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Background Few studies have evaluated the relationship between CDKN2A germline pathogenic variants (GPV), transcript (p16/p14ARF) alteration, and cancer risk. Methods Standardized incidence ratios (SIRs) comparing cancer risk with the general population were calculated for 385 CDKN2A GPV carriers from 2 large cohorts (259 United States and 126 Swedish individuals) using Poisson regression; statistical significance was defined as P less than .002 (Bonferroni correction). Cumulative incidence is reported for melanoma and nonmelanoma cancer. Results Incidence was increased for melanoma (SIR = 159.8, 95% confidence interval [CI] = 132.1 to 193.2), pancreatic cancer (SIR = 24.1, 95% CI = 14.7 to 39.4), head and neck squamous cell carcinoma (SIR = 16.2, 95% CI = 9.5 to 27.6), and lung cancer (SIR = 5.6, 95% CI = 3.4 to 9.1) in GPV carriers. Similar associations were observed with p16 alteration. Combined p16 and p14ARF alteration was associated with increased incidence of esophageal cancer (SIR = 16.7, 95% CI = 5.7 to 48.9) and malignant peripheral nerve sheath tumor (SIR = 113.0, 95% CI = 16.4 to 780.9), although cancer events were limited (n Conclusion These findings highlight the impact of p16 and p14ARF alteration on cancer risk. Smoking was an important risk factor for smoking-related cancers in our study.

Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Background It is unclear whether the established association between cutaneous melanoma (CM) and lymphoid neoplasms (LNs) differs across LN subtypes. This study quantifies risk for developing CM after specific LNs and, conversely, for developing specific LNs after CM, as well as assessing clinical impact. Methods We identified a cohort of Caucasian adults (age 20-83 years) initially diagnosed with CM or LN, as reported to 17 US population-based cancer registries, 2000-2014. Standardized incidence ratios (SIRs) quantified second cancer risk. We assessed impact of second cancer development on risk of all-cause mortality using Cox regression. Results Among 151 949 one-or-more-year survivors of first primary LN, second primary CM risk was statistically significantly elevated after chronic lymphocytic leukemia/small lymphocytic lymphoma (SIR = 1.96, 95% confidence interval [CI] = 1.74 to 2.21), follicular lymphoma (SIR = 1.32, 95% CI = 1.09 to 1.58), and plasma cell neoplasms (SIR = 1.33, 95% CI = 1.07 to 1.63). Risks for these same subtypes were statistically significantly elevated among 148 336 survivors of first primary CM (SIR = 1.44, 95% CI = 1.25 to 1.66; SIR = 1.47, 95% CI = 1.21 to 1.77; SIR = 1.25, 95% CI = 1.06 to 1.47; respectively). Risk for CM was statistically significantly elevated after diffuse large B-cell lymphoma (SIR = 1.22, 95% CI = 1.02 to 1.45) and Hodgkin lymphoma (SIR = 1.75, 95% CI = 1.33 to 2.26), but the reciprocal relationship was not observed. There were no statistically significant associations between marginal zone lymphoma and CM. Among survivors of most LN subtypes, CM statistically significantly increased risk of death (hazard ratio [HR] range = 1.52, 95% CI = 1.25 to 1.85, to 2.46, 95% CI = 1.45 to 4.16). Among survivors of CM, LN statistically significantly increased risk of death (HR range = 1.75, 95% CI = 1.15 to 2.65, to 6.28, 95% CI = 5.00 to 7.88), with the highest risks observed for the most aggressive LN subtypes. Conclusions Heterogeneous associations between CM and specific LN subtypes provide novel insights into the etiology of these malignancies, with the mutual association between CM and certain LN suggesting shared etiology. Development of second primary CM or LN substantially reduces overall survival.

The chromosome 9p21 region has been implicated in the pathogenesis of multiple cancers. We analyzed 9p21 single nucleotide polymorphisms (SNPs) from eight genome-wide association studies (GWAS) with data deposited in dbGaP, including studies of esophageal squamous cell carcinoma (ESCC), gastric cancer (GC), pancreatic cancer, renal cell carcinoma (RCC), lung cancer (LC), breast cancer (BrC), bladder cancer (BC) and prostate cancer (PrC). The number of subjects ranged from 2252 (PrC) to 7619 (LC). SNP-level analyses for each cancer were conducted by logistic regression or random-effects meta-analysis. A subset-based statistical approach (ASSET) was performed to combine SNP-level P values across multiple cancers. We calculated gene-level P values using the adaptive rank truncated product method. We identified that rs1063192 and rs2157719 in the CDKN2A/2B region were significantly associated with ESCC and rs2764736 (3' of TUSC1) was associated with BC (P ≤ 2.59 × 10(-6)). ASSET analyses identified four SNPs significantly associated with multiple cancers: rs3731239 (CDKN2A intronic) with ESCC, GC and BC (P = 3.96 × 10(-) (4)); rs10811474 (3' of IFNW1) with RCC and BrC (P = 0.001); rs12683422 (LINGO2 intronic) with RCC and BC (P = 5.93 × 10(-) (4)) and rs10511729 (3' of ELAVL2) with LC and BrC (P = 8.63 × 10(-) (4)). At gene level, CDKN2B, CDKN2A and CDKN2B-AS1 were significantly associated with ESCC (P ≤ 4.70 × 10(-) (5)). Rs10511729 and rs10811474 were associated with cis-expression of 9p21 genes in corresponding cancer tissues in the expression quantitative trait loci analysis. In conclusion, we identified several genetic variants in the 9p21 region associated with the risk of multiple cancers, suggesting that this region may contribute to a shared susceptibility across different cancer types.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10(-4)), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10(-6)) and in GC was CLK2 (P = 3.02 × 10(-4)). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P5 × 10(-8), and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19-1.40) and P= 7.63 × 10(-10). An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P=5 5.75× 3 10 -8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10 -14) and rs12617313 (P = 7.48 × 10 -12), both highly correlated withrs9679290 (r 2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r 2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10 -9, per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants. Published by Oxford University Press 2011.

International audience; Genome-wide association studies have identified prostate cancer susceptibility alleles on chromosome 11q13. As part of the Cancer Genetic Markers of Susceptibility (CGEMS) Initiative, the region flanking the most significant marker, rs10896449, was fine mapped in 10 272 cases and 9123 controls of European origin (10 studies) using 120 common single nucleotide polymorphisms (SNPs) selected by a two-staged tagging strategy using HapMap SNPs. Single-locus analysis identified 18 SNPs below genome-wide significance (P< 10(-8)) with rs10896449 the most significant (P= 7.94 × 10(-19)). Multi-locus models that included significant SNPs sequentially identified a second association at rs12793759 [odds ratio (OR) = 1.14, P= 4.76 × 10(-5), adjusted P= 0.004] that is independent of rs10896449 and remained significant after adjustment for multiple testing within the region. rs10896438, a proxy of previously reported rs12418451 (r(2)= 0.96), independent of both rs10896449 and rs12793759 was detected (OR = 1.07, P= 5.92 × 10(-3), adjusted P= 0.054). Our observation of a recombination hotspot that separates rs10896438 from rs10896449 and rs12793759, and low linkage disequilibrium (rs10896449-rs12793759, r(2)= 0.17; rs10896449-rs10896438, r(2)= 0.10; rs12793759-rs10896438, r(2)= 0.12) corroborate our finding of three independent signals. By analysis of tagged SNPs across ∼123 kb using next generation sequencing of 63 controls of European origin, 1000 Genome and HapMap data, we observed multiple surrogates for the three independent signals marked by rs10896449 (n= 31), rs10896438 (n= 24) and rs12793759 (n= 8). Our results indicate that a complex architecture underlying the common variants contributing to prostate cancer risk at 11q13. We estimate that at least 63 common variants should be considered in future studies designed to investigate the biological basis of the multiple association signals.

Epidemiological and mechanistic evidence on the association of quercetin-rich food intake with lung cancer risk and carcinogenesis are inconclusive. We investigated the role of dietary quercetin and the interaction between quercetin and P450 and glutathione S-transferase (GST) polymorphisms on lung cancer risk in 1822 incident lung cancer cases and 1991 frequency-matched controls from the Environment And Genetics in Lung cancer Etiology study. In non-tumor lung tissue from 38 adenocarcinoma patients, we assessed the correlation between quercetin intake and messenger RNA expression of the same P450 and GST metabolic genes. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintiles of intake were calculated using unconditional logistic regression adjusting for putative risk factors. Frequent intake of quercetin-rich foods was inversely associated with lung cancer risk (OR = 0.49; 95% CI: 0.37–0.67; P-trend < 0.001) and did not differ by P450 or GST genotypes, gender or histological subtypes. The association was stronger in subjects who smoked >20 cigarettes per day (OR = 0.35; 95% CI: 0.19–0.66; P-trend = 0.003). Based on a two-sample t-test, we compared gene expression and high versus low consumption of quercetin-rich foods and observed an overall upregulation of GSTM1, GSTM2, GSTT2, and GSTP1 as well as a downregulation of specific P450 genes (P-values < 0.05, adjusted for age and smoking status). In conclusion, we observed an inverse association of quercetin-rich food with lung cancer risk and identified a possible mechanism of quercetin-related changes in the expression of genes involved in the metabolism of tobacco carcinogens in humans. Our findings suggest an interplay between quercetin intake, tobacco smoking, and lung cancer risk. Further research on this relationship is warranted.

The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (>/=60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1-4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures.

BACKGROUND Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. Radiotherapy further increases the risk of death. Mortality information is limited among long-term survivors who were irradiated for hereditary retinoblastoma. METHODS We examined cause-specific mortality among 1854 retinoblastoma survivors who were diagnosed from January 1, 1914, through December 31, 1996, at two US institutions. Standardized mortality ratios (SMRs) were calculated by use of US mortality data to estimate expected numbers of deaths. The relative rates (RRs) of mortality due to subsequent malignant neoplasms associated with multiple risk factors were evaluated with Poisson regression models. Cumulative mortality from subsequent malignant neoplasms was calculated by treating other causes of death as competing risks. RESULTS A total of 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% confidence interval [CI] = 30 to 41) compared with 12 deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4). In this extended follow-up of retinoblastoma survivors, we found no evidence of excess mortality from non-neoplastic causes compared with the general population. However, excess mortality from subsequent malignant neoplasms (particularly sarcomas, melanomas, and cancers of the brain and other parts of the nervous system) among hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. The additional 13 years of follow-up since our last mortality study revealed a previously unreported increased risk of death due to cancers of the corpus uteri (primarily sarcomas) and confirmed the previously reported elevated risk of death from lung cancer among hereditary retinoblastoma survivors. Among hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality from subsequent malignant neoplasm were higher in those who had been treated with radiotherapy than in those who had not. Cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% CI = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors. CONCLUSIONS The temporal patterns of site-specific excess risks of subsequent malignant neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms.

Background Survivors of hereditary retinoblastoma have an increased risk for second malignancies, especially soft tissue sarcomas. However, the risks of individual histologic subtypes of soft tissue sarcomas have not been evaluated. Methods We estimated the risk for six subtypes of soft tissue sarcomas (fibrosarcoma, liposarcoma, histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and others) in a cohort of 963 one-year survivors of hereditary retinoblastoma among patients diagnosed at two US institutions from 1914 through 1984. We calculated standardized incidence ratios (SIRs) for specific subtypes of soft tissue sarcomas by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results database. We also calculated the cumulative risk for all soft tissue sarcomas combined. Results We observed 69 soft tissue sarcomas in 68 patients with hereditary retinoblastoma. Risks were elevated for soft tissue sarcomas overall (SIR = 184, 95% confidence interval [CI] = 143 to 233) and for individual subtypes. Leiomyosarcoma was the most frequent subtype (SIR = 390, 95% CI = 247 to 585), with 78% of leiomyosarcomas diagnosed 30 or more years after the retinoblastoma diagnosis (SIR = 435, 95% CI = 258 to 687). Among patients treated with radiotherapy for retinoblastoma, we found statistically significantly increased risks of soft tissue sarcomas in the field of radiation. Irradiated patients also had increased risks of soft tissue sarcomas, especially leiomyosarcomas, outside the field of radiation, and risks of soft tissue sarcomas were increased in nonirradiated patients as well, indicating a genetic predisposition to soft tissue sarcomas independent of radiation. The cumulative risk for any soft tissue sarcoma 50 years after radiotherapy for retinoblastoma was 13.1% (95% CI = 9.7% to 17.0%). Conclusion Long-term follow-up of a cohort of survivors of hereditary retinoblastoma revealed a statistically significant excess of leiomyosarcoma and other soft tissue sarcomas that persists decades after the retinoblastoma diagnosis. Retinoblastoma survivors should undergo regular medical surveillance for sarcomas in their adult years.

Measuring ultraviolet (UV) exposure in human populations is a complex task. The dominant source of ultraviolet radiation for humans is sunlight, which is always a mix of both ultraviolet A (UVA, usually 320– 400 nm) and ultraviolet B (UVB, 320–280 nm). Ultraviolet C ( 280 nm) is filtered by the atmosphere and does not reach the earth’s surface. Researchers cannot separate the individual effects of the different wavelengths in humans as can be done in experimental animals. For some subpopulations, such as welders and those who use artificial UV sources for tanning, exposures other than sunlight may contribute to the total individual dose. In epidemiologic studies in which sun exposure is estimated, the usual end point is skin dose. The major acute toxicities of sun exposure are photosensitivity reactions and sunburn; chronic toxicities include melanoma, non-melanoma skin cancers, cataracts, and photo-aging of the skin. Two major methodologies for estimating sunlight exposure have emerged: “geographic” estimates and personal, individual estimates. Geographic estimates of ground-level exposure must take into account latitude, altitude, day of year, time of day, cloud cover, ozone, particulates, smog, and reflectance from water, rock, or sand. All of these cofactors have important influences on the actual ground-level measurements. Several US agencies have had on-ground measurement devices in place for varying times. The National Cancer Institute (NCI) and the National Oceanic and Atmospheric Administration (NOAA) collaborated on placing Robertson-Berger meters, spectrometers measuring on-ground UVB flux, in areas with cancer registries. These meters were in place for extended periods of time. The limitations include only UVB measurements and yearly calibration of the instruments. These data have been used in analyses of risk of non-melanoma skin cancer and melanoma. The Environmental Protection Agency (EPA) had 21 multispectral (286.5–363 nm in 0.5 nm steps) Brewer meters spread over the United States in place for several years. The system is not functional now, but data are available for use. The US Department of Agriculture (USDA) has 37 monitoring stations in 29 states, Canada, and New Zealand. These, too, are multispectral, but are focused on UVB. Most are placed in rural agricultural areas, since the major end point for these measurements is the effect of UVB on crops. This system was initiated in the mid-1990s. NOAA has six stations in the western, central, and eastern United States with Brewer meters in place since late 2006. Data are also available from these stations. In addition to these on-ground measurement systems, NASA provides Total Ozone Mapping Spectrometer (TOMS) satellite data with on-ground estimates. The advantage of the TOMS data is that there is superior coverage from 180 degrees E to 180 degrees W and 65 degrees N to 65 degrees S from 1978 –1993. The disadvantage is that the estimates cannot take into account cofactors that alter the ground measurements. One study compared TOMS estimates with on-ground measurements and found agreement within 12% overall, which improved with clear skies (within 8%). Based on measurements in two not very urban areas (Billings, OK and Las Cruces, NM), the effect of aerosols was less than 5%, but would likely be higher in more congested areas. In addition to the geographic measures, personal dosimeters have also been developed. Polysulfone badges have been used for over a decade. They are calibrated to erythemal-weighted UVB and measure total dose over a specified time period. Placement of the badges is crucial because the topography and movement of a human being determines the total exposure. A major advantage of these badges is that they are easy to use and relatively inexpensive, making them feasible for moderate-sized studies. Multispectral dosimeDr. Tucker is with the Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA. Please address all correspondence to: Dr. Margaret Tucker, Director, Human Genetics Program, Chief, Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd., Room 7122, Bethesda, MD 20892-7236, USA; Phone: 301-496-4375; Fax: 301402-4489; E-mail: tuckerp@mail.nih.gov. doi: 10.1301/nr.2007.aug.S84–S86

A cross-sectional study may be more feasible than a cohort or case-control study for examining the effect of a genetic mutation on cancer penetrance outside of cancer families. The kin-cohort design uses volunteer probands selected from a population with a relatively high frequency of the mutations of interest. By considering the cancer risk in first-degree relatives of mutation-positive and -negative probands as a weighted average of the risk in carriers and noncarriers, with weights calculated assuming a known mode of inheritance, one can infer the penetrance of the mutations. The estimates of penetrance by age 70 years for three specific mutations in the BRCA1 and BRCA2 genes common among Ashkenazi Jews for the first occurrence of breast or ovary cancer is 63%. The kin-cohort design can be a useful tool for quickly estimating penetrance from volunteers in a setting in which the mutation prevalence is relatively high.

Background An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma. Methods Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method. Results Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking. Implications Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

BACKGROUND Patients with non-Hodgkin's lymphoma (NHL) are at increased risk for second cancers. Few studies, however, include long-term survivors, and none report risk for second cancer among NHL patients surviving 15 or more years. PURPOSE Our aim was to examine the pattern of second cancers among long-term survivors of NHL. METHODS A cohort of 6171 patients diagnosed with NHL as a first primary cancer and who survived 2 or more years was identified within population-based tumor registries in Sweden, Ontario, and Iowa and within the affiliated tumor registry of The Netherlands Cancer Institute. Nearly 1000 NHL patients lived 15 or more years after diagnosis. Tumor registry files were searched for new invasive primary malignancies. RESULTS Second cancers were reported in 541 subjects (observed-to-expected ratio [O/E] = 1.37; 95% confidence interval = 1.26-1.49), with significant excesses seen for all solid tumors (O/E = 1.28), acute nonlymphocytic leukemia (O/E = 4.83), melanoma (O/E = 2.38), Hodgkin's disease (O/E = 12.0), and cancers of the lung (O/E = 1.36), brain (O/E = 2.33), kidney (O/E = 2.07), and bladder (O/E = 1.77). Among 15-year survivors, significantly increased risks persisted for all second cancers (O/E = 1.45), solid tumors (O/E = 1.37), bladder cancer (O/E = 3.24), and Hodgkin's disease (O/E = 25.0). The actuarial risk of developing a second cancer 3-20 years after diagnosis of NHL was 21%, compared with a population expected cumulative risk of 15%. CONCLUSIONS Patients with NHL continue to be at significantly elevated risk of second primary cancer for up to two decades following diagnosis. The pattern of risk suggests the influence of treatment as well as factors associated with the underlying disease. IMPLICATIONS Quantitative studies of second cancer following NHL are needed to clarify the role of antecedent therapy, shared risk factors, host susceptibility, and other etiologic and diagnostic influences. Despite the generally advanced age of patients with NHL, the persistently elevated risk of second cancers should alert clinicians to the importance of continued medical surveillance.

The authors examined the relation between occupation and lung cancer in the large, population-based Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study. In 2002-2005 in the Lombardy region of northern Italy, 2,100 incident lung cancer cases and 2,120 randomly selected population controls were enrolled. Lifetime occupational histories (industry and job title) were coded by using standard international classifications and were translated into occupations known (list A) or suspected (list B) to be associated with lung cancer. Smoking-adjusted odds ratios and 95% confidence intervals were calculated with logistic regression. For men, an increased risk was found for list A (177 exposed cases and 100 controls; odds ratio = 1.74, 95% confidence interval: 1.27, 2.38) and most occupations therein. No overall excess was found for list B with the exception of filling station attendants and bus and truck drivers (men) and launderers and dry cleaners (women). The authors estimated that 4.9% (95% confidence interval: 2.0, 7.8) of lung cancers in men were attributable to occupation. Among those in other occupations, risk excesses were found for metal workers, barbers and hairdressers, and other motor vehicle drivers. These results indicate that past exposure to occupational carcinogens remains an important determinant of lung cancer occurrence.

Willingness of newly diagnosed lung cancer patients to volunteer names of friends as potential control subjects was assessed from August through December 1988 in a case-control study at the National Cancer Institute and Naval Hospital, Bethesda, Maryland. Friend controls appeared ideal to examine a genetically determined metabolic characteristic and lung cancer risk, since potentially confounding characteristics could be matched and cooperation should be high. Only 11 of 23 cases named at least one friend. Cases interviewed during the second study month were most likely to volunteer names. Either the recency of the diagnosis of a highly fatal disease or the referral to a tertiary care research hospital may have contributed to the reluctance of cases to volunteer names. No characteristic was identified that might offer a means to increase referral of friend controls.

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Cutaneous malignant melanoma (CMM) is a potentially fatal form of skin cancer whose etiology is heterogeneous and complex. Approximately 10% of the cases of CMM occur in persons with a familial predisposition (1), often in association with clinically dysplastic or atypical nevi (2). In 1993, a low-molecular-weight protein p16 was shown to inhibit the activity of the cyclin D1–cyclin-dependent kinase 4 or 6 (CDK4 or CDK6) complex (3). This complex phosphorylates the retinoblastoma protein, allowing the cell to pass through the G1 cell-cycle checkpoint. The CDKN2A gene that encodes p16 was localized to chromosome 9p21 (4,5), a region that has been implicated in melanoma by linkage, cytogenetic, and loss-of-heterozygosity studies (6-11). Somatic mutations in this gene have frequently been detected in many melanoma cell lines (4,5). Although initial reports of germline mutations in melanomaprone families (selected for genetic analyses) suggested that the p16 protein might be important in approximately one half of inherited melanoma (12-14), subsequent studies have revealed lower frequencies of mutations. To date, germline CDKN2A mutations have been detected in approximately one fourth of melanoma-prone kindreds (defined as having two or more first-degree relatives with confirmed CMM) from North America, Europe, and Australia (12-21). In this issue of the Journal, Platz et al. (22) present the first report of screening for germline mutations in a population-based cohort of melanoma-prone families. The results provide further evidence that CDKN2A mutations may not be as prevalent as originally thought. Platz et al. (22) identified 177 melanoma-prone families, defined by the occurrence of two or more relatives (including first-, second-, and third-degree relatives) with histopathologically confirmed CMM, in the County of Stockholm, Sweden. A representative selection of 181 individuals with CMM, from 100 of these families, was screened for germline mutations in CDKN2A. Of the 100 families, 64 kindreds had at least two cases of melanoma in first-degree relatives; 24 kindreds had melanoma in two or more second-degree relatives; and 12 kindreds had melanomas in third-degree or more distant relatives. Both direct sequencing and single-strand conformation polymorphism (SSCP) analyses of exons 1 and 2 were conducted. Of the 64 families with two or more first-degree relatives with CMM, five (7.8%) had potentially disease-related mutations. Four of the five families with mutations had more than the mean (2.3) number of melanoma cases. Ten kindreds without detectable mutations also had more than two cases of melanoma in first-degree relatives. No mutations were detected in the 36 families with melanoma in more distant relatives (22). The frequency of CDKN2A mutations detected by Platz et al. (22) was lower than that in the initial reports of families selected for genetic analyses, yet the observations are consistent with numerous later results (13,15,17,20,23). There are several possible explanations for the divergent frequencies. First, part of the difference may be due to chance, since several studies examined small numbers of families. Second, the families that were studied likely represented a heterogeneous mix of hereditary and nonhereditary melanoma-prone kindreds. Certain investigations required three or more first-degree relatives with CMM, others required only two such relatives, and still others required only two relatives with CMM not restricted to first degree. Third, germline mutations may have been present in some families but undetected either because only one patient per family was screened or because the mutation was not revealed by direct sequencing or SSCP analysis. Mutations outside the CDKN2A coding region that interfere with RNA splicing or expression would not have been detected (24). In addition, alternative processes linked to transcriptional and/or translational regulation including methylation might also inactivate p16 (25). The frequency of such undetected mutations and alternative mechanisms of inactivation is difficult to estimate. Finally, the complexity and heterogeneity of CMM likely contributed to the divergent frequencies. Previous studies (12,19,26) have demonstrated statistically significant evidence for genetic heterogeneity to the chromosome 9p21 region as well as the identification of a second melanoma gene CDK4 in two melanoma-prone families (27). All of these alternatives likely contribute to the divergent estimates of CDKN2A mutations across populations and make it difficult to determine precisely the proportion of hereditary melanoma cases associated with p16 alterations. Even with the uncertainty about the frequency of CDKN2A

Studies of family history of cancer have contributed to knowledge about susceptibility to cancer and cancer genetics. The gold standard is to validate reported history of cancer by review of medical records and death certificates. Difficulties encountered in validating the history of cancer include the following: inaccuracy of diagnoses from death certificates when compared with medical records or autopsy data (75); coding inconsistencies, such as the report of nonspecific site of cancer on death certificates when compared with medical records (4); and inability to obtain records (5). Retrieval of medical records and accuracy of data obtained are higher if the history is given by firstdegree relatives (5,6). All patients diagnosed with tumors classified as Ewing's sarcomas and treated at the National Cancer Institute between 1965 and 1992 as well as their family members were enrolled in a genetic epidemiology study of Ewing's sarcoma. Approval of the institutional review board was obtained (7). The informant (i.e., living proband or next of kin), after providing written consent, was asked to report diagnoses of cancers in the proband's first- and second-degree relatives. We present results of validation of reported cancer diagnoses in a subset of 122 of 320 deceased family members. Confirmation of reported cancer diagnoses through medical documentation (death certificates and medical records) was attempted systematically for diagnoses of melanoma, cancers of the brain, stomach, and lung, and for all cancers for which the accuracy of diagnosis was questioned. The methods have been fully described (7). Requests for death certificates were sent to vital records departments of the 30 states where case subjects resided. The mean waiting period was 2.5 months

The risk of leukemia was evaluated in 9,170 2-or-more-year survivors of childhood cancer in the 13 institutions of the Late Effects Study Group. Secondary leukemia occurred in 22 nonreferred individuals compared to 1.52 expected, based on general population rates [relative risk (RR) = 14; 95% confidence interval (CI), 9-22]. The influence of therapy for the first cancer on subsequent leukemia risk was determined by a case-control study conducted on 25 cases and 90 matched controls. Treatment with alkylating agents was associated with a significantly elevated risk of leukemia (RR = 4.8; 95% CI, 1.2-18.9). A strong dose-response relationship was also observed between leukemia risk and total dose of alkylating agents, estimated by an alkylator score. The RR of leukemia reached 23 in the highest dose category. Radiation therapy, however, did not increase risk. Although doxorubicin was also identified as a possible risk factor, the excess risk of leukemia following treatment for childhood cancer appears almost entirely due to alkylating agents.