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Background: Malignant melanoma has been one of the most rapidly increasing cancers within the United States with few modifiable risk factors. This study investigates risk related to dietary factors, which are potentially modifiable. Methods: Newly diagnosed patients with melanoma (n = 502) were recruited from pigment lesion clinics and controls (n = 565) were recruited from outpatient clinics. To investigate the relationship between melanoma and dietary factors in this case-control study, study subjects were requested to complete a food frequency questionnaire, which assessed diet over the previous year. Using logistic regression, odds ratios (ORs) for melanoma were computed for nutrient and alcohol intake. Results: Persons in high versus low quintiles of energy-adjusted vitamin D, α-carotene, β-carotene, cryptoxanthin, lutein, and lycopene had significantly reduced risk for melanoma (ORs ≤ 0.67), which remained after adjustment for presence of dysplastic nevi, education, and skin response to repeated sun exposure. Addition of micronutrients from supplements did not add an additional reduction in risk. High alcohol consumption was associated with an increased risk for melanoma, which remained after adjustment for confounders [OR (95% confidence interval) in highest versus lowest quintiles, 1.65 (1.09-2.49)]. Conclusions: Diets consisting of foods rich in vitamin D and carotenoids and low in alcohol may be associated with a reduction in risk for melanoma. These analyses should be repeated in large, prospective studies.

Background: The CDKN2A gene is the major known high-risk melanoma susceptibility gene. Susceptibility to other cancers has also been suggested. However, most studies examining the risks of other cancers classified individuals according to the family's CDKN2A mutation rather than determining individual mutation status. For non-population-based studies, risks could also be biased because of cancer occurrence prior to family ascertainment. Methods: We examined the risk of non-melanoma cancer in 117 mutation-positive and 136 mutation-negative members from 15 families that had at least two first degree relatives with melanoma and CDKN2A mutations restricting the analysis to the period after the families were ascertained (that is, the prospective period) and using individual mutation data. The families have been followed prospectively for 4–26 years starting in the 1970s. Results: Overall, there was no significant association for mutation-negative subjects (Obs/Exp = 0.3, 95% confidence interval (CI) 0.0 to 1.2) although this group had only two observed cancers. In contrast, mutation-positive subjects had a significantly increased risk for all cancers combined (Obs/Exp = 12/5.5 = 2.2, 95% CI 1.1 to 3.8) primarily because of digestive system tumours, particularly pancreatic cancer. No other organ systems or individual tumour sites showed significantly increased risks. Conclusions: Differences in CDKN2A–non-melanoma cancer associations across studies may result from variation in genetic backgrounds, insufficient follow up, misclassification of mutation carriers, or the presence of other genetic and/or environmental risk factors in both CDKN2A mutation carriers and non-carriers. Larger sample sizes, prospective follow up, and individual mutation data will be required to understand these differences.

Two recent papers suggest distorted sex and transmission ratios associated with BRCA1 mutations. If real, these would provide novel insights into the normal biological function of this gene and have implications for genetic epidemiologic methods used to estimate penetrance. We addressed these observations in two settings: offspring of 283 mutation carriers and 471 mutation negative subjects from BRCA1/2 mutation-positive families with multiple cases of breast and ovarian cancer (NCI families); and relatives of 115 BRCA1/2 mutation carriers from the Washington Ashkenazi Study (WAS). The male:female ratio was below one in both BRCA1 (0.85, 95% CI 0.7-1.1 in NCI families; 0.90, 95% CI 0.6-1.4 in WAS) and BRCA2 families (0.77, 95% CI 0.5-1.3 and 0.80, 95% CI 0.5-1.2, in the NCI and WAS study groups, respectively). None of the sex ratios deviated significantly from one, and there was no significant difference between BRCA1 and BRCA2 families. The reduced sex ratio was due largely to the offspring of males, a distortion that is probably an artifact of ascertainment biases. Among adult daughters without breast or ovarian cancer born to mutation carriers, as expected, fewer than 50% were mutation carriers (39% in BRCA1 families and 44% in BRCA2 families). It is difficult, due to ascertainment biases, to draw firm conclusions regarding sex ratios in studies of a sex-limited phenotype. Nonetheless, these observations do not support the idea that BRCA1 mutation carriers have a lower ratio of male offspring than BRCA2 mutation carriers.

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.

The CDKN2A gene, which encodes the proteins p16(INK4a) and p14(ARF), is located on chromosome 9p21. Germline mutations at this locus increase susceptibility to cutaneous malignant melanoma (CMM). In general, missense and nonsense mutations are primarily responsible for defective p16(INK4a) and possibly p14(ARF) protein function and account for approximately 20% of inherited CMM cases. We report a G>T transversion mutation in the last nucleotide of exon 2, affecting the aspartic acid residue at position 153 of CDKN2A-p16(INK4a) in a proband with melanoma. If splicing were unaffected, this mutation would change Asp to Tyr. RT-PCR analysis, however, revealed that this mutation, which we have termed D153spl(c.457G>T), and a previously described mutation at the next nucleotide, IVS2+1G>T, result in identical aberrant splicing affecting both p16(INK4a) and p14(ARF). The two main alternate splice products for each of the two normal transcripts includes a 74 bp deletion in exon 2, revealing a cryptic splice site, and the complete skipping of exon 2. The dual inactivation of p16(INK4a) and p14(ARF) may contribute to the CMM in these families.

Melanoma incidence rates are rising rapidly, particularly in older men. Older men are also more likely to have thick melanomas, which confer high mortality and morbidity. The reasons for the rate of increase are not known; increasing sun and UV exposure, however, is the major hypothesized explanation. In the past several years, two major susceptibility genes for melanoma, CDKN2A and CDK4, have been identified, but the two genes together account for a minority of familial melanoma. Other high-risk susceptibility genes are being sought actively. Genetic epidemiologic studies suggest that penetrance of each of the two identified genes is altered by other factors, either genetic or environmental. Epidemiologic studies have also identified other major host factors important in the development of melanoma. In European, North American, and Australian populations, the presence of clinically identified dysplastic nevi confers greatly increased risk of melanoma. A new measure of sun exposure, based on individual residential history, confers substantially increased risk of melanoma. Recent surveys of sun behavior in the US reveal extensive sunburning and use of tanning beds in adolescents and adults. Sun protective behaviors are not as prevalent as in Australia, where population rates of melanoma are stabilizing.

Chromosome 1 abnormalities are the most commonly detected aberrations in many cancers including malignant melanoma. Partial deletions and an allelic loss of the chromosome 1p36 region observed in melanoma indicate the presence of putative tumor suppressor gene(s) in this region. A candidate gene, CDC2L1, which encodes PITSLRE proteins related to p34(cdc2), is mapped to 1p36. To determine whether CDC2L1 mutation is involved in melanoma development, we examined 20 melanoma cell lines and 11 members of melanoma-prone families linked to chromosome 1p36. Mutation analysis throughout the entire coding region of the CDC2L1 gene revealed only 1 mutation (C-->T at nucleotide location 97 of exon 7, Ser-->Leu) in the melanoma cell line UACC 903 out of 20 melanoma cell lines and 6 melanoma cases. However, 4 polymorphic nucleotide changes, C-48T, G-53C, T-103C and T-210C, in the putative promoter region of CDC2L1 were identified. The 4 variants were located within or beside the conserved binding sites of transcription factors TCF11, MZF1 and TAAC box, indicating their potential effects on the regulation of CDC2L1 expression. No aberrant methylation of the CDC2L1 CpG island in the promoter region was observed by sodium bisulfite genomic sequencing. These results indicate that mutations are rare in the CDC2L1 gene in these melanoma cell lines and melanoma families and that the aberrant cytosine methylation of the CDC2L1 CpG island is not the mechanism of CDC2L1 repression in melanoma. The contribution of 4 promoter polymorphisms to the transcriptional regulation of the gene and its association with melanoma warrants further investigation.

Background: Currently, women are referred for BRCA1/2 mutation testing if their family history of breast and ovarian cancer indicates they have sufficient probability of carrying mutations. In contrast, calls have intensified for population-wide testing for BRCA1/2 founder mutations among Ashkenazi Jews, due to relatively high mutation prevalence (2.5%) and decreasing genotyping costs. However, population-wide testing would strain genetic counseling resources and incur costs from testing mostly mutation-negative women. We compared the performance of population-wide vs. carrier-probability-based BRCA1/2 testing in the community-based Washington Ashkenazi Study (WAS). Methods: BRCA1/2 carrier-probabilities based on reported family histories were calculated using BRCAPRO for 4589 probands (102 BRCA1/2 mutation-carriers) in WAS. For each carrier-probability threshold, we compared the percent of mutations found (sensitivity) vs. the percent of women requiring mutation testing, overall and by proband age. At example carrier-probability thresholds, undetected and detected carriers’ attributes were compared using nonparametric tests. Results: A 1.2% carrier-probability threshold identified 80% of BRCA1/2 mutations in the 35% of women with highest carrier-probability. For women under age 40, 94% of BRCA1/2 mutations were identified in the 50% of women with highest carrier-probability. Compared to identified mutation-carriers, missed mutation-carriers had no personal cancer history, no affected first- and second-degree relatives (p Conclusion: Carrier-probability-based BRCA1/2 mutation testing identified large majorities of mutation-carriers and would have avoided testing for many mutation-negative women. Missed mutation-carriers were older and cancer-free and would gain minimal benefit from risk-reducing interventions. A cost-effective carrier-probability threshold could acceptably tradeoff identifying BRCA1/2 mutation carriers before they get cancer while testing as few women as possible. Citation Format: Ana F. Best, Margaret A. Tucker, Hormuzd A. Katki. Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4271. doi:10.1158/1538-7445.AM2017-4271

In children and adolescents, osteosarcoma (OS) is the most common malignant bone tumor. OS occurs in certain cancer predisposition syndromes at a higher than expected frequency. However, outside of these rare syndromes, OS is significantly more common and its genetic etiology remains poorly understood. We conducted an evaluation of rare exonic variants in 545 unselected OS cases compared with 1061 cancer-free controls using whole-exome sequencing of blood or buccal cell DNA to estimate the prevalence and burden of rare deleterious germline variants. We assessed potentially pathogenic rare variants in 126 established cancer predisposing genes (CPG) and known somatically mutated genes. We also surveyed the exome for genes with a higher burden of rare variants in 342 EUR cases with 994 EUR controls sequenced at the same time. Rare genetic variants, defined by a MAF A total of 14.5% of cases had a predicted pathogenic or high impact variant in an autosomal dominant CPG. A significantly higher pathogenic rare variant burden was present in EUR cases compared with EUR controls (Pburden=3.7x10-05). TP53 had the highest prevalence of pathogenic mutations (5% of EUR cases; Pburden=1.05x10-09). CDKN2A, MEN1, MLH1, MUTYH, PALB2 and VHL had a significantly higher rare variant burden in the EUR cases. 7.5% of cases had a predicted pathogenic or probably pathogenic variant in an autosomal recessive CPG (Pburden=5.4x10-03). Additionally, two males had a pathogenic variant in the X-linked genes, DKC1 and GPC3. In total, 21% of cases had a predicted pathogenic or high impact variant in a CPG (Pburden=2.4x10-07). Exome-wide analysis identified two novel genes with significantly higher rare variant burdens in the cases compared to controls. In conclusion, several CPGs and two novel genes, not previously associated with OS, had an enrichment of rare variants in OS and warrant further follow-up. Our results indicate that a clinically significant fraction of OS cases may harbor one or more mutations worthy of consideration for further investigation and genetic counseling. Citation Format: Roelof Koster, Bin Zhu, Meredith Yeager, Michael Dean, Matthew Gianferante, Lei Song, Joshua Sampson, NCI DCEG Cancer Genomics Research Laboratory, Julie Gastier-Foster, Richard Gorlick, Silvia Regina Caminada de Toledo, Antonio Petrilli, Ana Patiño-Garcia, Fernando Lecanda, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, Adrienne Flanagan, Roberto Tirabosco, Maria Amary, Nilgün Kurucu, Inci Ergurhan Ilhan, Neriman Sari, Mandy Ballinger, David Thomas, Donald Barkauskas, Belynda Hicks, Margaret Tucker, Neil Caporaso, Robert Hoover, Stephen Chanock, Sharon Savage, Lisa Mirabello. Whole-exome sequencing identifies a high frequency of germline deleterious variants in cancer predisposition genes in individuals with osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4871. doi:10.1158/1538-7445.AM2017-4871

Previous studies have demonstrated elevated risks for tMDS/AML after chemotherapy for non-Hodgkin lymphoma, Hodgkin lymphoma, and plasma cell neoplasms, but current treatment practices have changed considerably. We utilized large-scale, population-based cancer registry data from the United States to quantify for the first time tMDS/AML risks after chemotherapy for lymphoid malignancies in the current treatment era, including analysis for specific non-Hodgkin lymphoma subtypes. In 17 registries, we identified 121,840 adults without HIV infection who survived ≥1 year following a first primary lymphoid malignancy diagnosis during 2000-2013 and were initially treated with chemotherapy. tMDS/AML risk was compared with that expected in the general population using SIRs. tMDS/AML risk was significantly increased 5- to 9-fold after chemotherapy for the most common lymphoid malignancies, including DLBCL, plasma cell neoplasms, follicular lymphoma, Hodgkin lymphoma, and CLL/SLL (Table 1). Approximately 5-fold increased risks were observed after chemotherapy for marginal zone lymphoma, LPL/WM, and other/unspecified lymphomas. In contrast, risks were strikingly elevated (>10-fold) after chemotherapy for precursor leukemia/lymphoma, Burkitt lymphoma/leukemia, peripheral T-cell lymphoma, and mantle cell lymphoma. Only chemotherapy for hairy cell leukemia was not associated with increased tMDS/AML risk (SIR=1.4), albeit based on small numbers. tMDS/AML risks were higher By time since lymphoid neoplasm diagnosisOverall1.0-4.9 years≥5 yearsFirst primary lymphoid malignancyTotal (N)Mean age at diagnosis (y)NSIR(95%CI)NSIR(95%CI)NSIR(95%CI)Hodgkin lymphoma16,74840.3659.0(6.9, 11.4)4310.7(7.8, 14.5)226.8(4.3, 10.3)CLL/SLL8,47864.31129.4(7.7, 11.3)729.2(7.2, 11.6)409.8(7.0, 13.3)DLBCL31,69259.72045.6(4.8, 6.4)1265.6(4.7, 6.7)785.5(4.4, 6.9)Follicular lymphoma15,65659.51457.8(6.6, 9.2)867.9(6.3, 9.8)597.7(5.8, 9.9)Marginal zone lymphoma4,22362.8295.5(3.7, 7.8)195.7(3.4, 8.9)105.1(2.4, 9.4)Plasma cell neoplasms22,75363.21176.1(5.0, 7.3)795.4(4.3, 6.8)388.2(5.8, 11.2)Precursor leukemia/lymphoma3,53042.73237.3(25.5, 52.7)2852.6(35.0, 76.1)412.3(3.3, 31.4)Mantle cell lymphoma3,52163.44010.1(7.3, 13.8)279.9(6.5, 14.4)1310.7(5.7, 18.3)LPL/WM1,95466.0134.3(2.3, 7.3)105.0(2.4, 9.2)32.8(0.6, 8.2)Peripheral T-cell lymphoma3,15655.73012.7(8.6, 18.1)2315.5(9.8, 23.2)78.0(3.2, 16.5)Burkitt lymphoma/leukemia1,18048.41924.3(14.6, 37.9)1328.6(15.2, 48.9)618.3(6.7, 39.8)Hairy cell leukemia1,70554.631.4(0.3, 4.2)~~Other, unspecified7,24462.0535.7(4.3, 7.4)386.6(4.7, 9.1)154.2(2.3, 6.9) Abbreviations: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); confidence interval (CI); diffuse large B-cell lymphoma (DLBCL); lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM); standardized incidence ratio (SIR); Surveillance, Epidemiology, and End Results (SEER); treatment-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML). Citation Format: Lindsay M. Morton, Graca M. Dores, Megan M. Herr, Martha S. Linet, Margaret A. Tucker, Rochelle E. Curtis. Risk of tMDS/AML after chemotherapy for first primary lymphoid malignancy, 2000-2013 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-236. doi:10.1158/1538-7445.AM2017-LB-236

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P

Purpose Hereditary retinoblastoma (Rb) survivors have increased risk of subsequent malignant neoplasms (SMNs). Previous studies reported elevated radiotherapy (RT) -related SMN risks, but less is known about chemotherapy-related risks. Patients and Methods In a long-term follow-up study of 906 5-year hereditary Rb survivors diagnosed from 1914 to 1996 and observed through 2009, treatment-related SMN risks were quantified using cumulative incidence analyses and multivariable Cox proportional hazards regression models with age as the underlying time scale. Results Nearly 90% of Rb survivors were treated with RT, and almost 40% received alkylating agent (AA) –containing chemotherapy (predominantly triethylenemelamine). Median follow-up time to first SMN diagnosis was 26.3 years. Overall SMN risk was not significantly elevated among survivors receiving AA plus RT versus RT without chemotherapy (hazard ratio [HR], 1.27; 95% CI, 0.99 to 1.63). AA-related risks were significantly increased for subsequent bone tumors (HR, 1.60; 95% CI, 1.03 to 2.49) and leiomyosarcoma (HR, 2.67; 95% CI, 1.22 to 5.85) but not for melanoma (HR, 0.74; 95% CI, 0.36 to 1.55) or epithelial tumors (HR, 0.89; 95% CI, 0.48 to 1.64). Leiomyosarcoma risk was significantly increased for survivors who received AAs at age < 1 (HR, 5.17; 95% CI, 1.76 to 15.17) but not for those receiving AAs at age ≥ 1 year (HR, 1.75; 95% CI, 0.68 to 4.51). Development of leiomyosarcoma was significantly more common after AA plus RT versus RT (5.8% v 1.6% at age 40 years; P = .01). Conclusion This comprehensive quantification of SMN risk after chemotherapy and RT among hereditary Rb survivors also demonstrates an AA-related contribution to risk. Although triethylenemelamine is no longer prescribed, our findings warrant further follow-up to investigate potential SMN risks associated with current chemotherapies used for Rb.

Background: With over 13 million cancer survivors in the United States today, second cancers are of rapidly growing importance. However, data on nontreatment risk factors for second cancers are sparse. We explored the feasibility of pooling data from cohort studies of cancer incidence to investigate second cancer etiology. Methods: We combined data from five prospective studies including more than 800,000 individuals. We compared study designs and populations; evaluated availability of and ability to harmonize risk factor data; compared incidence and survival for common first primary malignancies and incidence of second primary malignancies; and estimated sample size requirements. Results: Overall, 96,513 incident, first primary malignancies were diagnosed during 1985 to 2009. Incidence rates and survival following the first primary varied among the cohorts, but most of the heterogeneity could be explained by characteristics of the study populations (age, sex, smoking, and screening rates). A total of 7,890 second primary cancers (excluding original primary site) were identified, yielding sufficient statistical power (≥80%) for detecting modest associations with risk of all second cancers among survivors of common first primary malignancies (e.g., colorectal cancer); however, there were insufficient events for studying survivors of rarer cancers or identifying risk factors for specific second cancers. Conclusions: Pooling data from cohort studies to investigate nontreatment risk factors for second primary cancers seems feasible but there are important methodologic issues—some of which are barriers to specific research questions—that require special attention. Impact: Increased understanding of nontreatment risk factors for second cancers will provide valuable prevention and surveillance information. Cancer Epidemiol Biomarkers Prev; 23(8); 1598–608. ©2014 AACR.

Background: UV radiation (UVR) exposure is the primary risk factor for basal cell carcinoma (BCC). Although prescription diuretics have photosensitizing properties, the relationship between diuretic use and BCC remains unclear. Methods: Using data from the United States Radiologic Technologists Study, a large, nationwide prospective cohort, we assessed the relationship between diuretic use and first primary BCC while accounting for sun exposure history, constitutional characteristics, lifestyle factors, and anthropometric measurements for geographically dispersed individuals exposed to a wide range of ambient UVR. Results: After adjustment for potential confounders, we found a significantly increased risk of BCC associated with diuretic use [HR, 1.22; 95% confidence interval (CI), 1.07–1.38]. This relationship was modified by body mass index (P = 0.019), such that BCC risk was increased with diuretic use in overweight (HR, 1.43; 95% CI, 1.16–1.76) and obese individuals (HR, 1.43; 95% CI, 1.09–1.88), but not in normal weight individuals (HR, 0.99; 95% CI, 0.81–1.21). Conclusions: Increased risk of BCC associated with diuretic use in overweight and obese participants may be related to higher dosages, longer duration of medication use, reduced drug metabolism, or drug interactions. Impact: Future cohort studies should obtain more detailed information on medication use, consider factors that affect drug metabolism, and measure intermediate endpoints such as photosensitivity reactions. Cancer Epidemiol Biomarkers Prev; 23(8); 1539–45. ©2014 AACR.

Importance Tumor ulceration is an important prognostic factor for cutaneous melanoma (CM). Previous studies demonstrated that the proportion of ulcerated to nonulcerated CM rose with increasing tumor depth. These frequency-based studies, however, were not adjusted for the population at risk. Objective To determine the absolute incidence of ulcerated CM by tumor depth, stratified by sex and age at diagnosis. Design, Setting, and Participants We compared ulcerated CM by tumor thicknesses (≤1.00, 1.01-2.00, 2.01-4.00, and ≥4.01 mm), stratified by sex among younger (10-39 years) and older (40-84 years) non-Hispanic whites in the National Cancer Institute’s Surveillance, Epidemiology, and End Results database from 2004 through 2008. Types of CM included superficial spreading, nodular, and unclassified in 5106 cases among 3206 men and 1900 women. Main Outcomes and Measures Incidence of ulcerated CM by tumor depth for younger and older men and women. Results The incidence of tumor ulceration was stable across all tumor depths among younger men and older women. Among younger women, it declined for the thickest lesions (0.08 per 100 000 for tumor depth ≥4.01 mm), although the trend was not statistically significant. In contrast, among older men, there was a statistically significant increase in ulceration for CM with a depth of approximately 1.4 per 100 000 for tumor depth of 2.00 mm or thicker. Conclusions and Relevance Male sex is an age-specific effect modifier for ulcerated CM by tumor depth. Future studies and staging guidelines should consider the interaction among CM ulceration, thickness, sex, and age at diagnosis.

IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics. We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95% CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95% CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95% CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin.

We thank Pira and Coggiola for their comments1 on our paper.2 We agree that to estimate lifetime exposure to occupational carcinogens in a general population setting is a difficult task and requires valid assessment tools. It is for this reason that we chose as our job exposure matrix (JEM) the DOM-JEM that was developed specifically to be applied in studies of this kind.3 Pira and Coggiola express concern that the DOM-JEM is unable to distinguish between ‘no’, ‘low’ and ‘high’ exposed jobs/subjects. Their reasoning comes from the fact that among the 2529 men in our study classified as non-exposed to crystalline silica, two subjects reported at interview having been diagnosed with silicosis. We believe that our method is sound. First, with a JEM approach in a population-based study (as this lung cancer case-control is) the JEM constructors would have to aim for a more specific than sensitive JEM3 in order to prevent serious misclassification of non-exposed individuals and consequent attenuation of risk estimates.4 By creating a very specific JEM, like DOM-JEM, only jobs with relatively high intensity and high prevalence of exposed individuals performing these jobs will be assigned (high) exposure. So for instance, within DOM-JEM the job titles shown in Table 1, coded using the five-digit International Standard Classification for Occupations (ISCO) 1968 codes,5 are assigned a ‘high’ exposure to crystalline silica. Table 1 International Standard Classification for Occupations (ISCO) 1968 codes Also, to take into account the small actual difference in silica exposures between the ‘no’ and ‘low’ categories we decided to use the intensity weights of 0, 1 and 4 when estimating cumulative years of silica exposure. Second, as stated in our paper, the DOM-JEM has been compared with other JEMs and individual expert assessments in previous international studies.6,7 Notably, in the study of Peters et al.,6 the odds ratio for the association between lung cancer and silica obtained by applying the DOM-JEM was 1.26, almost identical to those obtained using case-by-case expert assessment (1.26) and a population-specific JEM (1.24). Similar results were obtained for exposure to diesel motor exhaust, whereas for asbestos DOM-JEM showed more consistent results as compared with the other two methods. Third, it is of course possible on rare occasions for a worker performing a theoretically non-exposed job to be exposed (e.g. a schoolteacher exposed to asbestos from a ceiling), but any resultant occurrence of cases of silicosis in the ‘no’ exposure group does not intrinsically invalidate the JEM. This misclassification can only be addressed (if at all) when the exposure can be assigned at the individual level, but it requires a much more detailed job history. Assigning all schoolteachers an exposure to asbestos based on an anecdotal example would be wrong and would create an enormous amount of falsepositively assigned exposures resulting in risk estimates attenuated towards the null. Fourth, the two cases of silicosis that we classified as non-exposed maybe incorrect due to reporting or diagnosis error. In fact, silicosis was only reported at interview in our study. Also, silicosis diagnosis is far from straightforward; radiographic evaluation even by qualified and experienced chest radiographers8 has a poor sensitivity and, whereas specificity is very good, false-positives may occur.9 In summary, we believe that the critique made by Pira and Coggiola of the DOM-JEM, based on a couple of (supposedly) misclassified subjects, without consideration of the whole study, is unfounded. DOM-JEM is a job-exposure matrix specifically developed for population-based studies, with only job-title information in the job histories and with the explicit philosophy of being rather more specific than sensitive in the assignment of exposures so as to avoid misclassification of non-exposed subjects as much as possible. The assigned levels are an informative relative ranking of ‘no’, ‘low’ and ‘high’ exposure and without calibration will have no absolute meaning on a ratio scale (e.g. mg/m3-years of silica exposure). Therefore, we stand by our conclusion that past occupational exposure to asbestos, silica and nickel-chromium, even at low levels, contributes substantially to the current lung cancer burden. Our estimates of population-attributable fractions of 18.1%, 5.7% and 7.0%, respectively, are necessarily imperfect but state-of-the-art and reasonable measures of the impact of these occupational carcinogens on lung cancer risk in this study population.2

A case–control study of non-familial melanoma including 183 incident cases and 179 controls was conducted in North-Eastern Italy to identify important risk factors and determine how combination of these affects risk in a Mediterranean population. Presence of dysplastic nevi (OR = 4.2, 95% CI = 2.4–7.4), low propensity to tan (OR = 2.4, 95% CI = 1.1–5.0), light eye (OR = 2.4, 95% CI = 1.1–5.2), and light skin colour (OR = 4.1, 95% CI = 1.4–12.1) were significantly associated with melanoma risk after adjustment for age, gender and pigmentation characteristics. A chart which identifies melanoma risk associated with combinations of these factors is presented; it can be used to identify subjects who would most benefit from preventive measures in Mediterranean populations. According to the combination of these factors, a relative risk range from 1 to 98.5 was found. Light skin colour, high number of sunburns with blistering, and low propensity to tan were significantly associated with melanoma thickness, possibly indicating that individuals with these characteristics underestimate their risk and seek attention when their lesion is already advanced. © 2001 Cancer Research Campaign

One of the most common melanoma-related CDKN2A mutations reported in North America is the V126D mutation. We examined nine markers surrounding CDKN2A in three American and four Canadian families carrying the V126D mutation. All seven families had a haplotype consistent with a common ancestor/founder for this mutation. In addition, the mutation appears to have originated 34–52 generations ago (1-LOD-unit support interval 13–98 generations). © 2001 Cancer Research Campaign http:///www.bjcancer.com

Introduction. Advances in treatment have improved prognosis after diagnosis with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Understanding factors that impact long-term morbidity and mortality of lymphoma survivors is therefore of increasing clinical importance. Elevated risk for developing cutaneous melanoma after lymphoma is well-established, but the potential extension of this association for rarer NHL subtypes and other types of cutaneous malignancies is unknown. Methods. We identified a cohort of 129,850 non-HIV infected adults (age ³20 years) who were initially diagnosed with one of the seven most common types of lymphoma (Table 1) during 2000-2013 and who survived ³1 year, as reported to 17 United States population-based cancer registries from the Surveillance, Epidemiology, and End Results program. Standardized incidence ratios (SIRs) and corresponding 95% confidence intervals (95% CI) quantified risks for second primary melanoma, Merkel cell carcinoma, and sebaceous carcinoma, comparing the observed number of cases to that expected in the general population based on age-, race-, sex- and calendar period-specific incidence rates. Results. Melanoma occurred in 258 survivors of CLL/SLL, nearly two-fold more often than expected in the general population (SIR=1.94, 95% CI=1.71-2.20). Risk also was significantly elevated among survivors of follicular lymphoma (N=108, SIR=1.32, 95% CI=1.08-1.32) and peripheral T-cell lymphoma (N=22, SIR=1.68, 95% CI=1.05-2.54), whereas SIRs were non-significantly greater than unity after other NHL subtypes except marginal zone lymphoma (N=37, SIR=1.06, 95% CI=0.74-1.46). Merkel cell carcinoma and sebaceous carcinomas were much rarer but were associated with substantially higher risks compared with melanoma. Merkel cell carcinoma also occurred most commonly after CLL/SLL (N=20, SIR=3.90, 95%CI=2.38-6.02) with significantly elevated SIRs after follicular lymphoma (N=8, SIR=2.99, 95%CI=1.29-5.89) and mantle cell lymphoma (N=7, SIR=16.04, 95% CI=6.45-33.04). In contrast, the risk patterns differed for sebaceous carcinoma, with elevated risks after CLL/SLL (N=10, SIR=5.04, 95% CI=2.42-9.27), DLBCL (N=7, SIR=5.13, 95% CI=2.06-10.57), marginal zone lymphoma (N=4, SIR=7.67, 95% CI=2.09-19.63), and lymphoplasmacytic lymphoma/Waldenstršm macroglobulinemia (N=3, SIR=14.15, 95% CI=2.92-41.35). Conclusions. Survivors of specific lymphoma subtypes have differential risks of developing a range of subsequent cutaneous malignancies. CLL/SLL is the lymphoma subtype most closely associated with cutaneous malignancy risk, whereas DLBCL survivors only have strongly elevated risk for sebaceous carcinoma. Further studies should investigate potential roles for immune dysfunction, infection, and genetic susceptibility in the etiology of cutaneous malignancies developing after NHL. Survivors and clinicians should consider the importance of regular full skin examinations to maximize opportunities for early detection of cutaneous malignancies to reduce morbidity. Disclosures No relevant conflicts of interest to declare.

Introduction Survivors of non-Hodgkin lymphoma (NHL) have elevated risk for developing new malignancies. Although infections have been associated with the etiology of certain NHL subtypes, understanding of the patterns of potential infection-related new malignancies among NHL survivors is limited. Methods We conducted a registry-based cohort study among non-HIV infected adult (aged ≥20 years) one-year survivors of NHL diagnosed and treated in the modern era (2000-2013). The eligible cohort survived at least one year following diagnosis with one of the four most common NHL subtypes [diffuse large B-cell lymphoma (DLBCL, n=36,869), chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL, n=38,377), follicular lymphoma (FL, n=27,388), and marginal zone lymphoma (MZL, n=12,773)], as reported to 17 Surveillance, Epidemiology, and End Results registries. Standardized incidence ratios (SIRs) and 95% confidence intervals were used to quantify risks of infection-related second cancers, defined according to the International Agency for Research on Cancer to include cancers of the lung, stomach, liver, salivary gland, cervix, and anus. Results Non-small cell lung cancer was the most commonly occurring infection-related second cancer, with consistently elevated 1.2-1.5-fold risk among survivors of all four NHL subtypes. Similarly, risk of salivary gland cancer was elevated but with a greater magnitude of risk, with SIRs ranging from 2.4 among DLBCL survivors to 3.0 after FL. In contrast, stomach cancer risk was only elevated among survivors of DLBCL (SIR=1.5) and MZL (2.8). Stratifying the cohort of NHL survivors by the NHL site revealed the highest stomach cancer SIRs among survivors of gastric DLBCL (2.8) and MZL (6.8). Liver cancer also was only elevated among DLBCL (1.8) and MZL (2.0) survivors. Anal cancer risk was elevated after DLBCL (2.3) and borderline significantly elevated for MZL (2.4) and CLL/SLL survivors (1.7). Risk for cervical cancer was not elevated among survivors of any of the four most common NHL subtypes. Discussion Certain infection-related cancers have elevated risks among all NHL survivors; in contrast, others are only elevated after DLBCL and MZL, which may reflect differences in infectious disease prevalence among primary NHL subtypes. For example, H. pylori and hepatitis C virus have been associated with the development of DLBCL and MZL and are also associated with second liver and stomach cancers, likely due to the increased prevalence of these infections among DLBCL and MZL survivors compared with the general population. In contrast, the persistently elevated risks for non-small cell lung cancer and cancer of the salivary gland among survivors of all four of the most common NHL subtypes warrants further investigation into potential infectious origins or immune dysfunction. Alternatively, the excess risk may be due to surveillance bias, as these patients receive regular CT scans and monitoring after their NHL diagnosis. To contradict this theory, when we investigated second lung and salivary gland cancer risks stratified by latency, we did not find a consistently elevated risk immediately following NHL diagnosis ( Conclusion Survivors of the four most common NHL subtype have elevated risks of certain infection-related cancers. Differential patterns of risk provide clues to second cancer etiology as well as highlighting survivors at higher risk who might benefit the most from more intensive surveillance. Table Table. Disclosures No relevant conflicts of interest to declare.

Dear Sir, Cutaneous malignant melanoma incidence has more than doubled over the past 25 yrs, and this trend continues across all age groups at a rate of over 3% per yr (Linos et al., 2009). Exposure to the ultraviolet (UV) portion of sunlight is strongly implicated in melanoma etiology and considered the major environmental risk factor. Higher melanoma risk is associated with burning UV doses, both intermittent and during childhood (Gandini et al., 2005). Alarmingly, melanomas are the most prevalent cancer in 25–29 yr old females, and a link to commercial tanning sunlamps use is suggested (Purdue et al., 2008). Melanoma prevention recommendations include avoiding mid-day sun and artificial UV light, wearing protective clothing and hats, and using sunscreen with a Sun Protective Factor (SPF) of 15 or higher (American Cancer Society, 2010). However, the SPF sunscreen rating describes erythema or sunburn protection; sunscreens are not rated for the prevention of melanoma or other skin cancers (FDA, 1999). Melanoma incidence reduction through sunscreen use has not yet been proven, and in fact has been controversial (Saraiya et al., 2003). We here present data that demonstrate for the first time significant sunscreen prevention in UV-dependent, melanoma-prone transgenic mice, and propose that when applied properly should be preventive in people. Human epidemiologic studies of melanoma prevention are limited by recall bias, insufficient statistical power, and non-uniform estimations of sun exposure and sunscreen use. Therefore, sunscreen use and melanoma risk reduction or mortality prevention are difficult to accurately assess and remain inconclusive (Bastuji-Garin and Diepgen, 2002; Saraiya et al., 2003). We evaluated sunscreen use as a risk factor for melanoma in a large case-control study with 717 non-Hispanic white, invasive melanoma patients and 945 matched controls (Fears et al., 2002). The univariate analyses of ever sunscreen use or regular use of sunscreen of SPF ≥ 8 indicated minimal risk associated with sunscreen use (relative odds 1.05 and 1.11, respectively). This association is suggested to reflect users’ sun sensitivity (burning and tanning tendencies), and not a property of sunscreen exposure per se (Dennis et al., 2003). A matched logistic regression analysis of sunscreen use adjusted for average UVB intensity of residences, adult hours outdoors, tan-type, number sunburns, age-group, study-site and gender (Appendix S1), showed that sunscreen use was not associated with melanoma (OR 0.90, 95% CI 0.70–1.16; Table 1). When evaluating sunscreen users and examining risk in those who burned easily and persons who did not burn in a single model, the relative odds for those who burned easily decreased slightly to 0.85 (0.62–1.19) and for those who did not burn was 0.91 (0.70–1.19) with no statistically significant difference in risks (Table 1). The changes in risks observed after appropriate adjustment likely reflect confounding, a spurious relationship, as persons using sunscreens may be more susceptible to melanoma. These data demonstrate the challenges of assessing complex behaviors, such as sunscreen use, outside of a prospective randomized study. Even in our large investigation, difficulty in addressing these challenges illustrates the urgent need for appropriate animal models, employed experimentally, to better assess the value of sunscreen use in melanoma prevention. Table 1 Melanoma in persons with no sunscreen use, and those who used any sunscreen, among sunscreen users by tendency to burn or sun sensitivity The availability of the Hepatocyte Growth Factor/Scatter Factor (HGF/SF) genetically engineered mouse, which develops neonatal UV-dependent skin lesions highly reminiscent of cutaneous malignant melanoma (Noonan et al., 2001), provides a favorable platform to demonstrate experimentally the capabilities of sunscreen in a melanoma prevention study. This mouse model has been used to support the notion that childhood sunburn constitutes a major melanoma risk factor (Noonan et al., 2001). Therefore, we hypothesized that blocking UV radiation-induced erythema with current dermatologist recommended SPF15 sunscreen would significantly decrease the incidence of melanoma in this relevant murine melanoma model. Neonatal mice were exposed to a single dose of UV radiation with prior application (15 min) of either vehicle-control lotion or SPF15 sunscreen containing FDA-approved active agents (Appendix S1). The UV dose corresponded to a human erythemally-weighted UV dose of 2.3 kJ/m2 or 23 Standard erythemal dose units, equivalent to a sun-burning dose in people (Noonan et al., 2001). The primary endpoint was melanoma development in the dorsal application area, confirmed by histopathology and positivity for melanocytic antigens. The SPF15 sunscreen-treated animals developed significantly fewer melanomas than the vehicle-control group (P = 0.043; Figure 1). In the sunscreen-treated group (n = 97), one mouse (1%) developed two dorsal melanomas, while the eight mice (7%) in the vehicle-control group (n = 118) developed 18 melanomas (Figure 1; Table S1). The multiplicity of melanomas per animal arising in the sunscreen-treated group was also lower, with two per animal versus up to seven per animal in the vehicle controls. Animals from both groups equally developed melanoma outside of lotion-treated areas (tails and/or hindquarters): two in vehicle controls and one in the SPF15 group. Figure 1 UV-induced melanomas and UV-induced DNA damage are significantly inhibited in sunscreen-treated compared to vehicle control-treated mice. Melanoma incidence per group and the average ratio of TT-dimer-containing cells to no TT-dimer-containing cells are ... The molecular mechanisms by which sun and artificial UV light initiate and/or promote melanoma development are being elucidated (Zaidi et al., 2008). Clearly, both direct and/or indirect DNA damage mechanisms, including thymine dimer and genotoxic reactive oxygen species formation, may play a mechanistic role. We therefore quantified DNA damage in skin cells of UV-treated control and SPF15 sunscreen-treated animals using an antibody to thymine-thymine (TT) dimers, a type of damage initiated by UVB irradiation. Cells were scored ‘positive’ if double-stained for TT dimers and nuclear counter-stain at seven minutes post-UV. The vehicle control lotion-treated skin averaged greater than five cells with nuclear DNA damage to each non-DNA damaged cell (Figure 2; Table S1). In sunscreen-treated skin, the TT:no-TT ratio was

The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.

Germline mutations within the coding region of CDKN2A have been observed in affected members of melanoma-prone families. G101W is the most common CDKN2A missense mutation identified to date. It has been reported in several families from around the world, with a particularly high occurrence in France and Italy. Given the frequency of this mutation, we were interested in determining whether the mutation resulted from a single origin or represented a mutational hotspot in the CDKN2A gene. In addition, given the geographical distribution of the mutation, we examined the date of origination of the mutation and its migratory spread. We examined 10 families from Italy, 4 families from the United States, and 6 families from France with the G101W mutation. The following eight markers were employed for the haplotype analysis: IFNA, D9S736, D9S1749, D9S942, D9S1748, D9S1604, D9S171, and D9S126. Our findings showed no significant evidence for mutational heterogeneity, suggesting that all studied families derived from a single ancestral haplotype on which the mutation arose. Using maximum-likelihood methods, we estimated the mutation to have arisen 97 generations ago (1-LOD-unit support interval 70–133 generations) providing some explanation for the wide geographical spread of this common mutation, particularly in southwestern Europe. The presence of a founder mutation in a defined geographic area can facilitate carrier detection and genetic counseling and can provide an opportunity to study disease penetrance and the effect of environmental factors on the background of a common genetic susceptibility.

Germline mutations of CDKN2A, at 9p21, are responsible for predisposition to melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mutations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have analyzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four sequence variants were detected. Two of these (A-191G and A-493T) did not segregate with disease and were present in a control population at a comparable frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previously described CDKN2A polymorphism Ala148Thr. The variant G-735A was detected in the control population, but segregation of this variant with melanoma within families could not be discounted. The fourth variant (G-34T), located in the 5' UTR, creates an aberrant initiation codon. This variant appeared to segregate with melanoma and was not detected in a control population. G-34T has recently been identified in a subset of Canadian melanoma families and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an important role in carcinogenesis in a small percentage of families; however, mutations in the CDKN2A promoter appear to have a limited role in predisposition to melanoma.

Background Various congenital anomalies have been associated with childhood cancer, but as yet no anomaly has been consistently found with Ewing sarcoma (ES). Recently a large case-control study of ES patients reported a greater number of hernias in both cases and their sibling controls than in population controls. Most of these hernias were inguinal. Because these anomalies were also reported previously in two case series, we looked for inguinal hernias in a different population of ES patients. Procedure We abstracted medical records for 306 pathologically confirmed ES/primitive neuroectodermal tumor (PNET) patients seen at NIH between 1960 and 1992. Epidemiological data on demographics and medical conditions were analyzed. The frequency of anomalies was compared to expected rates to calculate relative risk and confidence intervals. Results Anomalies were present in 67 (22%) cases. A particular anomaly, inguinal hernia, was reported for 13 (5%) NIH cases. Compared to population estimates for white children, the relative risk of inguinal hernia among white NIH cases was 13.3 (95% CI 3.60–34.1) for females and 6.67 (95% CI 2.67–13.7) for males. Conclusions The findings of inguinal hernias in some patients with ES suggest that a disruption in normal embryological development occurred. This may provide an important clue to the etiology of ES. We hypothesize that these hernias may relate to an in utero exposure or indicate an underlying genetic disorder. Future studies should carefully evaluate ES families for genetic disease and explore environmental factors. Med. Pediatr. Oncol. 34:195–199, 2000. Published 2000 Wiley-Liss, Inc.

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8–1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease-causing alleles were characterized. Thirty-seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in-frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease-causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein. Hum Mutat 16:232–246, 2000. © 2000 Wiley-Liss, Inc.

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.

Germ-line mutations in the CDKN2A tumor-suppressor gene (also known as p16, p16INK4a, and MTS1) have been linked to the development of melanoma in some families with inherited melanoma. Whether mutations in CDKN2A confer a predisposition to sporadic (nonfamilial) melanoma is not known. In some patients with sporadic melanoma, one or more additional primary lesions develop, suggesting that some of these patients have an underlying genetic susceptibility to the cancer. We hypothesized that this predisposition might be due to germ-line CDKN2A mutations.We used the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct DNA sequencing to identify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the functional importance of the CDKN2A variants.Of 33 patients with multiple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These included a 24-bp insertion at the 5' end of the coding sequence, three missense mutations (Arg24Pro, Met53Ile, and Ser56Ile), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In three families, CDKN2A mutations identical to those in the probands were found in other family members. In two families with mutations, we uncovered previously unknown evidence of family histories of melanoma.Some patients with multiple primary melanomas but without family histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in family members, who may benefit from melanoma-surveillance programs.

We describe a five-generation kindred with familial eosinophilia (FE; MIM131400), characterized by the occurrence of sustained eosinophilia of unidentifiable cause in multiple relatives. The inheritance pattern is consistent with an autosomal dominant pattern. Among 52 related subjects studied, 19 were affected and 33 were unaffected. Ten unaffected spouses were also evaluated. Four subjects with sustained eosinophilia were diagnosed with cardiac abnormalities and two of them also had neurologic symptoms. In comparison with the unaffected or spouses, evaluation of complete blood counts showed that the affected relatives had, as expected, significantly higher white cell (P < 0.005) and absolute eosinophil counts (P < 0.001) and lower red cell counts (P < 0.05). Evaluation of serum cytokine levels (IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GMCSF) and serology for parasitic helminth infection demonstrated no differences between the affected and unaffected individuals; no individuals studied had serologic evidence for parasitic infection. There were also no differences in anti-nuclear antibody, serum cobalamin (vitamin B12) level, immunoglobulin level, leukocyte alkaline phosphatase, rheumatoid factor, HLA analysis, and stool findings for ova and parasites. Among eight affected persons who had peripheral blood or bone marrow karyotype analysis, two carried the same chromosome abnormality, a pericentric inversion of chromosome 10, inv (10) (p11.2q21.2). A gene mapping study is currently underway to study the underlying genetic mechanism(s) of this syndrome. Am. J. Med. Genet. 76:229–237, 1998. © 1998 Wiley-Liss, Inc.

Although some cases of dysplastic naevi (DN) and familial melanoma have been linked to anonymous markers on chromosome 1p36, the gene has not been identified. A candidate gene, RPA2, which codes for the 32 kDa subunit of replication protein A, is located in the 1p35-36 region. We examined the RPA2 gene in seven lymphoblastoid cell lines from members of melanoma-prone families linked to chromosome 1p36. Southern and Northern blot analyses showed the DNA and RNA bands were of normal size and intensity. DNA sequencing demonstrated no nucleotide alterations in the RPA2 cDNA. Western blot analysis exhibited normal electrophoretic migration and intensity of the RPA2 protein. These results indicate that alterations do not occur in the RPA2 gene in these DN/familial melanoma families linked to chromosome 1p36.

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

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 Carriers of germ-line mutations in BRCA1 and BRCA2 from families at high risk for cancer have been estimated to have an 85 percent risk of breast cancer. Since the combined frequency of BRCA1 and BRCA2 mutations exceeds 2 percent among Ashkenazi Jews, we were able to estimate the risk of cancer in a large group of Jewish men and women from the Washington, D.C., area. Methods We collected blood samples from 5318 Jewish subjects who had filled out epidemiologic questionnaires. Carriers of the 185delAG and 5382insC mutations in BRCA1 and the 6174delT mutation in BRCA2 were identified with assays based on the polymerase chain reaction. We estimated the risks of breast and other cancers by comparing the cancer histories of relatives of carriers of the mutations and noncarriers. Results One hundred twenty carriers of a BRCA1 or BRCA2 mutation were identified. By the age of 70, the estimated risk of breast cancer among carriers was 56 percent (95 percent confidence interval, 40 to 73 percent); of ovar...

PURPOSE This late effects study was designed to determine if survivors of Ewing's sarcoma family tumors (ESFT) had adverse outcomes in employment, marital status, fertility, and functional status when compared to sibling controls. SUBJECTS AND METHODS Eighty-nine survivors (case subjects) of ESFT treated at the National Cancer Institute between 1965 and 1992 and 97 sibling controls completed a questionnaire probing aspects of quality of life. The answers from case subjects were compared to pooled and matched sibling controls for all key variables. Odds ratios (OR) and p values from pooled analyses are presented. RESULTS Although case subjects and controls did not differ in educational achievement, case subjects were less likely to be employed full-time (OR 0.4, p < 0.01), to be married (OR 0.2, p < 0.01), and to have children (OR 0.3, p < 0.01). Their most common treatment-related difficulties included permanent hair and skin changes (43%), lung problems (18%), neurologic problems (14%), visual difficulties (10%), second malignancy (7%), and amputation (5%). Functional status, measured by Karnofsky performance scale, was also adversely affected in case subjects. Case subjects did not differ from sibling controls in health care insurance status or in utilization of health services. CONCLUSIONS Important aspects of life such as employment, marital status, fertility, and functional status are affected in survivors of ESFT. More studies are needed to better define the health status of adult survivors of pediatric cancer and the impact of cancer in adolescence on psychosocial development.

To estimate the risk of secondary leukemias after treatment with etoposide (VP-16), we evaluated subjects treated for Langerhans' cell histiocytosis (LCH) according to cooperative protocols in Italy or in Austria, Germany, Holland and Switzerland (AGDS). For each subject, information was collected on the cumulative dosages of chemotherapy and radiotherapy received, vital status and occurrence of secondary leukemia. The expected number of leukemias was estimated using age-specific incidence rates from the cancer registries in Italy and Germany. Standardized incidence ratios (SIR) were used to measure the risk of secondary leukemia among LCH patients. Five leukemias occurred among the 241 Italian study patients (SIR 520), whereas no cases were reported among the 363 AGDS patients. Interestingly, and in contrast to previous descriptions of epipodophyllotoxin-related leukemias which are mostly FAB M4 or M5, these leukemias showed typical FAB M3 features, and received a dose of VP-16 > 4,000 mg/m2. Among the AGDS cohort, very few subjects were exposed to high doses of VP-16. The risk of secondary acute non-lymphoblastic leukemia (s-ANLL) among the Italian subjects exposed to VP-16 was more than 1,000 times greater than expected. The study suggests that high doses of VP-16 appear to increase the risk of s-ANLL in LCH patients. The fact that all the leukemias described in the Italian LCH cohort were promyelocytic, and evidence of a higher incidence of promyelocytic leukemias among Italians and Latinos, suggest that high doses of etoposide in subjects of Latino origin may lead to aberrations on chromosomes 15 and 17.

Medulloblastoma, one of the most common central nervous system(CNS)tumors in children, requires aggressive multimodality therapy including surgery, radiation therapy, and occasionally chemotherapy. Given its intensive treatment regimen and improved survival during the past 20 years, it is likely that a cohort of survivors will result who may incur consequences of therapy, including a second cancer. We used population-based data from the United States and Sweden to estimate risks of second neo plasms in patients with histologically confirmed medulloblastoma (n = 1,262).Overall, there was a 5.4-fold excess of second neoplasms (95 percent confidence interval = 3.3-8.4) based on 20 observed and 3.7 expected cancers. The second cancers occurred eight to 432 months after initial diagnosis(median, 73 months) with significantly elevated ratios for all intervals examined except for less than one year after initial diagnosis. Significantly elevated risks were seen for cancers of the salivary glands, cervix uteri, brain and CNS, thyroid gland, and acute lymphoblastic leukemia. Of the 15second cancers with treatment data, seven occurred in the radiation field or within areas of scatter while two others may have been radiation-related. Although based on small numbers of second cancers, the results suggest that as survival increases, some patients with medulloblastoma will have an increased risk of a second cancer, particularly a radiation-related cancer. Thus, as survival improves, late-occurring consequences of diagnosis and treatment will need to be carefully assessed. Identification of patients hypersensitive to radiation therapy, such as those with Gorlin Syndrome, should also be attempted in order to reduce the sequelae from intensive radiation exposure.

INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.

Therapy-related acute myeloid leukemia (tAML) is a rare but highly fatal complication of cytotoxic chemotherapy. Despite major changes in cancer treatment, data describing tAML risks over time are sparse. Among 426 068 adults initially treated with chemotherapy for first primary malignancy (9 US population-based cancer registries, 1975-2008), we identified 801 tAML cases, 4.70 times more than expected in the general population (P < .001). Over time, tAML risks increased after chemotherapy for non-Hodgkin lymphoma (n = 158; Poisson regression Ptrend < .001), declined for ovarian cancer (n = 72; Ptrend < .001), myeloma (n = 62; Ptrend = .02), and possibly lung cancer (n = 65; Ptrend = .18), and were significantly heterogeneous for breast cancer (n = 223; Phomogeneity = .005) and Hodgkin lymphoma (n = 58; Phomogeneity = .007). tAML risks varied significantly by age at first cancer and latency and were nonsignificantly heightened with radiotherapy for lung, breast, and ovarian cancers. We identified newly emerging elevated tAML risks in patients treated with chemotherapy since 2000 for esophageal, cervical, prostate, and possibly anal cancers; and since the 1990s for bone/joint and endometrial cancers. Using long-term, population-based data, we observed significant variation in tAML risk with time, consistent with changing treatment practices and differential leukemogenicity of specific therapies. tAML risks should be weighed against the benefits of chemotherapy, particularly for new agents and new indications for standard agents.

Dysplastic nevi are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these 2 entities. Since initially being reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biologic importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still no single, universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi should be considered important because of their association with an increased risk for melanoma. Cancer Epidemiol Biomarkers Prev; 22(4); 528–32. ©2013 AACR.

Background: The chromosome 9p21.3 region has been implicated in the pathogenesis of multiple cancers. Methods: We systematically examined up to 203 tagging SNPs of 22 genes on 9p21.3 (19.9–32.8 Mb) in eight case–control studies: thyroid cancer, endometrial cancer (EC), renal cell carcinoma, colorectal cancer (CRC), colorectal adenoma (CA), oesophageal squamous cell carcinoma (ESCC), gastric cardia adenocarcinoma and osteosarcoma (OS). We used logistic regression to perform single SNP analyses for each study separately, adjusting for study-specific covariates. We combined SNP results across studies by fixed-effect meta-analyses and a newly developed subset-based statistical approach (ASSET). Gene-based P-values were obtained by the minP method using the Adaptive Rank Truncated Product program. We adjusted for multiple comparisons by Bonferroni correction. Results: Rs3731239 in cyclin-dependent kinase inhibitors 2A (CDKN2A) was significantly associated with ESCC (P=7 × 10−6). The CDKN2A-ESCC association was further supported by gene-based analyses (Pgene=0.0001). In the meta-analyses by ASSET, four SNPs (rs3731239 in CDKN2A, rs615552 and rs573687 in CDKN2B and rs564398 in CDKN2BAS) showed significant associations with ESCC and EC (P

In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.

Background CDKN2A and CDK4 are high risk susceptibility genes for cutaneous malignant melanoma. Melanoma families with CDKN2A germline mutations have been extensively characterised, whereas CDK4 families are rare and lack a systematic investigation of their phenotype. Methods All known families with CDK4 germline mutations (n=17) were recruited for the study by contacting the authors of published papers or by requests via the Melanoma Genetics Consortium (GenoMEL). Phenotypic data related to primary melanoma and pigmentation characteristics were collected. The CDK4 exon 2 and the complete coding region of the MC1R gene were sequenced. Results Eleven families carried the CDK4 R24H mutation whereas six families had the R24C mutation. The total number of subjects with verified melanoma was 103, with a median age at first melanoma diagnosis of 39 years. Forty-three (41.7%) subjects had developed multiple primary melanomas (MPM). A CDK4 mutation was found in 89 (including 62 melanoma cases) of 209 tested subjects. CDK4 positive family members (both melanoma cases and unaffected subjects) were more likely to have clinically atypical nevi than CDK4 negative family members (p

Several studies suggest that the Epstein-Barr virus (EBV) is etiologically linked to Hodgkin's disease (HD). This study was undertaken to examine the role of EBV in familial HD (FHD). Among 60 FHD patients from 27 families with two or more cases per family, we tested available paraffinized tumor tissues from 46 cases by in situ hybridization for EBV-encoded RNA (EBER1) expression. Thirteen of 46 FHD patients (28%) had EBER1 expressed in the Reed-Sternberg cells. Concordance rate of EBV positivity was evaluated among 34 first-degree related pairs from 17 families for which both cases had available paraffinized tumor tissues. Only two of 17 pairs were concordant for EBER1 positivity. There was no excess of positive concordance (P = .18). Serologically, FHD patients had higher geometric mean antibody titers (GMTs) to the viral capsid antigen (VCA) and early antigen D (EA-D). There was no difference in seroprevalence between patients and control groups, nor was there concordance in elevated serology among 15 pairs of first-degree related FHD cases. Young adult unaffected family members (UFM) may not react to EBV in the same way as the general population as evidenced by the lower titer of VCA, although not statistically significant, and significantly lower titers of EA-D, compared with age-matched controls. While EBV might have some role in a subset of HD, lack of concordance of EBER1 expression and EBV serology among the FHD cases in the same family suggest that EBV does not play an important role in FHD.

In an effort to understand the effect of cancer diagnosis and treatment in children and adolescents, and to identify issues that should be addressed with newly diagnosed patients, 85 patients with Ewing's sarcoma family tumors (ESFT) were interviewed about their experience of having cancer. This represents 90% of all eligible patients who survived at least 3 years since their diagnosis and who were treated for ESFT at the National Cancer Institute (NCI) from 1965-1993. The mean age of patients at the time of diagnosis was 15.8 +/- 5.3 years, and mean time since diagnosis was 13.6 +/- 6.4 years. Patients from this cohort had a disease usually related to poor outcome. Patients answered five open-ended written questions. Negative experiences that they described included transient and permanent discomfort and disabilities related to cancer; disruption of life or relationships; and emotional aspects of cancer diagnosis or treatment. Positive aspects of having cancer included changed attitudes about self and life, improved relationships with others, or better job performance. Advice for newly diagnosed patients most often dealt with the emotional aspects of cancer. The importance of patient-to-patient support was frequently described. Overall, having cancer was not an entirely negative experience, and it may result in introspection and improved relationships with others.

Cutaneous malignant melanoma (CMM) is an etiologically heterogenous disease with genetic, environmental (sun exposure), and host (pigmentation/nevi) factors and their interactions contributing to risk. Recently, epigenetic changes involving reduced levels of global DNA methylation in blood have been associated with genomic instability and cancer risk. We thus examined whether global methylation was associated with CMM risk in individuals from melanoma-prone families with and without CDKN2A germline mutations. We measured global DNA methylation using bisulfite pyrosequencing at four CpG sites of the long interspersed nucleotide element-1 (LINE-1) sequences in peripheral blood mononuclear cells (PBMCs) from individuals in 64 melanoma-prone families including 114 CMM cases (45 CDKN2A-positive and 69 CDKN2A-negative) and 121 unaffected individuals (31 CDKN2A-positive and 90 CDKN2A-negative). We used unconditional logistic regression to evaluate the association between CMM status and LINE-1 methylation levels, adjusting for age at blood draw and accounting for familial correlation in the variance. We found that male sex was significantly associated with higher overall LINE-1 methylation (P=0.0001). However, the overall and site-specific levels of LINE-1 methylation did not vary significantly by CMM status (overall odds ratio: 1.57, 95% confidence interval: 0.84-2.95, P=0.16; comparing lowest to highest or reference methylation group). Similar results were obtained when CDKN2A-positive and CDKN2A-negative families were analyzed separately. Our findings did not support a significant association between constitutional LINE-1 methylation in PBMCs and risk of CMM in melanoma-prone families with or without CDKN2A mutations.