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Background: Childhood cancer survivors treated with chest radiotherapy have substantially elevated risk for developing breast cancer. Although numerous breast cancer susceptibility variants have been established, genetic predisposition for breast cancer after childhood cancer remains poorly understood. Methods: We conducted the first genome-wide association study of subsequent breast cancer in female childhood cancer survivors within two large-scale cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study [CCSS; 178 breast cancer cases, 2200 controls (survivors without subsequent neoplasm) of European descent] and the St. Jude Lifetime Cohort (SJLIFE; 29 cases, 574 controls). Genotyping on the Illumina HumanOmni5MExome (CCSS) or Affymetrix 6.0 (SJLIFE) array and imputation based on the 1000 Genomes Project yielded >16 million high quality genotyped or imputed variants available in both studies. Assuming an additive genetic model, we used multivariate Cox regression to quantify the effect of each variant in the overall population and stratified by receipt of ≥10 Gray (Gy) or Results: We identified two loci associated with breast cancer risk among children who received ≥10 Gy radiation to the chest (131 cases, 493 controls): one at 1q41 [rs4342822, risk allele frequency (RAF) = 0.46 in controls, pooled per allele hazard ratio (HR) = 1.94, 95% confidence interval (CI) = 1.50-2.51, Pexact = 1.20×10−8] and another at 11q23 (rs74949440, RAF = 0.02 in controls, HR = 3.71, 95%CI = 2.18-6.32, Pexact = 2.00×10−9). Neither locus was associated with breast cancer risk among children who received 10% of breast cancers in The Cancer Genome Atlas data. The variant rs74949440 is intronic to TAGLN, whose expression levels have been associated with breast cancer prognosis and altered cell death resistance following irradiation in human carcinoma cell lines. Conclusion: These findings represent the first evidence outside of identified high-risk cancer susceptibility genes that certain individuals are genetically predisposed to developing breast cancer after radiotherapy and suggest that radiation exposure may interact with germline genetics to modify breast cancer risk. Citation Format: Lindsay M. Morton, Joshua N. Sampson, Gregory T. Armstrong, Ting-Huei Chen, Melissa Hudson, Eric Karlins, Casey L. Dagnall, Shenchao Li, Carmen L. Wilson, Kumar Srivastava, Wei Liu, Guolian Kang, Kevin Oeffinger, Tara O. Henderson, Chaya S. Moskowitz, Todd M. Gibson, Diana M. Merino, Jeannette R. Wong, Sue Hammond, Joseph P. Neglia, Lucie M. Turcotte, Jeremy Miller, Laura Bowen, William A. Wheeler, Wendy M. Leisenring, John A. Whitton, Laurie Burdette, Belynda D. Hicks, Mitchell J. Machiela, Aurelie Vogt, Zhaoming Wang, Meredith Yeager, Geoffrey Neale, Matthew Lear, Louise C. Strong, Yutaka Yasui, Marilyn Stovall, Rita E. Weathers, Susan A. Smith, Rebecca Howell, Stella M. Davies, Gretchen A. Radloff, Amy Berrington de González, Peter D. Inskip, Preetha Rajaraman, Joseph F. Fraumeni, Smita Bhatia, Stephen J. Chanock, Margaret A. Tucker, Leslie L. Robison. Genome-wide association study identifies two susceptibility loci that modify radiation-related risk for breast cancer after childhood cancer: A report from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2691.

10572Background: Survivors of certain pediatric cancers, particularly first primary sarcomas, have increased risks of developing subsequent sarcomas. However, understanding of the full spectrum of ...

10510Background: Survivors of childhood cancer treated with cranial irradiation have a dose-dependent increased risk of meningiomas, which may cause significant morbidity. However, surveillance gui...

Background Hoyeraal-Hreidarsson syndrome is a dyskeratosis congenita–related telomere biology disorder that presents in infancy with intrauterine growth retardation, immunodeficiency, and cerebellar hypoplasia in addition to the triad of nail dysplasia, skin pigmentation, and oral leukoplakia. Individuals with Hoyeraal-Hreidarsson syndrome often develop bone marrow failure in early childhood. Germline mutations in DKC1, TERT, TINF2, RTEL1, ACD, or PARN cause about 60% of individuals with Hoyeraal-Hreidarsson syndrome. Patient Description We describe 14 years of follow-up of an individual with Hoyeraal-Hreidarsson syndrome who initially presented as an infant with intrauterine growth retardation, microcephaly, and central nervous system calcifications. He was diagnosed with Hoyeraal-Hreidarsson syndrome at age 6 years and had a complicated medical history including severe developmental delay, cerebellar hypoplasia, esophageal and urethral stenosis, hip avascular necrosis, immunodeficiency, and bone marrow failure evolving to myelodysplastic syndrome requiring hematopoietic cell transplantation at age 14 years. He had progressive skin pigmentation, oral leukoplakia, and nail dysplasia leading to anonychia. Whole exome sequencing identified novel biallelic variants in PARN . Conclusions This patient illustrates that the constellation of intrauterine growth retardation, central nervous system calcifications, and cerebellar hypoplasia, esophageal or urethral stenosis, and cytopenias, in the absence of congenital infection, may be due to Hoyeraal-Hreidarsson syndrome. Early diagnosis of Hoyeraal-Hreidarsson syndrome is important to optimize medical management and provide genetic counseling.

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.

Evidence about the role for reproductive and hormonal factors in the etiology of lung cancer in women is conflicting. To clarify this question, we examined 407 female cases and 499 female controls from the Environment And Genetics in Lung cancer Etiology population-based case-control study. Subjects were interviewed in person using a computer-assisted personal interview to assess demographics, education, smoking history, medical history, occupational history, reproductive and hormonal factors. Associations of interest were investigated using logistic regression models, adjusted for catchment area and age (matching variables), cigarette smoking (status, pack-years and time since quitting). Additional confounding variables were investigated but did not substantially affect the results. We observed a reduced risk of lung cancer among women with later age at first live birth [≥31 years: odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.31-1.06, p-trend = 0.05], later age at menopause (≥51 years: OR = 0.49, 95%CI = 0.31-0.79, p-trend = 0.003) and longer reproductive periods (≥41 years: OR = 0.44, 95%CI = 0.25-0.79, p-trend = 0.01). A reduced risk was also observed for hormone replacement therapy (OR = 0.63, 95%CI = 0.42-0.95, p = 0.03) and oral contraceptive use (OR = 0.67, 95%CI = 0.45-1.00, p = 0.05) but no trend with duration of use was detected. Menopausal status (both natural and induced) was associated with an augmented risk. No additional associations were identified for other reproductive variables. This study suggests that women who continue to produce estrogens have a lower lung cancer risk. Large studies with great number of never smoking women, biomarkers of estrogen and molecular classification of lung cancer are needed for a more comprehensive view of the association between reproductive factors and lung cancer risk.

The XPD(ERCC2) gene encodes a DNA helicase involved in DNA repair and transcription. Patients with mutations in XPD may have different autosomal recessive phenotypes including trichothiodystrophy (TTD) or xeroderma pigmentosum (XP). TTD patients have sulfur-deficient, brittle hair, short stature and developmental delay. In contrast, XP patients have freckle-like pigmentation and a greatly increased risk of sun-induced skin cancers. Mothers of TTD patients have been reported to have a high frequency of pregnancy and neonatal complications. We performed a molecular epidemiological study of 15 mothers of 17 TTD patients and 13 mothers of 17 XP patients, all with XPD mutations. We found that 94% (16/17) of the TTD pregnancies had pre-term delivery, pre-eclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, prematurity or low birth weight. None of the 17 XP pregnancies had these complications (P

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of > 2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 x 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 x 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.

Introduction Despite the large number of adolescents and young adults in employment training programs, a population that has poorer health and greater health risk than similarly aged in-school peers, we are unaware of any health interventions that have been evaluated in this setting. The primary objective of our study was to evaluate changes in depressive symptoms, coping strategies, and receipt of mental health services among low-income African American adolescents and young adults receiving a mental health intervention integrated into an employment training program. Methods The intervention consisted of an on-site mental health clinician, a peer-led depression prevention intervention, and training sessions for employment training staff. A pretest-posttest design assessed depressive symptoms, coping strategies, and receipt of mental health services at baseline and 12-month follow-up. Complete baseline and follow-up data were available for 136 of 218 eligible participants. Most study participants were African American (98%); average age was 18.8 years. Results The intervention had no effect on depressive symptoms or coping strategies. The percentage of participants who used mental health services at follow-up increased, but not significantly. Age was associated with use of active and support-seeking coping strategies, whereas use of mental health services before program enrollment was associated with use of mental health services at follow-up. Conclusion Alternative intervention strategies may be needed to decrease the severity of depressive symptoms and increase use of coping strategies among adolescents and young adults in employment training programs. Future research evaluating such interventions should use quasi-experimental or experimental designs to provide evidence of intervention effect.

INTRODUCTION Despite the large number of adolescents and young adults in employment training programs, a population that has poorer health and greater health risk than similarly aged in-school peers, we are unaware of any health interventions that have been evaluated in this setting. The primary objective of our study was to evaluate changes in depressive symptoms, coping strategies, and receipt of mental health services among low-income African American adolescents and young adults receiving a mental health intervention integrated into an employment training program. METHODS The intervention consisted of an on-site mental health clinician, a peer-led depression prevention intervention, and training sessions for employment training staff. A pretest-posttest design assessed depressive symptoms, coping strategies, and receipt of mental health services at baseline and 12-month follow-up. Complete baseline and follow-up data were available for 136 of 218 eligible participants. Most study participants were African American (98%); average age was 18.8 years. RESULTS The intervention had no effect on depressive symptoms or coping strategies. The percentage of participants who used mental health services at follow-up increased, but not significantly. Age was associated with use of active and support-seeking coping strategies, whereas use of mental health services before program enrollment was associated with use of mental health services at follow-up. CONCLUSION Alternative intervention strategies may be needed to decrease the severity of depressive symptoms and increase use of coping strategies among adolescents and young adults in employment training programs. Future research evaluating such interventions should use quasi-experimental or experimental designs to provide evidence of intervention effect.

Purpose To evaluate the risk of second cancer (SC) in long-term survivors of retinoblastoma (Rb) according to classification of germline mutation, based on family history of Rb and laterality. Patients and Methods We assembled a cohort of 1,852 1-year survivors of Rb (bilateral, n = 1,036; unilateral, n = 816). SCs were ascertained by medical records and self-reports and confirmed by pathology reports. Classification of RB1 germline mutation, inherited or de novo, was inferred by laterality of Rb and positive family history of Rb. Standardized incidence ratios and cumulative incidence for all SCs combined and for soft tissue sarcomas, bone cancers, and melanoma were calculated. The influence of host- and therapy-related risk factors for SC was assessed by Poisson regression for bilateral survivors. Results We observed a relative risk (RR) of 1.37 (95% CI, 1.00 to 1.86) for SCs in bilateral survivors associated with a family history of Rb, adjusted for treatment, age, and length of follow-up. The risk for melanoma was significantly elevated for survivors with a family history of Rb (RR, 3.08; 95% CI, 1.23 to 7.16), but risks for bone or soft tissue sarcomas were not elevated. The cumulative incidence of SCs 50 years after diagnosis of bilateral Rb, with adjustment for competing risk of death, was significantly higher for survivors with a family history (47%; 95% CI, 35% to 59%) than survivors without a family history (38%; 95% CI, 32% to 44%; P = .004). Conclusion Rb survivors with bilateral disease and an inherited germline mutation are at slightly higher risk of an SC compared with those with a de novo germline mutation, in particular melanoma, perhaps because of shared genetic alterations.

We examined whether mental health training for staff of an employment training program for out-of-school youth aged 16 to 22 years would increase mental health discussions and referrals. We reviewed case files of participants at 1 Baltimore program who enrolled 6 months before (n = 303) and after (n = 263) a 2-day training program. Chi-square analyses indicated increases in the percentage of participants with discussions (1% to 9%, χ2 = 4.91, P < .05) and referrals (11% to 16%, χ2 = 5.16, P < .05). Brief, intensive training increased mental health discussion and referrals among job training staff.

AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study. METHODS: About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression. RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10-4. The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression. CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.

Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggests that the alteration of CXC chemokine genes may confer susceptibility to melanoma.

Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.Seven SNPs had p-values for linear trend0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.

Background Bricklayers may be at increased risk of lung cancer, although a firm association has not been established. We examined this association within the EAGLE (Environment And Genetics in Lung cancer Etiology) study, a population-based case–control study conducted in Italy between 2002 and 2005. Methods For men in selected occupations in the construction sector we calculated smoking-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). For bricklayers we estimated the population attributable fraction (PAF) and the attributable community risk (ACR). Results We found increased lung cancer risk for bricklayers (OR 1.57, 95% CI 1.12–2.21; 147 cases, 81 controls). The PAF was 3.9% (95% CI 0.7–7.0), corresponding to an ACR of 4.1 cases annually per 100,000 men (95% CI 0.7–7.3) in the whole community. Among bricklayers, there were increased risks for squamous cell (OR 2.03, 95% CI 1.32–3.13, 56 exposed cases) and small cell carcinomas (OR 2.29, 95% CI 1.29–4.07, 21 exposed cases), while no excess (OR 1.06, 95% CI 0.68–1.65, 41 exposed cases) was found for adenocarcinoma. Conclusions Our findings provide additional evidence of increased lung cancer risk in Italian bricklayers. The association is plausible because they are exposed to several carcinogens, notably crystalline silica. Am. J. Ind. Med. 55:423–428, 2012. © 2012 Wiley Periodicals, Inc.

Quantitative changes in mitochondrial DNA (mtDNA) have been associated with the risk of a number of human cancers; however, the relationship between constitutive mtDNA copy number in blood and the risk of familial cutaneous malignant melanoma (CMM) has not been reported. We measured mtDNA copy number using quantitative PCR in blood-derived DNA from 136 CMM cases and 302 controls in 53 melanoma-prone families (23 segregating CDKN2A germline mutations). MtDNA copy number did not vary by age, sex, pigmentation characteristics, or CMM status. However, germline CDKN2A mutation carriers had significantly higher mean mtDNA copy number compared to non-carriers, particularly among CMM cases (geometric mean mtDNA copy number of 144 and 111 for carrier versus non-carrier, respectively; P= 0.02). When adjusting for age, sex, and familial correlation, having increasing mtDNA copy number was significantly associated with CDKN2A mutation status among CMM cases (OR=1.47, Ptrend=0.024). In particular, individuals with specific CDKN2A mutations with the potential to inactivate or reduce the level of the p16-INK4 reactive oxygen species (ROS) protective function had significantly increased mtDNA copy number levels (P=0.035). Future research in prospective studies is required to validate these findings and to further investigate mtDNA copy number in both blood and melanoma tissues in relation to CMM risk and CDKN2A mutation status.

Malignant melanoma of the skin (CMM) is associated with ultraviolet radiation exposure, but the mechanisms and even the wavelengths responsible are unclear. Here we use a mammalian model to investigate melanoma formed in response to precise spectrally defined ultraviolet wavelengths and biologically relevant doses. We show that melanoma induction by ultraviolet A (320–400 nm) requires the presence of melanin pigment and is associated with oxidative DNA damage within melanocytes. In contrast, ultraviolet B radiation (280–320 nm) initiates melanoma in a pigment-independent manner associated with direct ultraviolet B DNA damage. Thus, we identified two ultraviolet wavelength-dependent pathways for the induction of CMM and describe an unexpected and significant role for melanin within the melanocyte in melanomagenesis., Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.

Introduction. Treatment-related acute myeloid leukemia/myelodysplastic syndrome (tAML/MDS) is a rare but often fatal complication of systemic therapy for primary malignancy. Leukemogenicity of specific agents is variable, with particularly high risks associated with platinum-containing agents, certain alkylating agents, topoisomerase II inhibitors, and purine analogs. Current treatment practices increasingly include (neo)adjuvant and multiple courses of systemic therapy for a number of first primary malignancies. However, no large-scale study has quantified risks of tAML/MDS and other myeloid neoplasms after chemotherapy in the modern treatment era. Methods. We identified a cohort of 746,007 adults who were initially treated with chemotherapy and survived ≥1 year following diagnosis with first primary malignancy during 2000-2012, as reported to 17 US population-based cancer registries from the Surveillance, Epidemiology, and End Results program. Risks for second primary AML/MDS, chronic myeloid leukemia (CML), and other myeloproliferative neoplasms (MPNs) and MDS/MPNs were compared to that expected in the general population (based on age-, race-, sex- and calendar period-specific incidence rates) using standardized incidence ratios (SIRs). Results. tAML/MDS was identified in 2071 individuals following chemotherapy, four times more than expected based on general population rates (SIR=4.1, 95%CI=3.9-4.2). We identified novel elevations in tAML/MDS risk after chemotherapy for most gastrointestinal malignancies, including the oral cavity/pharynx (N=45, SIR=2.6, 95%CI=1.9-3.5), esophagus (N=28, SIR=4.3, 95%CI=2.9-6.2), liver (N=10, SIR=2.6, 95%CI=1.2-4.8), stomach (N=22, SIR=2.7, 95%CI=1.7-4.0), rectum (N=65, SIR=1.5, 95%CI=1.2-1.9), and anus (N=22, SIR=3.6, 95%CI=2.3-5.5), but not colon (N=67, SIR=1.1, 95%CI=0.8-1.3). Novel increased risks of tAML/MDS also were observed after chemotherapy for cancers of the pancreas (N=15, SIR=3.3, 95%CI=1.8-5.4), larynx (N=20, SIR=4.2, 95%CI=2.6-6.5), bladder (N=30, SIR=1.8, 95%CI=1.2-2.6), and melanoma (N=4, SIR=3.7, 95%CI=1.0-9.6) Similar to previous studies, tAML/MDS occurred most commonly after female breast cancer (N=543, SIR=4.1, 95%CI=3.8-4.5), non-Hodgkin lymphoma (NHL; N=515, SIR=7.3, 95%CI=6.7-7.9), and lung cancer (N=185, SIR=4.1, 95%CI=3.5-4.7). We further confirmed previous observations of strikingly elevated risks of tAML/MDS after chemotherapy for cancers of the bone (N=10, SIR=35.1, 95%CI=16.9-64.6), testis (N=18, SIR=15.6, 95%CI=9.2-24.6), and soft-tissue (N=20, SIR=12.6, 95%CI=7.7-19.4), and more modestly elevated risks of tAML/MDS after chemotherapy for cancers of brain (N=18, SIR-7.8, 95%CI=4.6-12.4), ovary (N=84, SIR=5.5, 95%CI=4.3-6.7), endometrium (N=28, SIR=4.4, 95%CI=2.9-6.3), cervix (N=22, SIR=4.4, 95%CI=2.8-6.6), and prostate (N=15, SIR=2.7, 95%CI=1.5-4.4), as well as Hodgkin lymphoma (N=54, SIR=8.7, 95%CI=6.6-11.4), chronic lymphocytic leukemia (N=52, SIR=7.7, 95%CI=5.8-10.2), and myeloma (N=102, SIR=6.3, 95%CI=5.1-7.6). Risks were non-significantly heightened with radiotherapy plus chemotherapy for breast, lung, and stomach cancers compared with chemotherapy alone. Elevated risks also were observed for CML after chemotherapy for lung cancer (N=12, SIR=2.5, 95%CI=1.3-4.4), breast cancer (N=35, SIR=1.8, 95%CI=1.3-2.5), and NHL (N=16, SIR=2.1, 95%CI=1.2-3.4), and for chronic myelomonocytic leukemia after chemotherapy for breast cancer (N=15, SIR=3.0, 95%CI=1.7-5.0) and NHL (N=16, SIR=4.2, 95%CI=2.4-6.9). In contrast, risks were not increased for other MPNs after chemotherapy for any first primary malignancy. Conclusions. Despite the availability of modern cancer chemotherapy and targeted agents, risks of tAML/MDS are elevated across a broad spectrum of first primary cancers and extend to other myeloid neoplasms. Risks are consistent with those expected from expanded use of leukemogenic systemic therapy, particularly for specific cancers, such as cervical cancer, that are commonly treated with platinum-based regimens. More research is needed to quantify risks associated with specific agents and doses in the (neo)adjuvant and treatment setting. Risks for treatment-related myeloid neoplasms should be weighed against benefits of systemic therapy. Disclosures No relevant conflicts of interest to declare.

Incident cases of in situ and invasive cutaneous malignant melanoma diagnosed during 1975-90 were identified through the National Cancer Institute's Surveillance, Epidemiology, and End Results program. We studied the 32,868 white subjects diagnosed with melanoma, who were living in nine cancer registry areas covering approximately 10% of the population of the USA. The summer-to-winter ratio, defined as the ratio of the number of melanomas diagnosed during June to August (summer), to the number of melanomas diagnosed during December to February (winter), was determined according to gender, stage, histologic type and anatomic site. Summer-to-winter ratios were 1.47 (95% confidence interval (CI) 1.37-1.58) for in situ; 1.43 (95% CI 1.38-1.48) for local stage; 1.24 (95% CI 1.12-1.38) for regional stage; and 0.95 (95% CI 0.82-1.11) for distant stage melanoma. For the melanomas staged as local at diagnosis (86% of the invasive melanomas staged), a July peak was observed. For each of the major histological types of local stage melanoma, summer-to-winter ratios were significantly elevated in men (range 1.24-1.41) and women (range 1.44-1.90). For the major anatomic sites (including the head and neck, which are exposed throughout the year) of local stage melanoma, summer-to-winter ratios were elevated for men (range 1.28-1.45) and for women (range 1.31-1.75).(ABSTRACT TRUNCATED AT 250 WORDS)

The study evaluated 139 patients diagnosed with Langerhans' cell histiocytosis (LCH) and enrolled in any protocol of the Italian Association of Pediatric Hematology/Oncology since 1982. Treatment was etoposide (VP-16) only in 50 patients, VP-16 and other drugs with an already established leukemogenic effect in 17 patients, only drugs with leukemogenic effect in 6 patients, other drugs in 35 patients, and surgery only in 31 patients. Median length of follow-up after diagnosis was 65 months (range, 1 to 126 months) for a total of 742.5 person-years at risk (PYRs). Three cases of acute myelogenous leukemia (AML) were reported; only 0.0044 case was expected. The standard incidence ratio (SIR) of AML in this cohort was 680.5 [95% confidence interval (CI), 140.2-1988.5], and the incidence rate per 1000 PYRs was 4.0 (95% CI, 0.8-11.8). For the subgroup treated with single-agent VP-16, the SIR after treatment was 2270.0 (95% CI, 275-8199), and the incidence rate after treatment was 14.7 (95% CI, 1.8-42.8). The study confirms a higher risk of leukemia after LCH and supports the hypothesis of an association between treatment-related acute nonlymphocytic leukemia and single-agent treatment with VP-16.

Statistical imputation of genotype data is an important technique for analysis of genome-wide association studies (GWAS). We have built a reference dataset to improve imputation accuracy for studies of individuals of primarily European descent using genotype data from the Hap1, Omni1, and Omni2.5 human SNP arrays (Illumina). Our dataset contains 2.5-3.1 million variants for 930 European, 157 Asian, and 162 African/African-American individuals. Imputation accuracy of European data from Hap660 or OmniExpress array content, measured by the proportion of variants imputed with R^2^>0.8, improved by 34%, 23% and 12% for variants with MAF of 3%, 5% and 10%, respectively, compared to imputation using publicly available data from 1,000 Genomes and International HapMap projects. The improved accuracy with the use of the new dataset could increase the power for GWAS by as much as 8% relative to genotyping all variants. This reference dataset is available to the scientific community through the NCBI dbGaP portal. Future versions will include additional genotype data as well as non-European populations.

Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk of bone and soft tissue sarcomas. This predisposition to sarcomas has been attributed to genetic susceptibility due to inactivation of the RB1 gene as well as past radiotherapy for Rb. The majority of bone and soft tissue sarcomas among hereditary Rb survivors occur in the head, within the radiation field, but they also occur outside the radiation field. Sarcomas account for almost half of the second primary cancers in hereditary Rb survivors, but they are very rare following non-hereditary Rb. Sarcomas among hereditary Rb survivors arise at ages similar to the pattern of occurrence in the general population. There has been a trend over the past two decades to replace radiotherapy with chemotherapy and other focal therapies (laser or cryosurgery), and most recently, chemosurgery in order to reduce the incidence of sarcomas and other second cancers in Rb survivors. Given the excellent survival of most Rb patients treated in the past, it is important for survivors, their families and health care providers to be aware of the heightened risk for sarcomas in hereditary patients.

Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value

International audience; Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case-control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10(-8) with the most significant association with rs4430796 (P = 1.62 × 10(-24)). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r(2)= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10(-23)) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10(-8)); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10(-10)), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.

In the National Cancer Institute Cancer Genetic Markers of Susceptibility (CGEMS) genome-wide association study of breast cancer, a single nucleotide polymorphism (SNP) marker, rs999737, in the 14q24.1 interval, was associated with breast cancer risk. In order to fine map this region, we imputed a 3.93 MB region flanking rs999737 for Stages 1 and 2 of the CGEMS study (5,692 cases, 5,576 controls) using the combined reference panels of the HapMap 3 and the 1000 Genomes Project. Single-marker association testing and variable-sized sliding-window haplotype analysis were performed, and for both analyses the initial tagging SNP rs999737 retained the strongest association with breast cancer risk. Investigation of contiguous regions did not reveal evidence for an additional independent signal. Therefore, we conclude that rs999737 is an optimal tag SNP for common variants in the 14q24.1 region and thus narrow the candidate variants that should be investigated in follow-up laboratory evaluation.

DNA damage is an important mechanism in carcinogenesis, so genes related to maintaining genomic integrity may influence papillary thyroid cancer (PTC) risk. Candidate gene studies targeting some of these genes have identified only a few polymorphisms associated with risk of PTC. Here, we expanded the scope of previous candidate studies by increasing the number and coverage of genes related to maintenance of genomic integrity. We evaluated 5077 tag single-nucleotide polymorphisms (SNPs) from 340 candidate gene regions hypothesized to be involved in DNA repair, epigenetics, tumor suppression, apoptosis, telomere function and cell cycle control and signaling pathways in a case–control study of 344 PTC cases and 452 matched controls. We estimated odds ratios for associations of single SNPs with PTC risk and combined P values for SNPs in the same gene region or pathway to obtain gene region-specific or pathway-specific P values using adaptive rank-truncated product methods. Nine SNPs had P values

To identify the frequency of pregnancy and neonatal complications in pregnancies carrying fetuses affected with trichothiodystrophy (TTD).We identified pregnancy and neonatal complications and serum screening results from mothers of TTD patients in a DNA repair diseases study from 2001 to 2011.Pregnancy reports of 27 TTD patients and their 23 mothers were evaluated and 81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, and 4% had an emergency c-section for fetal distress, while 44% had two or more complications. Only 19% of the pregnancies delivered at term without complications. Eight of the ten pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotrophin. Eighty-five percent of the neonates had complications: 70% were low birth weight (2500 g), 35% had birth weight10 centile for gestational age, 70% had NICU admission, 67% had a collodion membrane, and 31% of the 16 males had cryptorchidism. Cataracts were present in 54% of the TTD patients examined.TTD is a multisystem disease that predisposes mothers of affected patients to substantial risks for pregnancy complications and TTD neonates have a high incidence of multiple abnormalities.

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.

Patients treated for Hodgkin’s disease with radiation therapy, chemotherapy, or both, are often cured with potential lives ahead of them. It is now obvious, however, that many of these patients will develop solid tumors in the years after their successful treatment for Hodgkin’s disease. These tumors include non-Hodgkin’s lymphomas, lung cancers, sarcomas, and gastrointestinal malignancies, as well as other solid tumors. Understanding the epidemiology of the development of these solid tumors should allow us to design therapies in the future that diminish the risk of developing these second cancers.

Background: Although dysplastic nevi are an important risk factor for melanoma, little is understood about the epidemiology of these nevi. To further characterize some of the correlates of dysplastic nevi, we reexamined patients from one of the original prevalence reports and their first-degree relatives. Objective: Our purpose was to characterize the prevalence and correlates of dysplastic nevi. Methods: We studied 25 persons originally diagnosed with dysplastic nevi in 1980 and 1981, 28 controls stratified by age, sex, race, and date of initial examination, and all willing first-degree relatives of both patients (n = 78) and control subjects (n = 76). Each study subject underwent a full skin examination and biopsy of nevi suspected of being dysplastic nevi, if willing. Results: Eighty percent of the case kindreds were multiplex (2 members or more affected) for dysplastic nevi; the relative risk of having dysplastic nevi was 7.2 (95% confidence interval 2.1 to 24) if one or more relatives had dysplastic nevi. Three of the cases (12%) in multiplex families also had a first-degree relative with melanoma. Cases and relatives with dysplastic nevi of both patients and control subjects tended to have increased numbers of nevi. The risk of having dysplastic nevi rose 99-fold in persons with more than five nevi 4 mm or larger and/or scars on their back (p Conclusion: These data support the hypothesis that family members of unselected persons with dysplastic nevi are likely to have dysplastic nevi and may be at increased risk of melanoma.

We evaluated the risk of developing melanoma over time in members of 23 melanoma-prone families. All 23 families had dysplastic nevi as well as melanoma. Forty-seven melanomas occurred prospectively, all in family members with dysplastic nevi. The prospective melanomas were markedly thinner than the melanomas diagnosed prior to or at the time of the subject's entry into the study. The cumulative risk of melanoma by age 50 years among people with dysplastic nevi was 48.9% +/- 4.2%. Overall, the relative risk of a prospective melanoma among family members with previous melanoma was 229 (95% confidence interval 110-422). The risk varied by time interval and was 362 in the first 5 years, decreasing to 120 after 5 years. The risk of developing melanoma was 85 times increased (95% confidence interval 41-156) in family members with dysplastic nevi and also declined over time in this group. There was no significant excess of cancers other than melanoma. Close surveillance of these high-risk families has led to diagnosis of melanoma at an earlier developmental stage, which should result in a decrease in mortality over time.

Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM). In addition to CDKN2A, the major known high-risk susceptibility gene for CMM, recent studies suggest that other 9p21 genes may be involved in melanoma/nevi development. To identify 9p21 variants that influence susceptibility to CMM and number of nevi in CMM-prone families with and without CDKN2A mutations, we analyzed 562 individuals (183 CMM) from 53 families (23 CDKN2A+, 30 CDKN2A-) for 233 tagging SNPs in 21 genes at 9p21. Single SNP- and gene-based regression analyses were used to assess the risk of CMM, nevi count, skin complexion, and tanning ability associated with these SNPs and genes. We found that SNP rs7023329 in the MTAP gene was associated with number of nevi (P (trend) = 0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (P (trend) = 0.002), rs17288067 (P (trend) = 0.0009), and rs10813813 (P (trend) = 0.005), showed the strongest associations with CMM risk. None of the examined 9p21 SNPs was associated with skin complexion, whereas two SNPs, rs10964862 in IFNW1 (P (trend) = 0.003), and rs13290968 in TUSC1 (P (trend) = 0.0006), were associated with tanning ability. Gene-based analyses suggested that the ACO1 gene was significantly associated with CMM (P = 0.0004); genes IFNW1 (P = 0.002) and ACO1 (P = 0.0002) were significantly associated with tanning ability. Our findings are consistent with recent proposals that additional 9p21 genes may contribute to CMM susceptibility in CMM-prone families. These genetic variants may, at least partially, exert their effects through nevi and tanning ability.

Background: Genome-wide association studies have identified multiple genetic variants associated with susceptibility to prostate cancer (PrCa). In the two-stage Cancer Genetic Markers of Susceptibility prostate cancer scan, a single-nucleotide polymorphism (SNP), rs10486567, located within intron 2 of JAZF1 gene on chromosome 7p15.2, showed a promising association with PrCa overall (P = 2.14 × 10−6), with a suggestion of stronger association with aggressive disease (P = 1.2 × 10−7). Methods: In the third stage of genome-wide association studies, we genotyped 106 JAZF1 SNPs in 10,286 PrCa cases and 9,135 controls of European ancestry. Results: The strongest association was observed with the initial marker rs10486567, which now achieves genome-wide significance [P = 7.79 × 10−11; ORHET, 1.19 (95% confidence interval, 1.12-1.27); ORHOM, 1.37 (95% confidence interval, 1.20-1.56)]. We did not confirm a previous suggestion of a stronger association of rs10486567 with aggressive disease (P = 1.60 × 10−4 for aggressive cancer, n = 4,597; P = 3.25 × 10−8 for nonaggressive cancer, n = 4,514). Based on a multilocus model with adjustment for rs10486567, no additional independent signals were observed at chromosome 7p15.2. There was no association between PrCa risk and SNPs in JAZF1 previously associated with height (rs849140; P = 0.587), body stature (rs849141, tagged by rs849136; P = 0.171), and risk of type 2 diabetes and systemic lupus erythematosus (rs864745, tagged by rs849142; P = 0.657). Conclusion: rs10486567 remains the most significant marker for PrCa risk within JAZF1 in individuals of European ancestry. Impact: Future studies should identify all variants in high linkage disequilibrium with rs10486567 and evaluate their functional significance for PrCa. Cancer Epidemiol Biomarkers Prev; 19(5); 1349–55. ©2010 AACR.

To quantify the risk of subsequent primary cancers among patients with primary cutaneous malignant melanoma.Population-based registry study.We evaluated data from 9 cancer registries of the Surveillance, Epidemiology, and End Results program from 1973-2006.We included 89 515 patients who survived at least 2 months after their initial melanoma diagnosis.Of the patients with melanoma, 10 857 (12.1%) developed 1 or more subsequent primary cancers. The overall risk of a subsequent primary cancer increased by 28% (observed to expected [O:E] ratio = 1.28). One quarter of the cancers were subsequent primary melanomas (O:E = 8.61). Women with head and neck melanoma and patients younger than 30 had markedly increased risks (O:E = 13.22 and 13.40, respectively) of developing a subsequent melanoma. Second melanomas were more likely to be thin than were the first of multiple primary melanomas (thickness at diagnosis1.00 mm, 77.9% vs 70.3%, respectively; P.001). Melanoma survivors had increased risk of developing several cancers; the most common cancers with elevated risks were breast, prostate, and non-Hodgkin lymphoma (O:E = 1.10, 1.15, and 1.25, respectively).Melanoma survivors have an approximately 9-fold increased risk of developing subsequent melanoma compared with the general population. The risk remains elevated more than 20 years after the initial melanoma diagnosis. This increased risk may be owing to behavioral factors, genetic susceptibility, or medical surveillance. Although the percentage of subsequent primary melanomas thicker than 1 mm is lower than for the first of multiple primary melanomas, it is still substantial. Melanoma survivors should remain under surveillance not only for recurrence but also for future primary melanomas and other cancers.

Purpose: The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histologic subtypes and predict survival for non–small cell lung cancer. Experimental Design: We analyzed miR expression in 165 adenocarcinoma and 125 squamous cell carcinoma (SQ) tissue samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using a custom oligo array with 440 human mature antisense miRs. We compared miR expression profiles using t tests and F tests and accounted for multiple testing using global permutation tests. We assessed the association of miR expression with tobacco smoking using Spearman correlation coefficients and linear regression models, and with clinical outcome using log-rank tests, Cox proportional hazards, and survival risk prediction models, accounting for demographic and tumor characteristics. Results: MiR expression profiles strongly differed between adenocarcinoma and SQ (Pglobal < 0.0001), particularly in the early stages, and included miRs located on chromosome loci most often altered in lung cancer (e.g., 3p21-22). Most miRs, including all members of the let-7 family, were downregulated in SQ. Major findings were confirmed by quantitative real time-polymerase chain reaction (qRT-PCR) in EAGLE samples and in an independent set of lung cancer cases. In SQ, the low expression of miRs that are downregulated in the histology comparison was associated with 1.2- to 3.6-fold increased mortality risk. A five-miR signature significantly predicted survival for SQ. Conclusions: We identified a miR expression profile that strongly differentiated adenocarcinoma from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches. Clin Cancer Res; 16(2); 430–41

CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM) but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A+, 9 CDKN2A−) for 1536 SNPs in 152 genes involved in DNA repair, apoptosis, and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway- and gene-based permutation analyses were used to assess the risk of CMM associated with genes in the five pathways (DNA repair, apoptosis, TNF/NFκB, TH1:TH2, and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9, and JAK3 that were associated with CMM risk (P

Objective To investigate the risk of cataract extraction among adult retinoblastoma survivors. Design A retrospective cohort study was performed on retinoblastoma survivors who received the diagnosis from 1914 to 1984 and were interviewed in 2000. Lens doses were estimated from radiotherapy records. The cumulative time interval to cataract extraction between dose groups was compared using the log-rank test and Cox regression. Results Seven hundred fifty-three subjects (828 eyes) were available for analysis for an average of 32 years of follow-up. During this period, 51 cataract extractions were reported. One extraction was reported in an eye with no radiotherapy compared with 36 extractions in 306 eyes with 1 course of radiotherapy and 14 among 38 eyes with 2 or 3 treatments. The average time interval to cataract extraction in irradiated eyes was 51 years (95% confidence interval [CI], 48-54) following 1 treatment and 32 years (95% CI, 27-37) after 2 or 3 treatments. Eyes exposed to a therapeutic radiation dose of 5 Gy or more had a 6-fold increased risk (95% CI, 1.3-27.2) of cataract extraction compared with eyes exposed to 2.5 Gy or less. Conclusions The results emphasize the importance of ophthalmologic examination of retinoblastoma survivors who have undergone radiotherapy. The risk of cataract extraction in untreated eyes with retinoblastoma is comparable with the risk of the general population.

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.

BACKGROUND: Emerging data suggest that cutaneous malignant melanomas (CMM) may arise through divergent cancer pathways that are linked to intermittent versus accumulated sun exposure. However, numerous questions remain regarding the timing and/or age of exposure. METHODS: The authors systematically examined the effect of aging on CMM incidence in data from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Standard descriptive epidemiology was supplemented with mathematical models. The impact of advancing age on CMM incidence was assessed by sex, histopathologic classification (superficial spreading melanoma [SSM] or lentigo maligna melanoma [LMM]), and anatomic site (face, head, and neck [FHN] or lower extremity [LE]). RESULTS: Sex, histopathology, and anatomic site were age-specific effect modifiers for CMM that indicated divergent (bimodal) early-onset and late-onset cancer pathways. Early-onset melanomas were associated predominantly with women, SSM, and LE. Late-onset melanomas were correlated with men, LMM, and FHN. Early- and late-onset melanoma populations were confirmed with age-period-cohort models that were adjusted for period and cohort effects. Two-component mixture models also fit the data better than a single cancer population. CONCLUSIONS: The current results were consistent with a divergent and age-dependent solar hypothesis for CMM. Early-onset melanomas may represent gene-sun exposure interactions that occur early (and/or intermittently) in life among susceptible individuals. Late-onset melanomas may reflect accumulated, lifelong sun exposure in comparatively less susceptible individuals. Future analytical studies should be powered adequately to account for this age-dependent effect modification both for acknowledged melanoma risk factors (sex, histopathology, and anatomic site) and for suspected melanoma risk factors, such as constituent genetic variants. Cancer 2009. Published 2009 by the American Cancer Society.

Dear Sir, The CDKN2A gene on chromosome 9p21.3 is the major known high-risk melanoma susceptibility gene. However, despite the fact that more than half of familial melanoma has been linked to chromosome 9p, only about 20–40% of melanoma-prone families have mutations in CDKN2A (De Snoo and Hayward, 2005; Goldstein et al., 2006). Several groups have found recurrent regions of loss of heterozygosity (LOH) and deletion on chromosome 9p in both sporadic and familial melanoma that do not encompass the CDKN2A locus (Figure 1A; Puig et al., 1995; Parris et al., 1999; Pollock et al., 2001). Therefore, an additional unidentified tumor suppressor gene(s) on chromosome 9p may also be responsible for inherited susceptibility to melanoma. Figure 1 (A) Schematic of chromosome 9p showing the location of the CDKN2A gene at 9p21.3 (21.958–21.984 Mb) and the PTPRD gene at 9p23–24.1 (8.304–10.603 Mb). Recurrent regions of LOH in a panel of 37 melanomas (Pollock et al., 2001) are ... The PTPRD gene at chromosome 9p23–24.1 encodes one of 21 known human receptor-type protein tyrosine phosphatases, a family of proteins which are increasingly thought to be important in cancer development and progression (for reviews see Tonks, 2006; Ostman et al., 2006). PTPRD was first theorized to be a tumor suppressor by Urushibara et al. (1998) who described a selective reduction in PTPRD expression in hepatomas. This theory was supported by the discovery of genomic deletions of PTPRD in several human cancer cell lines by Cox et al. (2005). Subsequent studies have reported homozygous deletions of PTPRD in a broad spectrum of human tumor types including lung adenocarcinoma (Nagayama et al., 2007; Sato et al., 2005; Weir et al., 2007; Zhao et al., 2005), pancreatic carcinoma (Calhoun et al., 2006), melanoma (Stark and Hayward, 2007), neuroblastoma (Stallings et al., 2006), glioblastoma multiforme (Solomon et al., 2008), and cutaneous squamous cell carcinoma (Purdie et al., 2007). Somatic mutations of PTPRD in human cancer were first discovered by Sjoblom et al. (2006) who identified three missense substitutions in a panel of 35 colorectal cancers. Two additional studies have since described mutation of PTPRD in lung adenocarcinoma (Ding et al., 2008; Weir et al., 2007). Most recently, somatic mutations of PTPRD were discovered in glioblastoma multiforme (GBM) and melanoma (Solomon et al., 2008). While, PTPRD was mutated in only a modest fraction of lung cancers (6%) and GBMs (6%), the 12% mutation frequency in melanoma makes PTPRD among the most commonly mutated genes in sporadic melanoma reported to date, which include B-Raf (~60%), p53 (0–25%), N-Ras (10–15%), PTEN (~10%), CDKN2A (0–5%), and PIK3CA (

Melanoma is a complex, heterogeneous cancer that continues to increase in incidence. Multiple studies have consistently identified major host and environmental risk factors for melanoma. Nevi, particularly dysplastic nevi, confer much higher risks than most pigmentary characteristics. Ultraviolet radiation exposure is the predominant environmental risk factor for melanoma. Recently, both rare high risk susceptibility genes and common polymorphic genes contributing to melanoma risk have been identified.

Family history (FH) of lung cancer is an established risk factor for lung cancer, but the modifying effect of smoking in relatives has been rarely examined. Also, the role of FH of non-malignant lung diseases on lung cancer risk is not well known. We examined the role of FH of cancer and FH of non-malignant lung diseases in lung cancer risk, overall, and by personal smoking, FH of smoking, and histology in 1,946 cases and 2,116 population-based controls within the Environment And Genetics in Lung cancer Etiology (EAGLE) study. Odds ratios (ORs) and 95% CI from logistic regression were calculated adjusting for age, gender, residence, education, and cigarette smoking. FH of lung cancer in any family member was associated with increased lung cancer risk (OR = 1.57, 95% CI = 1.25–1.98). The odds associated with fathers’, mothers’ and siblings’ history of lung cancer were 1.41, 2.14, and 1.53, respectively. The associations were generally stronger in never smokers, younger subjects, and for the adenocarcinoma and squamous cell carcinoma subtypes. FH of chronic bronchitis and pneumonia were associated with increased (OR =1.49, 95% CI = 1.23–1.80) and decreased (OR = 0.73, 95% CI = 0.61–0.87) lung cancer risk, respectively. FH of lung cancer and FH of non-malignant lung diseases affected lung cancer risk independently, and did not appear to be modified by FH of smoking.

To examine incidence and survival patterns of acral lentiginous melanoma (ALM) in the United States.Population-based registry study. We used the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute to evaluate data from 17 population-based cancer registries from 1986 to 2005.A total 1413 subjects with histologically confirmed cases of ALM. Main Outcome Measure Incidence and survival patterns of patients with ALM.The age-adjusted incidence rate of ALM overall was 1.8 per million person-years. The proportion of ALM among all melanoma subtypes was greatest in blacks (36%). Acral lentiginous melanoma had 5- and 10-year melanoma-specific survival rates of 80.3% and 67.5%, respectively, which were less than those for all cutaneous malignant melanomas overall (91.3% and 87.5%, respectively; P.001). The ALM 5- and 10-year melanoma-specific survival rates were highest in non-Hispanic whites (82.6% and 69.4%), intermediate in blacks (77.2% and 71.5%), and lowest in Hispanic whites (72.8% and 57.3%) and Asian/Pacific Islanders (70.2% and 54.1%). Acral lentiginous melanoma thickness and stage correlated with survival according to sex and in the different racial groups.Population-based data showed that ALM is a rare melanoma subtype, although its proportion among all melanomas is higher in people of color. It is associated with a worse prognosis than cutaneous malignant melanoma overall. Hispanic whites and Asian/Pacific Islanders have worse survival rates than other groups, and factors such as increased tumor thickness and more advanced stage at presentation are the most likely explanations.

Background Although the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined. Methodology/Principal Findings Using mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D.C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2–10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: −0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: −0.1, 10.4) and 3.7 years for men (95% CI: −0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p = 0.024). Conclusions/Significance These findings suggest that there may be unknown effects of BRCA1/2 mutations on non-neoplastic diseases that cause death at older ages.

Nonmelanoma skin cancer. Nonmelanoma skin cancer (NMSC) is the most common malignant neoplasm in the US white population, and its incidence has been increasing for several decades. An estimated 600,000 cases will occur in 1990.’ NMSCs generally are not reported to tumor registries, and statistics on skin cancer are not readily available from hospital sources. Because most patients are treated in outpatient settings, populationbased estimates of NMSC incidence require special surveys to collect data. The National Cancer Institute (NCI) has conducted two such US surveys. The first was conducted as an adjunct of the Third National Cancer Survey* in 197 l1972 in four geographic areas with varying ultraviolet radiation (UVR) intensities. The second and more comprehensive survey identified 30,000 individu