Cancer In First-degree Relatives Research Articles

Association between melanocytic nevi and risk of breast diseases: The French E3N prospective cohort.

While melanocytic nevi have been associated with genetic factors and childhood sun exposure, several observations also suggest a potential hormonal influence on nevi. To test the hypothesis that nevi are associated with breast tumor risk, we explored the relationships between number of nevi and benign and malignant breast disease risk. We prospectively analyzed data from E3N, a cohort of French women aged 40-65 y at inclusion in 1990. Number of nevi was collected at inclusion. Hazard ratios (HRs) for breast cancer and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models. Associations of number of nevi with personal history of benign breast disease (BBD) and family history of breast cancer were estimated using logistic regression. Over the period 15 June 1990-15 June 2008, 5,956 incident breast cancer cases (including 5,245 invasive tumors) were ascertained among 89,902 women. In models adjusted for age, education, and known breast cancer risk factors, women with "very many" nevi had a significantly higher breast cancer risk (HR = 1.13, 95% CI = 1.01-1.27 versus "none"; ptrend = 0.04), although significance was lost after adjustment for personal history of BBD or family history of breast cancer. The 10-y absolute risk of invasive breast cancer increased from 3,749 per 100,000 women without nevi to 4,124 (95% CI = 3,674-4,649) per 100,000 women with "very many" nevi. The association was restricted to premenopausal women (HR = 1.40, ptrend = 0.01), even after full adjustment (HR = 1.34, ptrend = 0.03; phomogeneity = 0.04), but did not differ according to breast cancer type or hormone receptor status. In addition, we observed significantly positive dose-response relationships between number of nevi and history of biopsy-confirmed BBD (n = 5,169; ptrend<0.0001) and family history of breast cancer in first-degree relatives (n = 7,472; ptrend = 0.0003). The main limitations of our study include self-report of number of nevi using a qualitative scale, and self-reported history of biopsied BBD. Our findings suggest associations between number of nevi and the risk of premenopausal breast cancer, BBD, and family history of breast cancer. More research is warranted to elucidate these relationships and to understand their underlying mechanisms.

How is the increased risk of colorectal cancer in first-degree relatives of patients communicated?

Compared with the general population, first-degree relatives (FDRs) of colorectal cancer (CRC) patients have a two-fold to four-fold higher risk of developing CRC. Little data is available regarding communication between doctors and CRC patients about risk to FDRs. We aimed to evaluate CRC patients' knowledge of FDRs' increased CRC risk, and FDRs' knowledge of this risk and adherence to CRC screening. In this retrospective, single-center, population-based observational study, patients aged 18-80 years who underwent surgery for CRC between January 2005 and May 2010 were asked to complete a questionnaire. A questionnaire sent to the patients' FDRs (siblings and children) asked whether they had been advised to undergo any CRC screening examination, whether they had done so, and if so, when initiated and by whom. Main outcome measurements were: CRC patients' and their FDRs' information status regarding the FDRs' increased CRC risk and screening status. Of 343 index patients (390 contacted, 47 deceased/moved), 134 replied to the survey (39.1% response rate). Among index patients, 82.1% (110/134) were informed about FDRs' increased CRC risk. This information was provided mainly by gastroenterologists and general practitioners (65.7 and 28.4%, respectively). Among FDRs, 85.1% (143/168) were informed about their increased CRC risk, but 69% did not undergo a screening colonoscopy. Among the FDRs more than 50 years of age, 40.8% did not undergo a screening colonoscopy. In Switzerland, CRC patients and their FDRs are well informed about FDRs' increased CRC risk. However, the majority of FDRs do not undergo the recommended CRC screening.

Clinical features of young patients (below age 40) with pancreatic ductal adenocarcinoma.

199 Background: The median age of pancreatic ductal adenocarcinomas (PDAC) patients is approximately 70 years. We investigated clinical features of PDAC occurring in young patients (&lt; 40 years) in order to determine if any difference exists in comparison to older patients. Methods: We reviewed a single-institution database of 785 patients with pathologically proven PDAC between 2001 and 2012. We examined the clinical features in patients with PDAC below 40 years of age and compared it to those in older patients (≥ 40 years). Results: Of these 785 patients, a total of 10 patients (1.3%) under the age of 40 were identified, with a range of 28 to 37 years. Clinical features in young and older patients have been summarized (table). There are no differences between groups in terms of sex, smoking, tumor location, UICC stage, a family history of PDAC and a family history of any cancer. In the young patients group, three of them were diagnosed with localized diseases, two others with locally advanced diseases, and five others with metastatic diseases. Two of the three patients with localized diseases underwent curative operation. The five patients with metastatic diseases received chemotherapy, and only one patient achieved a partial response treated with FOLFIRINOX regimen. Two of the patients were long-term survivors, having survived over three years. Six of the patients had a family history of other cancers in first-degree relatives. Unexpectedly and most importantly, only one patient had a family history of PDAC. Conclusions: Cases of patients with PDAC below 40 years of age are rare. The clinical features in young patients were generally similar to those in older patients. Almost all young patients had no family history of PDAC, which suggests that hereditary genetic factors have a weak relationship with cases of onset of PDAC at a young age in Japan. [Table: see text]

Abstract P5-13-05: Richer and wiser: Factors correlated with chemoprevention use in the United States

Abstract Introduction: Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer by up to 50%, yet the uptake of these agents remains poor. We sought to determine factors associated with chemoprevention uptake in a nationally representative sample. Methods: The National Health Interview Survey (NHIS) is a population-based survey conducted annually by the CDC and is designed to be representative of the non-institutionalized civilian population in the United States. We utilized data from the 2010 NHIS cancer supplement to determine factors associated with chemoprevention uptake in women ≥ 35 years of age. Statistical analyses were conducted using SUDAAN software. Results: In 2010, 10,959 women ≥ 35 years of age were surveyed, representing 83,377,082 people in the population. Of these, 0.21% reported taking chemoprevention, using either tamoxifen or raloxifene. On bivariate analyses, factors correlating with chemoprevention uptake included age, race/ethnicity, education, insurance, income and geographic region (see Table). Interestingly, MRI use, family history of premenopausal breast cancer in first degree relatives, and personal risk perception were not associated with chemoprevention use. On multivariate analysis, education and income remained independent predictors of chemoprevention use. Conclusion: Approximately 0.2% of women take chemoprevention. It is concerning that sociodemographic factors of education and income are independent predictors of the use of chemopreventive agents for breast cancer, while risk perception and family history do not seem to correlate with uptake rates. These findings are a call to action for improved education and counseling of those who are at greatest risk, and highlight potential disparities in access to appropriate chemoprevention across all sociodemographic groups. Bivariate and Multivariate Analyses of Factors Correlated with Chemoprevention UptakeFactorBivariate AnalysisMultivariate Analysis Chemoprevention (%)No Chemoprevention (%)p-valueOR (95% CI)p-valueAge 0.0481 0.1087&amp;lt; 40 yr3.2211.93 1.00 40-49 yr5.8726.11 0.78 (0.05-12.44) 50-59 yr11.7024.88 1.44 (0.10-21.43) 60-69 yr23.8218.54 3.15 (0.32-31.41) 70-79 yr44.4110.77 8.62 (0.78-94.75) 80+ yr10.997.77 1.53 (0.10-23.66) Race/ethnicity 0.0006 0.8372Hispanic3.9011.06 00.81 (0.11-5.85) White96.1071.63 1.00 Black011.80 - Asian04.61 - Other00.89 - Education 0.0371 &amp;lt;0.0001&amp;lt; Grade 127.1214.15 1.00 High School25.8627.73 1.86 (0.35-9.75) Some college/Assoc21.4229.97 1.85 (0.36-9.45) Bachelors15.5917.49 1.44 (0.13-16.35) Masters11.708.37 3.23 (0.41-25.14) Prof/Doctorate18.302.28 25.22 (4.30-147.87) Insurance 0.0002 0.0686Not covered012.44 - Medicare72.6129.38 1.00 Medicaid3.224.50 2.38 (0.22-26.15) Military01.74 - Private24.1751.94 0.28 (0.06-1.26) Income 0.0005 0.0306&amp;lt;$35K32.3934.53 1.00 $35K-$74,99926.1131.53 0.97 (0.21-4.42) $75K-$99,999012.08 - $100K+41.6021.86 3.78 (0.94-15.22) Region 0.0441 0.1649Northeast27.9318.62 1.00 Midwest31.6022.88 0.92 (0.32-2.64) South34.4935.66 0.65 (0.21-2.04) West5.9822.84 0.16 (0.03-0.86) Oophorectomy40.1115.160.08132.17 (0.77-6.09)0.1404MRI use2.315.170.2597 Family History2.315.130.2601 Risk Perception 0.1451 High41.5212.50 Average25.8947.49 Low32.5940.01 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-05.

BRCA1 and BRCA2 Germline Mutations Are Frequently Demonstrated in a Pancreatic Ductal Adenocarcinoma Cohort Referred For Genetic Testing

Purpose: Ten percent of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition including the BRCA1/2 germline mutations. Patients with a prior diagnosis of PDAC were referred to our high risk pancreatic prevention and genetics program and offered genetic counseling and if appropriate, evaluation for possible predisposing mutations. Our aim was to determine the prevalence of BRCA 1/2 germline mutations in this PDAC cohort. Methods: Patients were referred to our program after a diagnosis of PDAC. After meeting with a clinician and genetic counselor, patients underwent genetic testing for BRCA1/2 mutations (multisite 3 for Ashkenazi Jewish (AJ) patients and comprehensive testing for all others). Results: Thirty-two patients underwent BRCA1 and BRCA2 genetic testing following a diagnosis of PDAC. The mean age was 60.2, 59.3% male, 81.3% AJ, 100% Caucasian. Five of 24 patients were demonstrated to have AJ founder mutations (two BRCA1, three BRCA2), and 2 of 8 patients had a BRCA2 mutation on comprehensive testing. The diagnostic yield was 7/32 (21.8%). The mean age of PDAC diagnosis amongst BRCA1/2 mutation carriers was 54.5 years (range 48-66, SD 8.55) compared to 61.5 years (range 35-82, SD 11.97, p=.19) for those without a mutation. None of the PDAC patients who tested positive for BRCA1/2 mutations had a history of tobacco use or heavy alcohol use. Only two patients had a first degree relative with a BRCA1/2 related cancer. None of the seven BRCA1/2 mutation carriers had any first- or second degree relatives with PDAC, although one 49 year-old patient with a BRCA2 mutation had three third-degree relatives with PDAC. Conclusion: We demonstrate a high diagnostic yield of 21.8% for BRCA1 and BRCA2 mutations in a cohort of PDAC patients referred to our pancreatic prevention and genetics program. Those who tested positive for BRCA1/2 mutations had a trend towards a younger age at PDAC diagnosis. There was a notable absence of PDAC and very few BRCA related cancers in first degree relatives of BRCA1/2 carriers. Even in the absence of a family history of breast and ovarian cancer, especially in the AJ population, clinical BRCA1 and BRCA2 testing for risk stratification and family counseling should be considered in patients with a personal or family history of PDAC.

Family history of cancer and the risk of cancer: a network of case–control studies

BackgroundThe risk of many cancers is higher in subjects with a family history (FH) of cancer at a concordant site. However, few studies investigated FH of cancer at discordant sites. Patients and methodsThis study is based on a network of Italian and Swiss case–control studies on 13 cancer sites conducted between 1991 and 2009, and including more than 12 000 cases and 11 000 controls. We collected information on history of any cancer in first degree relatives, and age at diagnosis. Odds ratios (ORs) for FH were calculated by multiple logistic regression models, adjusted for major confounding factors. ResultsAll sites showed an excess risk in relation to FH of cancer at the same site. Increased risks were also found for oral and pharyngeal cancer and FH of laryngeal cancer (OR = 3.3), esophageal cancer and FH of oral and pharyngeal cancer (OR = 4.1), breast cancer and FH of colorectal cancer (OR = 1.5) and of hemolymphopoietic cancers (OR = 1.7), ovarian cancer and FH of breast cancer (OR = 2.3), and prostate cancer and FH of bladder cancer (OR = 3.4). For most cancer sites, the association with FH was stronger when the proband was affected at age <60 years. ConclusionsOur results point to several potential cancer syndromes that appear among close relatives and may indicate the presence of genetic factors influencing multiple cancer sites.

Frequency of Cancer in First-Degree Relatives of Patients with Cleft Lip and/or Palate in the Brazilian Population

Congenital malformations and cancer may share common etiological factors and the association between nonsyndromic cleft lip and/or palate (NSCL/P) and cancers has been observed in different studies. The objective of this study was to evaluate the frequency of cancer in relatives of patients with NSCL/P. This investigation was a cross-sectional, case-controlled study, evaluating 358 patients with NSCL/P treated at a Referral Center for craniofacial deformities (case group) and 358 patients without craniofacial alterations (control group). Information concerning the gender, age and family history of cancer in first-degree relatives for both groups was obtained. The frequency of cancer was 6.4% (n=46) in the studied population, with 18 subjects in the case group (5%) and 28 (7.8%) in control. In both groups, the most frequently reported cases were those of breast, colorectal, stomach, prostate and uterus cancers, but there was no association between the two groups. There was no association with a family history of cancer among the first-degree relatives (odds ratio=0.62; 95% IC: 0.34 to 1.15), neither when the analysis was made by type of cancer. In conclusion, both epidemiological and genetic studies have suggested common etiological factors for NSCL/P and cancer. However, in this population-based study, no association between cancer and NSCL/P could be confirmed.

Abstract 4836: Gene and environment interactions of height and selected candidate SNPs in prostate cancer: results from the PRACTICAL consortium.

Abstract Abstract We analysed data from the PRACTICAL (PRostate cancer AssoCiation group To Investigate Cancer Associated aLterations in the genome) consortium on height and over 160 selected candidate SNP's predominantly in growth factor pathways. 12 case-control and nested case-control studies provided epidemiological data including information on height (5064 cases and 3074 controls). We present results here on the associations of height and the selected SNPs on prostate cancer risk and on their interaction. The mean height was 176.3 cm in cases and 176.9 cm in controls. Results of meta-analysis of the association between height and prostate cancer risk indicated study homogeneity and thus data were pooled to obtain pooled odds ratios (ORs). Mean and standard deviation (sd) was used to define subjects as normal (mean ±sd), short (&amp;lt;mean- sd) and tall stature (&amp;gt;mean+sd). Analyses were adjusted for age and family history of prostate cancer in first degree relatives. Height was not significantly associated with risk in shorter and taller men compared to men with a normal height: OR of 1.08 (95%CI 0.91-1.29) and 0.98 (95% CI 0.84-1.15), respectively. For the genotyping results, a log additive model was used to assess the associations between the SNPs and prostate cancer risk and the results showed that 3 SNPs (rs1509461, OR 1.09 (95%CI 1.01-1.17) in the GHR gene, rs2946834 OR 1.13 (95%CI 1.04-1.22) and rs1520220 OR 1.10 (95%CI 1.00 -1.22) in the IGF-1 gene) were significantly associated with prostate cancer after adjusting for age and family history of prostate cancer, all P-values &amp;lt;0.05. For gene and environment interaction analyses, the synergy factor estimation and an empirical Bayes method were used. Only one SNPs showed a marginal negative interaction with height in tall statured men (rs1520220 in the IGF-1 gene) with a synergy factor of 0.76, 95% CI 0.59-0.99. In summary, height did not show any significant association with prostate cancer risk. Three candidates SNP's showed modest increased risks. Overall there was little indication of an effect of height and/or its interaction with the candidate SNPs. Citation Format: Kenneth R. Muir, Artitaya Lophatananon, Rosalind Eeles, Graham G. Giles, Zsofia Kote Jarai, Richard M. Martin, Jong Park, Gianluca Severi, Janet Standford, Fredrick Schumacher, Sarah Stewart Brown, Ruth Travis, Fredrik Wiklund, Douglas Easton, The PRACTICAL CONSORTIUM. Gene and environment interactions of height and selected candidate SNPs in prostate cancer: results from the PRACTICAL consortium. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4836. doi:10.1158/1538-7445.AM2013-4836 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries

BackgroundWe aimed to estimate lifetime cumulative risk of thyroid cancer (CRTC) in first-degree relatives of patients with non-medullary thyroid cancers (NMTC), including papillary (PTC)/follicular/oxyphilic/anaplastic thyroid carcinoma, by histology and age...

Clinical Factors Related with Helicobacter Pylori Infection - Is there an Association with Gastric Cancer History in First-Degree Family Members?

The aim of this study was to assess clinical factors associated with Helicobacter pylori positivity and to evaluate the incidence of gastric carcinoma in first-degree family members of infected patients. A total of 580 patients (mean age:38±17) with gastrointestinal complaints underwent C-14 urea breath test (UBT). Patients were grouped as: Group-1, untreated patients (n:384); and Group-2, patients who previously treated with eradication triple therapy (n:196). C-14 UBT was performed 1-2 months after the completion of eradication therapy. Associations of H pylori positivity with age, gender, ABO and Rhesus groups, smoking, dietary habits, and history of gastric cancer in first-degree family members were evaluated. The frequency of H pylori positivity was significantly higher in group-1 (58%) compared to group-2 (20%), p=0.001. There were no correlations between H pylori positivity and age, gender, ABO groups, Rhesus subgroups, smoking and dietary habits in both patient groups. The frequency of gastric cancer in family members was significantly higher in patients with H pylori infection among group-1, compared to infected patients among group-2 (56% vs. 28.6% respectively, p=0.03). We observed a significant association between H pylori positivity and the presence of gastric cancer in first-degree relatives of group-1 patients. Our results provide some confirmation of the presence of a link between gastric cancer development and H pylori. C-14 UBT is a sensitive, reliable and a widely recommended test for the detection of H pylori infection and recurrence. We suggest that detection and eradication of H pylori may contribute to a reduced risk of gastric cancer in the family members of infected patients.

Risk factors for young-onset colorectal cancer

We investigated risk factors for colorectal cancer in early-onset cancers, to provide quantitative estimates for major selected risk factors. We analyzed data from three Italian and Swiss case-control studies conducted between 1985 and 2009, including 329 colorectal cancer cases and 1,361 controls aged ≤45 years. We computed odds ratios (ORs) from unconditional logistic regression models, adjusted for major confounding factors. The OR of young-onset colorectal cancer was 4.50 for family history of colorectal cancer in first-degree relatives, the association being higher in subjects with affected siblings (OR 11.68) than parents (OR 3.75). The ORs of young-onset colorectal cancer were 1.56 for ≥14 drinks/week of alcohol, 1.56 for the highest tertile of processed meat, 0.40 for vegetables, 0.75 for fruit, and 0.78 for fish intake. Among micronutrients, the ORs were 0.52 for β-carotene, 0.68 for vitamin C, 0.38 for vitamin E, and 0.59 for folate. No significant associations emerged for physical activity, overweight, and diabetes. This study-the largest on young-onset colorectal cancer-confirms that several recognized risk factors for colorectal cancer are also relevant determinants of young-onset colorectal cancer. Family history of colorectal cancer in particular is a stronger risk factor in young subjects, as compared to middle age and elderly ones.

Abstract 66: Genetic predictors of DNA repair capacity in melanoma patients: A genome-wide approach.

Abstract Cutaneous melanoma (CM) is the most serious form of skin cancer. DNA repair has been implicated in the etiology of CM in patients of xeroderma pigmentosum (XP), an autosomal recessive genetic disorder of DNA repair. We have reported that reduced cellular DNA repair capacity (DRC, as assessed by an in vitro lymphocyte-based assay) for removing UV-induced DNA damage is an independent risk factor for sporadic CM and may contribute to susceptibility to sunlight-induced CM in the general population. Recently, we completed a genome-wide association study (GWAS) of melanoma and we also have data on DRC phenotype measured as luciferase activity in the in vitro host-cell reactivation assay using study subjects' lymphocytes for 1042 CM patients. The life-style questionnaire data are also available for these patients included in the GWAS. This is a unique study population and opportunity for us to identify genetic predictors of DRC in CM patients using a genome-wide approach. We found that the DRC varies 6 folds among 1042 CM patients and that the history of sunburn modified the DRC levels. However, we did not find the significant difference within categories of other demographic, exposure and clinical factors including age, sex, smoking and drinking status, the presence of moles and dysplastic nevi, family history of any cancer in first-degree relatives, eye color, hair color, skin color, freckling in the sun as a child, tanning ability, tumor stage, thickness, clark level, ulceration and anatomic site. We applied a generalized linear model with SNPs as predictors and DRC (a continuous variable) as the outcome. The covariates of age, sex, DRC assay-related variables were adjusted in the model. Several suggestive loci contributing to the DRC phenotype have been identified at the significance level of 10−5, including rs1799787 (intron) and rs1799793 (codon 312) in ERCC2/XPD in all CM patients, and rs12342322 near RASEF in 931 CM patients with stage I – IV. The results indicate that DRC phenotype is genetically determined by the genes involved in the nucleotide excision repair pathway and that newly identified SNPs may help understand the underlying mechanism in DRC's role in CM initiation and progression [This work was supported by National Institute of Health grants R01CA100264 (Q. Wei), P50CA093459 (E. Grimm), and P30 CA016672 (The University of Texas M. D. Anderson Cancer Center)]. Citation Format: Li-E Wang, Hongliang Liu, Jeffrey E. Gershenwald, Victor G. Prieto, Elizabeth A. Grimm, Jeffery E. Lee, Christopher I. Amos, Qingyi Wei. Genetic predictors of DNA repair capacity in melanoma patients: A genome-wide approach. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 66.

Risk factors for multiple myeloma: A hospital-based case–control study in Northwest China

BackgroundThe distinctive racial/ethnic and geographic distribution of multiple myeloma (MM) suggests that both family history and environmental factors may contribute to its development. MethodsA hospital-based case–control study consisting of 220 confirmed MM cases and 220 individually matched patient controls, by sex, age and hospital was carried out at 5 major hospitals in Northwest China. A questionnaire was used to obtain information on demographics, family history, and the frequency of food items consumed. ResultsBased on multivariate analysis, a significant association between the risk of MM and family history of cancers in first degree relatives was observed (OR=4.03, 95% CI: 2.50–6.52). Fried food, cured/smoked food, black tea, and fish were not significantly associated with the risk of MM. Intake of shallot and garlic (OR=0.60, 95% CI: 0.43–0.85), soy food (OR=0.52, 95% CI: 0.36–0.75) and green tea (OR=0.38, 95% CI: 0.27–0.53) was significantly associated with a reduced risk of MM. In contrast, intake of brined vegetables and pickle was significantly associated with an increased risk (OR=2.03, 95% CI: 1.41–2.93). A more than multiplicative interaction on the decreased risk of MM was found between shallot/garlic and soy food. ConclusionOur study in Northwest China found an increased risk of MM with a family history of cancer, a diet characterized by low consumption of garlic, green tea and soy foods, and high consumption of pickled vegetables. The effect of green tea in reducing the risk of MM is an interesting new finding which should be further confirmed.

Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers

The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper-Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.

Risk factors for primary lung cancer among never smokers by gender in a matched case–control study

Lung cancers that occur in never smokers differ from those that occur in smokers. We performed an analysis of potential epidemiological risk factors for lung cancer among never smokers. In this hospital-based matched case-control study, all 1,540 matched case-control pairs were Han Chinese in Taiwan. The data on demographic characteristics, smoking habit, exposure to environmental tobacco smoke, medical history of lung diseases, family history of lung cancer, and female characteristics were collected from a structured questionnaire. A multiple conditional logistic regression was used to estimate odds ratios and 95% confidence intervals after adjusting for possible confounders. Overall, several epidemiological factors of lung cancer in never smokers were different between males and females. For the female population, subjects who were exposed to environmental tobacco smoke (OR=1.39, 95% CI=1.17-1.67) with a history of pulmonary tuberculosis and with family history of lung cancer in first-degree relatives (OR=2.44, 95% CI=1.79-3.32) had higher risk of lung cancer, while subjects with a history of hormone replacement therapy and using fume extractors for those who cooked were protective. For the male population, only subjects with family history of lung cancer in first-degree relatives (OR=2.77, 95% CI=1.53-5.01) were significantly associated with risk of lung cancer. This study provides insights about the epidemiological factors of lung cancer in never smokers, adding to existing evidence that family history of lung cancer and environmental tobacco smoke may moderate lung cancer risk.

Functional single-nucleotide polymorphisms in the BRCA1 gene and risk of salivary gland carcinoma

Polymorphic BRCA1 is a vital tumor suppressor gene within the DNA double-strand break repair pathways, but its association with salivary gland carcinoma (SGC) has yet to be investigated. In a case-control study of 156 SGC patients and 511 controls, we used unconditional logistical regression analyses to investigate the association between SGC risk and seven common functional single-nucleotide polymorphisms (A1988G, A31875G, C33420T, A33921G, A34356G, T43893C and A55298G) in BRCA1. T43893C TC/CC genotype was associated with a reduction of SGC risk (adjusted odds ratio=0.55, 95% CI: 0.38-0.80, Bonferroni-adjusted p=0.011), which was more pronounced in women, non-Hispanic whites, and individuals with a family history of cancer in first-degree relatives. The interaction between T43893C and family history of cancer was significant (p=0.009). The GATGGCG and AACAACA haplotypes, both of which carry the T43893C minor allele, were also associated with reduced SGC risk. Our results suggest that polymorphic BRCA1, particularly T43893C polymorphism, may protect against SGC.

Family history of malignant and benign thyroid diseases and risk of thyroid cancer: a population-based case–control study in New Caledonia

Exceptionally high incidence rates of thyroid cancer have been observed in New Caledonia, particularly in Melanesian women, but familial aggregation of thyroid diseases in this population is unknown. We study the association between family history of malignant or benign thyroid diseases and non-medullary thyroid cancer in this country. We conducted a population-based case-control study including 332 cases with papillary or follicular carcinoma diagnosed in 1993-1999 and 412 controls, matched by sex and 5-year age-group. Thyroid cancer was associated with a history of thyroid cancer in first-degree relatives (odds ratio (OR), 3.2; 95% CI, 1.6-6.2) and with a family history of multinodular goiter (OR, 3.6; 95% CI, 1.9-7.0). The ORs did not change by age at diagnosis and with the number of affected relatives. The study provides evidence that the familial component of thyroid cancer is particularly strong in men. Thyroid cancer was not associated with a family history of thyroid diseases in Melanesians from the Loyalty Islands, the area with the highest incidence rates for thyroid cancer, possibly indicating a high frequency of genetic susceptibility variants and lack of genetic variation in this population subgroup. Overall our findings confirm an elevated risk of thyroid cancer in individuals with a family history of malignant or benign thyroid diseases, particularly in Melanesians where familial aggregation of thyroid cancer had never been investigated before. The study of genetic variants in candidate susceptibility genes for thyroid cancer may help clarifying the absence of an association in the subgroup of Melanesians from the Loyalty Islands.

Combined effects of E2F1 and E2F2 polymorphisms on risk and early onset of squamous cell carcinoma of the head and neck

Deregulated expression of most members of the E2F family has been detected in many human cancers. We examined the association of common single nucleotide polymorphisms (SNPs) of E2F transcription factors 1 and 2 (E2F1 and E2F2) with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1,096 SCCHN patients and 1,090 cancer-free controls. We genotyped 10 selected SNPs in E2F1 and E2F2, including those at the near 5'-untranslated region (UTR), microRNA (miRNA)-binding sites at the near 3'-UTR and tagSNPs according to bioinformatics analysis. Although none of the selected SNPs alone was significantly associated with risk of SCCHN, there was a statistically significantly increased risk of SCCHN associated with the combined risk genotypes (i.e., rs3213182 AA, rs3213183 GG, rs3213180 GG, rs321318121 GG, rs2742976 GT+TT, rs6667575 GA+AA, rs3218203 CC, rs3218148 AA, rs3218211 CC, and rs3218123 GT+TT). Compared with those with 0-4 risk genotypes, an increased risk was observed for those who carried 5-8 risk genotypes (adjusted OR = 1.04; 95% CI = 0.86-1.26) and 9-10 risk genotypes (adjusted OR = 1.62; 95% CI = 1.14-2.30) in a dose-response manner (P = 0.045). Furthermore, the joint effect was more pronounced among patients with oropharyngeal cancer, younger adults (≤57 yr old), men, non-smokers, non-drinkers, and individuals with family history of cancer in first-degree relatives. Additionally, we also observed that those with 5-10 risk genotypes had an earlier SCCHN onset than those with 0-4 risk genotypes, particularly for non-smokers and/or non-drinkers. We concluded that E2F1 and E2F2 genetic variants may jointly play important roles in head and neck carcinogenesis.

Evaluation of apoptosis along with BCL-2 and Ki-67 expression in patients with intestinal metaplasia

The primary aim is to compare individuals with intestinal metaplasia (IM), chronic active gastritis (CAG), and normal gastric mucosa (NGM) in terms of apoptosis, proliferation, and Bcl-2 expression. The secondary aim is to determine whether these parameters are different between patients with and without gastric cancer in first-degree relatives. We enrolled 106 patients whose histopathological results were consistent with IM (n: 42), CAG (n: 51), or NGM (n: 13). Antral biopsies were immunohistochemically stained for Bcl-2 and Ki-67 expression. Apoptosis was detected using TUNEL assay. While no significant difference was determined between three groups with regard to apoptosis and Bcl-2 expression (p>0.05), Ki-67 expression was significantly higher in the IM group when compared with the CAG and NGM groups (29.90±22.87 vs. 18.18±16.22 vs. 18.54±20, respectively; p=0.012). Helicobacter pylori was determined to increase apoptosis (49.3% vs. 25.7%, p<0.05), nevertheless, it had no significant effect on proliferation and Bcl-2 expression. Bcl-2 and Ki-67 expression and apoptosis were not different among patients with and without a history of gastric cancer in first degree relatives. Although intestinal metaplasia cases demonstrate an increase in proliferation, no elevation is observed in apoptosis. This can be an important factor in the progression to gastric cancer.

Polyposis syndromes– what to do when genotyping seems not informative

identifiable. The new NHMRC guidelines out for public comment recommend follow up of patients: As multiplicity of adenomas is a strong determinant of risk of metachronous advanced and non advanced neoplasia, follow up should be at twelve months for those with five or more adenomas, and sooner in those with ten or more adenomas. The risk of colorectal cancer to relatives of patients with multiple adenomas is related to the number of adenomas in the proband – outside FAP and MYH. Therefore, as distinct from patients with small numbers of adenomas, relatives of patients with larger numbers (10 +) should be offered colonoscopy at an age relative to the age of presentation of the proband. The interval is not well defined but I would suggest 5 yearly. Hyperplastic polyposis HPS has no defined genetic basis as yet. These patients are at high risk of colorectal cancer, either through the serrated pathway or through their concurrent adenomas. Two yearly colonoscopy is advised. Although the mode of inheritance is also poorly defined, it is thought it may be recessive. Therefore siblings are offered surveillance, though usually not expected to be found with HPS themselves. There is however, a high risk of colorectal cancer in first degree relatives (siblings or parents) so colonoscopy should be offered to these relatives 5 yearly. Low level mosaicism, gonadal mosaicism, somatic mosaicism Somatic mosaicism is now well described in FAP, with respect to the APC gene; cases of multiple adenomatous polyposis may therefore be found with no germline (lymphocytic) APC mutati on. We have been searching for the same APC mutation in multiple polyps, and in