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1.  Dysplastic Nevi and Melanoma 
Dysplastic nevi (DN) are described as being on a continuum between common acquired nevi and melanoma because they are morphologically and biologically intermediate between these two 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 biological 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.
PMCID: PMC3616416  PMID: 23549396
2.  Ancient origin of a Japanese xeroderma pigmentosum founder mutation 
Journal of dermatological science  2012;69(2):175-176.
PMCID: PMC3570715  PMID: 23194742
DNA repair; xeroderma pigmentosum; skin cancer; neurodegeneration; genetic epidemiology
3.  Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum 
European Journal of Human Genetics  2012;20(12):1308-1310.
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<0.001). As mutations in XPD may have differential effects on DNA repair and transcription, these observations should provide insights into the role of XPD in human pregnancy and fetal development.
PMCID: PMC3499748  PMID: 22617342
DNA repair; pre-eclampsia; transcription factor IIH
4.  Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations 
Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors, and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families.
We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (−)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. P-values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p=0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p=0.0006). 28~56% of genotyped SNPs in these genes had single SNP p<0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (−) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
PMCID: PMC3274649  PMID: 21671477
5.  Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family 
Pigment cell & melanoma research  2012;25(2):243-247.
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.
PMCID: PMC3288577  PMID: 22225770
Familial melanoma; Germline copy number variations; disease susceptibility; CXC chemokines; chromosome 4q13
6.  Risk factors for esophageal and gastric cancers in Shanxi Province, China: A case-control study 
Cancer epidemiology  2011;35(6):e91-e99.
Smoking and alcohol consumption explain little of the risk for upper-gastrointestinal (UGI) cancer in China, where over half of all cases in the world occur.
We evaluated questionnaire-based risk factors for UGI cancers in a case-control study from Shanxi Province, China, including 600 esophageal squamous cell carcinomas (ESCC), 599 gastric cardia adenocarcinomas (GCA), 316 gastric noncardia adenocarcinomas (GNCA), and 1514 age- and gender-matched controls.
Ever smoking and ever use of any alcohol were not associated with risk of UGI cancer; only modest associations were observed between ESCC risk and highest cumulative smoking exposure, as well as GNCA risk and beer drinking. While several associations were noted for socioeconomic and some dietary variables with one or two UGI cancers, the strongest and most consistent relations for all three individual UGI cancers were observed for consumption of scalding hot foods (risk increased 150% to 219% for daily vs never users) and fresh vegetables and fruits (risk decreased 48% to 70% for vegetables and 46% to 68% for fruits, respectively, for high vs low quartiles).
This study confirms the minor role of tobacco and alcohol in UGI cancers in this region, and highlights thermal damage as a leading etiologic factor.
PMCID: PMC3215853  PMID: 21846596
smoking; alcohol; socioeconomic status; diet
Prenatal Diagnosis  2011;31(11):1046-1053.
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 and81% of the pregnancies had complications: 56% had preterm delivery, 30% had preeclampsia, 19% had placental abnormalities, 11% had HELLP syndrome, 4% had an emergency c-section for fetal distress; while44% had two or more complications. Only19% of the pregnancies delivered at term without complications. Eight of the 10 pregnancies tested had abnormal multiple marker results including elevated levels of human chorionic gonadotropin. Eighty-five percent of the neonates had complications: 70 % were low birth weight (<2500g), 35% had birth weight <10 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.
PMCID: PMC3266696  PMID: 21800331
Trichothiodystrophy; Pregnancy; Maternal Serum Screening; hCG; Preeclampsia; HELLP syndrome
8.  A gene expression signature from peripheral whole blood for stage I lung adenocarcinoma 
Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology (EAGLE) study using PWB and paired snap-frozen tumor and non-involved lung tissue samples. Analyses were conducted using unpaired t-tests, linear mixed effects and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (False Discovery Rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus non-involved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer-related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case-control study (n=212) and a tumor-non tumor paired tissue study (n=54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC=0.81, 95% CI=0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future.
PMCID: PMC3188352  PMID: 21742797
microarray gene expression; peripheral blood; lung cancer; stage I
9.  Clinical Features Distinguish Childhood Chordoma Associated with Tuberous Sclerosis Complex (TSC) from Chordoma in the General Pediatric Population 
Journal of medical genetics  2011;48(7):444-449.
Chordoma, an age-dependent rare cancer, arises from notochordal remnants. Fewer than 5% of chordomas occur in children. Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous syndrome characterized by abnormal tissue growths in multiple organ systems. Reports of chordoma in patients with TSC suggest that TSC1 and TSC2 mutations may contribute to chordoma etiology.
To determine whether the 10 TSC-associated chordomas reported in the literature are representative of chordoma in the general pediatric population, we compared age at diagnosis, primary site and outcome in them to results from a systematic assessment of 65 pediatric chordoma cases reported to the US population-based cancer registries contributing to the SEER Program of the National Cancer Institute.
TSC-associated chordomas differed from chordomas in the general pediatric population: median age at diagnosis (6.2 months, TSC vs. 12.5 years, SEER); anatomic site (40% sacral, TSC vs. 9.4% sacral, SEER); and site-specific age at diagnosis (all 4 sacral chordomas diagnosed during the fetal or neonatal period, TSC vs. all 6 sacral chordomas diagnosed at > 15 years, SEER). Finally, 3 of 4 patients with TSC-associated sacral chordoma were alive and tumor-free at 2.2, 8 and 19 years following diagnosis vs. a median survival of 36 months among pediatric sacral chordoma patients in SEER.
These results strengthen the association between pediatric chordoma and TSC. Future clinical and molecular studies documenting the magnitude and clinical spectrum of the joint occurrence of these two diseases should provide the basis for delineating the biological relationship between them.
PMCID: PMC3235000  PMID: 21266383
chordoma; tuberous sclerosis complex; bone cancer; pediatric; childhood cancer
10.  Prognostic Utility of Anti-EBV Antibody Testing for Defining NPC Risk among Individuals from High-Risk NPC Families 
Clinical Cancer Research  2011;17(7):1906-1914.
Epstein–Barr virus (EBV) infection and a family history of nasopharyngeal carcinoma (NPC) are associated with NPC risk. We examined the risk associated with EBV markers and their clinical utility to identify NPC susceptibles within high-risk NPC families.
Experimental Design
We evaluated antibody titers against viral capsid antigen (VCA) IgA, EBV nuclear antigen-1 (EBNA1) IgA, and DNase among unaffected relatives of NPC cases from 358 multiplex families in Taiwan. Incident NPC cases were identified via linkage to the National Cancer Registry. Clinical examinations of 924 individuals were also done to identify occult, asymptomatic NPC. Baseline EBV serology was used to estimate NPC risk using rate ratios with 95% CI. Associated sensitivity/specificity and receiver operating characteristic (ROC) curves were calculated.
A total of 2,444 unaffected individuals with 15,519 person-years (6.5 years median follow-up) yielded 14 incident NPC cases (nearly 11 times the general population rate). The absolute rate of NPC among anti-EBV EBNA1 IgA seropositives using a standard positivity cutoff versus an optimized cutoff point defined by ROC analyses was 265/100,000 person-years with a 4.7-fold increased risk of NPC (95% CI: 1.4–16) and 166/100,000 person-years with a 6.6-fold increase (95% CI: 1.5–61), respectively. Sensitivity and specificity using the optimized positivity cutoff points were 85.7% and 51.2%, respectively. It is estimated that active evaluation of 49% of individuals from high-risk NPC families seropositive for this marker could lead to earlier detection of up to 86% of NPC cases. Risks associated with the other three EBV markers were weaker.
Future efforts are needed to identify susceptibility markers among high-risk NPC families that maximize both sensitivity and specificity.
PMCID: PMC3268357  PMID: 21447725
11.  Chapter Seven – Hereditary Genodermatoses with Cancer Predisposition 
Hereditary genodermatoses with cancer predisposition are reviewed, including Nevoid Basal Cell Carcinoma Syndrome, Neurofibromatosis Types 1 and 2, Tuberous Sclerosis Complex, Xeroderma Pigmentosum, and Dyskeratosis Congenita. Hereditary melanoma is also included, though it differs from the others in several respects. The underlying genetic aberrations causing these syndromes are largely known, allowing novel treatments to be developed for some of these disorders. Early recognition and diagnosis allows for close follow-up and surveillance for associated malignancies.
PMCID: PMC3276063  PMID: 20816579
genodermatoses; Nevoid Basal Cell Carcinoma Syndrome; Neurofibromatosis Type 1; Neurofibromatosis Type 2; Tuberous Sclerosis; melanoma; Xeroderma Pigmentosum; Dyskeratosis Congenita
12.  Lack of germline PALB2 mutations in melanoma-prone families with CDKN2A mutations and pancreatic cancer 
Familial cancer  2011;10(3):545-548.
The presence of pancreatic cancer (PC) in melanoma-prone families has been consistently associated with an increased frequency of CDKN2A mutations, the major high-risk susceptibility gene identified for melanoma. However, the precise relationship between CDKN2A, melanoma and PC remains unknown. We evaluated a recently identified PC susceptibility gene PALB2 using both sequencing and tagging to determine whether PALB2 might explain part of the relationship between CDKN2A, melanoma, and PC. No disease-related mutations were identified from sequencing PALB2 in multiple pancreatic cancer patients or other mutation carrier relatives of PC patients from the eight melanoma-prone families with CDKN2A mutations and PC. In addition, no significant associations were observed between 11 PALB2 tagging SNPs and melanoma risk in 23 melanoma-prone families with CDKN2A mutations or the subset of 11 families with PC or PC-related CDKN2A mutations. The results suggested that PALB2 does not explain the relationship between CDKN2A, melanoma, and pancreatic cancer in these melanoma-prone families.
PMCID: PMC3244023  PMID: 21614589
CDKN2A; PALB2; familial melanoma; pancreatic cancer; germline mutation
13.  CDKN2A Mutations and Melanoma Risk in the Icelandic Population 
Journal of medical genetics  2008;45(5):284-289.
Germline CDKN2A mutations have been observed in 20-40% of high-risk melanoma-prone families, however little is known about their prevalence in population-based series of melanoma cases and controls.
We resequenced the CDKN2A gene, including the p14ARF variant and promoter regions, in approximately 703 registry-ascertained melanoma cases and 691 population-based controls from Iceland, a country in which the incidence of melanoma has increased rapidly.
We identified a novel germline variant, G89D that was strongly associated with increased melanoma risk and appeared to be an Icelandic founder mutation. The G89D variant was present in about 2% of Icelandic invasive cutaneous malignant melanoma cases. Relatives of affected G89D carriers were at significantly increased risk of melanoma, head & neck cancers, and pancreatic carcinoma compared to relatives of other melanoma patients. Nineteen other germline variants were identified, but none conferred an unequivocal risk of melanoma.
This population-based study of Icelandic melanoma cases and controls showed a frequency of disease-related CDKN2A mutant alleles ranging from 0.7% to 1.0%, thus expanding our knowledge about the frequency of CDKN2A mutations in different populations. In contrast to North America and Australia where a broad spectrum of mutations was observed at a similar frequency, in Iceland, functional CDKN2A mutations consists of only one or two different variants. Additional genetic and/or environmental factors are likely critical for explaining the high incidence rates for melanoma in Iceland. This study adds to the geographic regions for which population-based estimates of CDKN2A mutation frequencies are available.
PMCID: PMC3236640  PMID: 18178632
melanoma; CDKN2A; G89D; pancreatic cancer; population-based
14.  Jasmine tea consumption and upper gastrointestinal cancer in China 
Cancer causes & control : CCC  2009;20(10):1997-2007.
Epidemiological data on green/jasmine tea and esophageal as well as gastric cancer are limited and inconclusive. In order to study the effect of jasmine tea in upper gastrointestinal (UGI) cancers, we evaluated 600 esophageal squamous cell carcinoma (ESCC), 598 gastric cardia adenocarcinoma (GCA), and 316 gastric non-cardia adenocarcinoma (GNCA) cases and 1514 age-, gender-, and neighborhood-matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated from logistic regression adjusted for matching factors and potential confounders. Among controls, 35% of males and 8% of females reported consumption of jasmine tea; other tea consumption was rare. Consumption of jasmine tea (ever vs. never) was not associated with risk of ESCC (OR=1.15, 95% CI 0.92–1.44), GCA (OR=1.14, 95% CI 0.88–1.37), or GNCA (OR=0.85, 95% CI 0.64–1.15) in males and females combined. Among males, cumulative lifetime consumption showed a significant positive dose-response relation with ESCC risk, but not for GCA and GNCA. In exploratory analyses, occupation affected the relation between tea and ESCC such that consumption in males was associated with increased risk only in non-office workers. Overall, we found no evidence for a protective effect of tea in esophageal or gastric cancer. Further studies of the potential effects of thermal damage, tea quality, and water quality on UGI cancers are suggested.
PMCID: PMC3236106  PMID: 19597950
jasmine tea; esophageal cancer; gastric cancer
Journal of medical genetics  2010;48(3):168-176.
We determined the frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair in a four decade natural history study.
All 106 XP patients admitted to the NIH from 1971 to 2009 were evaluated from clinical records and follow-up.
In the 65 percent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10,000–fold and melanoma was increased 2,000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n= 38), a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with marked burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total UV exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02).
This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the etiology of skin cancer and neurologic degeneration.
PMCID: PMC3235003  PMID: 21097776
genetic epidemiology; DNA repair; skin cancer; neurologic degeneration; xeroderma pigmentosum
16.  Associations of 9p21 variants with cutaneous malignant melanoma, nevi, and pigmentation phenotypes in melanoma-prone families with and without CDKN2A mutations 
Familial cancer  2010;9(4):625-633.
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 (Ptrend=0.003) confirming a recent finding by a genome-wide association study. In addition, three SNPs in the ACO1 gene, rs7855483 (Ptrend=0.002), rs17288067 (Ptrend=0.0009), and rs10813813 (Ptrend=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 (Ptrend=0.003), and rs13290968 in TUSC1 (Ptrend=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.
PMCID: PMC3233727  PMID: 20574843
melanoma; nevi; chromosome 9p21; SNP; CDKN2A
17.  Rising melanoma incidence rates of the trunk among younger women in the United States 
Melanoma rates are rising among young women, possibly due to increasing ultraviolet radiation to previously protected body sites. Therefore, we examined melanoma incidence trends by age, gender, and body site. Descriptive methods were complemented with the age-period-cohort parameters net drift and longitudinal age trend.
Case and population data were obtained from the Surveillance, Epidemiology, and End Results 9 Registries Database (1975-2006). Net drift summarized the average annual percentage change in log-linear rates per year of calendar-time (or year of diagnosis). Longitudinal age trend summarized the average annual percentage change by attained age at diagnosis. Early-and late-onset melanomas have low and high longitudinal age trends, respectively.
There were 105,829 melanomas diagnosed in the SEER 9 Registries. The overall age-adjusted incidence rate (IR)for melanoma was 17.7/100,000 person-years. Age specific IRs were greater among women than men prior to age 40 years. Among women, Irs decreased for all anatomic sites relative to the trunk. The highest net drift occurred in truncal lesions among women (net drift = 3.8%/year of calendar time; 95% CI = 3.5%-4.0%). The lowest longitudinal age trends also were observed for truncal lesions among women (longitudinal age trend = 5.4%/year of attained age; 95% CI = 5.1-5.7).
Though melanoma Irs overall have risen for decades, the combination of high net drift and low longitudinal age trend demonstrate that melanomas are rising preferentially on the trunk among young women.
Future surveillance and analytic studies should consider melanoma effect modification by age, gender, and body site.
PMCID: PMC2939095  PMID: 20826837
Epidemiology; melanoma; skin cancer
18.  MicroRNA expression differentiates histology and predicts survival of lung cancer 
The molecular drivers that determine histology in lung cancer are largely unknown. We investigated whether microRNA (miR) expression profiles can differentiate histological subtypes and predict survival for non-small cell lung cancer.
Experimental design
We analyzed miR expression in 165 adenocarcinoma (AD) and 125 squamous cell carcinoma (SQ) tissue samples from the Environmental 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.
MiR expression profiles strongly differed between AD and SQ (global p<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 down-regulated in SQ. Major findings were confirmed by QRT-PCR in EAGLE samples and in an independent set of lung cancer cases. In SQ, low expression of miRs down-regulated in the histology comparison was associated with 1.2 to 3.6-fold increased mortality risk. A 5-miR signature significantly predicted survival for SQ.
We identified a miR expression profile that strongly differentiated AD from SQ and had prognostic implications. These findings may lead to histology-based therapeutic approaches.
PMCID: PMC3163170  PMID: 20068076
19.  MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells 
Previous studies have identified several dysregulated microRNAs in esophageal squamous cell carcinoma (ESCC); however, to date there are no ex vivo analyses comparing expression levels of these regulatory molecules in esophageal squamous cell tumors versus patient-matched normal epithelium. We describe here a technical strategy to evaluate microRNAs in normal esophageal basal cells (NB), normal esophageal differentiated cells (ND), and tumor cells (T). Laser capture microdissection was used to procure target populations from five cases and 18 ESCC-associated microRNAs were measured by RT-qPCR. Five microRNAs (miR-25, miR-106b, miR-21, miR-203, and miR-145) demonstrated consistent differential expression in at least one of the three comparisons: T vs. NB, T vs. ND, or NB vs. ND. The potential regulatory role of the microRNAs in ESCC was further evaluated by correlating their expression with a matched mRNA dataset, which included the same five cases and cell populations. In conclusion, the present work demonstrates the feasibility of studying microRNA levels in precisely dissected cell populations from clinical samples, and sheds light on the molecular mechanisms associated with ESCC.
PMCID: PMC3142940  PMID: 21796275
Esophageal squamous cell carcinoma; laser capture microdissection; microRNA; basal layer; differentiated layer; miR-25; miR-106b; miR-21; miR-203; miR-145
20.  MicroRNA analysis of microdissected normal squamous esophageal epithelium and tumor cells 
Previous studies have identified several dysregulated microRNAs in esophageal squamous cell carcinoma (ESCC); however, to date there are no ex vivo analyses comparing expression levels of these regulatory molecules in esophageal squamous cell tumors versus patient-matched normal epithelium. We describe here a technical strategy to evaluate microRNAs in normal esophageal basal cells (NB), normal esophageal differentiated cells (ND), and tumor cells (T). Laser capture microdissection was used to procure target populations from five cases and 18 ESCC-associated microRNAs were measured by RT-qPCR. Five microRNAs (miR-25, miR-106b, miR-21, miR-203, and miR-145) demonstrated consistent differential expression in at least one of the three comparisons: T vs. NB, T vs. ND, or NB vs. ND. The potential regulatory role of the microRNAs in ESCC was further evaluated by correlating their expression with a matched mRNA dataset, which included the same five cases and cell populations. In conclusion, the present work demonstrates the feasibility of studying microRNA levels in precisely dissected cell populations from clinical samples, and sheds light on the molecular mechanisms associated with ESCC.
PMCID: PMC3142940  PMID: 21796275
Esophageal squamous cell carcinoma; laser capture microdissection; microRNA; basal layer; differentiated layer; miR-25; miR-106b; miR-21; miR-203; miR-145
21.  Increased Risk of Second Primary Cancers After a Diagnosis of Melanoma 
Archives of dermatology  2010;146(3):265-272.
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 diagnosis <1.00mm, 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.
PMCID: PMC3076705  PMID: 20231496
22.  Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk 
Carcinogenesis  2009;31(4):634-642.
Epidemiological and mechanistic evidence on the association of quercetin-rich food intake with lung cancer risk and carcinogenesis are inconclusive. We investigated the role of dietary quercetin and the interaction between quercetin and P450 and glutathione S-transferase (GST) polymorphisms on lung cancer risk in 1822 incident lung cancer cases and 1991 frequency-matched controls from the Environment And Genetics in Lung cancer Etiology study. In non-tumor lung tissue from 38 adenocarcinoma patients, we assessed the correlation between quercetin intake and messenger RNA expression of the same P450 and GST metabolic genes. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintiles of intake were calculated using unconditional logistic regression adjusting for putative risk factors. Frequent intake of quercetin-rich foods was inversely associated with lung cancer risk (OR = 0.49; 95% CI: 0.37–0.67; P-trend < 0.001) and did not differ by P450 or GST genotypes, gender or histological subtypes. The association was stronger in subjects who smoked >20 cigarettes per day (OR = 0.35; 95% CI: 0.19–0.66; P-trend = 0.003). Based on a two-sample t-test, we compared gene expression and high versus low consumption of quercetin-rich foods and observed an overall upregulation of GSTM1, GSTM2, GSTT2, and GSTP1 as well as a downregulation of specific P450 genes (P-values < 0.05, adjusted for age and smoking status). In conclusion, we observed an inverse association of quercetin-rich food with lung cancer risk and identified a possible mechanism of quercetin-related changes in the expression of genes involved in the metabolism of tobacco carcinogens in humans. Our findings suggest an interplay between quercetin intake, tobacco smoking, and lung cancer risk. Further research on this relationship is warranted.
PMCID: PMC2847089  PMID: 20044584
23.  Lower Risk of Lung Cancer after Multiple Pneumonia Diagnoses 
Although pneumonia has been suggested as a risk factor for lung cancer, previous studies have not evaluated the influence of number of pneumonia diagnoses in relation to lung cancer risk.
The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based study of 2,100 cases and 2,120 controls collected information on pneumonia more than one year before enrollment from 1,890 cases and 2,078 controls.
After adjusting for study design variables, smoking, and chronic bronchitis, pneumonia was associated with decreased risk of lung cancer (odds ratio (OR), 0.79; 95% confidence interval (CI), 0.64–0.97), especially among individuals with ≥3 diagnoses versus none (OR, 0.35; 95% CI, 0.16–0.75). Adjustment for chronic bronchitis contributed to this inverse association. In comparison, pulmonary tuberculosis was not associated with lung cancer (OR, 0.96; 95% CI, 0.62–1.48).
The apparent protective effect of pneumonia among individuals with multiple pneumonia diagnoses may reflect an underlying difference in immune response and requires further investigation and confirmation.
Careful evaluation of number of pneumonia episodes may shed light on lung cancer etiology.
PMCID: PMC2837523  PMID: 20200440
pneumonia; epidemiology; lung cancer; multiple infections; tuberculosis
24.  A Novel Flexible Multiplex Bead-based Assay for Detecting Germline CDKN2A and CDK4 Variants in Melanoma-Prone Kindreds 
The presence of recurrent high-risk mutations in CDKN2A and CDK4 among melanoma-prone kindreds suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. Moreover, with the emergence of new melanoma risk single nucleotide polymorphisms (SNPs) through genome-wide association studies, a flexible platform that can easily accommodate these new risk alleles is needed for more accurate genetic risk profiling. To this end, we have developed a novel melanoma-associated mutation detection method using a multiplex bead-based assay. This assay is suitable for high-throughput CDKN2A and CDK4 genotyping and can be eventually adapted to multiple loci across various constituent populations.
Genomic DNA from a 1603 subjects (1005 in training set, 598 in validation set) were amplified by multiplex PCR using five primer sets followed by multiplex allele-specific primer extension for 39 different known germline variants. The products were then sorted on an xMAP™ (formerly Tag-It™) array and detected by use of the Luminex xMAP™ system. Genotypes were compared to previously-determined sequence data.
In the Toronto training cohort, variants were detected in 145 samples, giving complete concordance between the bead assay and direct sequencing results. Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77% concordance). Overall, the bead assay correctly genotyped 1540/1603 (96.07%) of all individuals in the study and 1540/1545 (99.68%) of individuals whose mutations were represented in the probe set. Out of a total of 62,512 SNP calls, 62,517 (99.99%) were correctly assigned.
In this initial evaluation, the multiplex bead-based assay for familial melanoma appears to be a highly accurate method for genotyping CDKN2A and CDK4 variants.
PMCID: PMC3045700  PMID: 21085193
Melanoma; CDKN2A; CDK4; p14ARF; familial; high-throughput
25.  Assessment of Human Papillomavirus in Lung Tumor Tissue 
Lung cancer kills more than 1 million people worldwide each year. Whereas several human papillomavirus (HPV)–associated cancers have been identified, the role of HPV in lung carcinogenesis remains controversial.
We selected 450 lung cancer patients from an Italian population–based case–control study, the Environment and Genetics in Lung Cancer Etiology. These patients were selected from those with an adequate number of unstained tissue sections and included all those who had never smoked and a random sample of the remaining patients. We used real-time polymerase chain reaction (PCR) to test specimens from these patients for HPV DNA, specifically for E6 gene sequences from HPV16 and E7 gene sequences from HPV18. We also tested a subset of 92 specimens from all never-smokers and a random selection of smokers for additional HPV types by a PCR-based test for at least 54 mucosal HPV genotypes. DNA was extracted from ethanol- or formalin-fixed paraffin-embedded tumor tissue under strict PCR clean conditions. The prevalence of HPV in tumor tissue was investigated.
Specimens from 399 of 450 patients had adequate DNA for analysis. Most patients were current (220 patients or 48.9%) smokers, and 92 patients (20.4%) were women. When HPV16 and HPV18 type–specific primers were used, two specimens were positive for HPV16 at low copy number but were negative on additional type-specific HPV16 testing. Neither these specimens nor the others examined for a broad range of HPV types were positive for any HPV type.
When DNA contamination was avoided and state-of-the-art highly sensitive HPV DNA detection assays were used, we found no evidence that HPV was associated with lung cancer in a representative Western population. Our results provide the strongest evidence to date to rule out a role for HPV in lung carcinogenesis in Western populations.
PMCID: PMC3057981  PMID: 21293027

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