; adjusted OR, 1.91; 95% CI, 1.03-3.53, respectively). There was a significant dose-effect relation between the AT allele and HPV-16-positive tumor status in patients with SCCHN (trend test: P = .014). Moreover, the stratified analyses indicated that the association between HPV-16-positive tumor status and the combined p73 GC/AT + AT/AT genotypes was more pronounced among several subgroups of patients who were older, men, ever drinkers, and those with oropharyngeal cancer. CONCLUSIONS: The p73 polymorphism was associated with HPV-16 status in SCCHN and may serve as a marker of positive HPV-16 tumor status in patients with SCCHN, particularly those with oropharyngeal cancer. Cancer 2009. © 2009 American Cancer Society.