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Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival., Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed., Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant., Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS., Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma., (©2022 American Association for Cancer Research.)

Background: Borderline ovarian tumors (BOTs) are a subgroup of ovarian malignancies with low malignant potential. Very limited earlier data are available on familial clustering of BOTs with other cancers. We aim to explore histology-specific familial associations among BOTs and associations between BOTs and any invasive cancers. Methods: On the basis of 16.1 million individuals in the Swedish Family-Cancer Database, we estimated familial risks for overall or histology-specific patients with BOT considering both BOT and any invasive cancers in first-degree relatives (parents or siblings), as well as familial risks for invasive cancers considering family history of BOTs. Results: A total of 4,199 BOT cases were found in the offspring generation; among them, 34 (0.8%) cases had first-degree relatives diagnosed with any BOT, and 2,489 (59.3%) cases with any invasive cancers. A family history of BOT was associated with risks for all BOTs (RR = 2.20, P < 0.001). Papillary BOT in first-degree relatives was associated with the increased risk of having the same type of BOT (RR = 10.10, P < 0.001). BOTs showed familial associations with some invasive cancers, most consistently with colorectal, ovarian, pancreatic, lung, and bone cancers, and with leukemia. In histologic analyses, associations of BOT with even rare cancers of the anus, thyroid, and endocrine glands were noted. Conclusions: BOTs may share susceptibility with themselves and a number of invasive cancers. Impact: These results provide insight into familial associations of BOT for the first time, which may help with the etiologic mechanism and preventive strategy of BOTs, as well as the genetic counseling for patients with BOT. Cancer Epidemiol Biomarkers Prev; 27(11); 1358-63. ©2018 AACR., (©2018 American Association for Cancer Research.)

Background: Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of differentiated thyroid carcinoma (DTC)., Methods: We combined the results from a genome-wide association study (GWAS) performed by our group and from published studies on DTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons). With the second approach, meta-analyses were performed between literature and GWAS when both sources suggested an association, increasing the statistical power of the analysis., Results: rs1799814 (CYP1A1), rs1121980 (FTO), and 3 SNPs within 9q22 (rs965513, rs7048394, and rs894673) replicated the associations described in the literature. In addition, the meta-analyses between literature and GWAS revealed 10 more SNPs within 9q22, six within FTO, two within SOD1, and single variations within HUS1, WDR3, UGT2B7, ALOX12, TICAM1, ATG16L1, HDAC4, PIK3CA, SULF1, IL11RA, VEGFA, and 1p31.3, 2q35, 8p12, and 14q13., Conclusion: This analysis confirmed several published risk loci that could be involved in DTC predisposition., Impact: These findings provide evidence for the role of germline variants in DTC etiology and are consistent with a polygenic model of the disease. Cancer Epidemiol Biomarkers Prev; 25(4); 700-13. ©2016 AACR., (©2016 American Association for Cancer Research.)

Background: Observational studies have consistently associated obesity with colorectal cancer risk. Because both traits are genetically determined and share some metabolic biomarkers, we hypothesized that obesity-related polymorphisms could also influence the risk of developing colorectal cancer., Methods: We conducted a comprehensive population-based case-control study in 1,792 German colorectal cancer cases and 1,805 controls to explore associations between 28 obesogenic variants identified through genome-wide association studies (GWAS) and colorectal cancer risk. We also evaluated interactions between polymorphisms and body mass index (BMI), type II diabetes (T2D), and gender., Results: No evidence of association between obesogenic variants and colorectal cancer risk was observed after correction for multiple testing. There was only a remarkable interaction between the LTArs1041981 polymorphism and gender, which modified the risk of colorectal cancer [Pinteraction = 0.002; males: odds ratio (OR), 1.14; 95% confidence intervals (CI), 1.00-1.30 vs. females: OR, 0.83; 95% CI, 0.71-0.97]., Conclusions: Our findings showed that obesogenic variants are not a major pathogenetic risk factor for colorectal cancer., Impact: This comprehensive population-based case-control study does not provide evidence of a shared genetic component between obesity and colorectal cancer., (©2014 American Association for Cancer Research.)

Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1β mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development., (©2013 AACR.)

Epidemiologic studies suggest that exposure to sunlight is the primary etiologic agent for basal cell carcinoma. Formation of UV-induced DNA damage is believed to be a crucial event in the process leading to skin cancer. In this study, repair of photoproducts in DNA was followed in the skin of patients with basal cell carcinoma and control subjects. The subjects were exposed to 800 J/m(2) Commission Internationale de 1'Eclairag of solar-simulating radiation on buttock skin. Biopsies were taken at 0 hour, 24 hours, and 3 weeks after the exposure. Two cyclobutane pyrimidine dimers, TT=C and TT=T, were measured using a sensitive (32)P-postlabeling assay. Initial levels of both TT=C and TT=T differed between individuals in both groups. The levels of TT=T in patients with basal cell carcinoma and controls were similar (9.9 +/- 4.0 and 9.2 +/- 2.9 products per 10(6) normal nucleotides), whereas the level of TT=C was significantly lower in controls than in patients with basal cell carcinoma (6.2 +/- 3.1 versus 10.9 +/- 4.5 products per 10(6) normal nucleotides). The fractions of TT=T remaining after 24 hours and 3 weeks were significantly higher in patients with basal cell carcinoma (72% and 11%) compared with controls (48% and 5%). A slower removal in patients with basal cell carcinoma than in controls was indicated also for TT=C (52% versus 42% remaining at 24 hours); however, the difference between groups was not significant. When including data from our previously reported small-scale study, the fraction of dimers remaining at 24 hours was significantly higher in patients with basal cell carcinoma for both TT=C and TT=T. The data suggest that patients with basal cell carcinoma have a reduced capacity to repair UV-induced DNA lesions.

Background: The objective of this study is to assess the risk of second primary cancers following a first primary esophageal cancer as well as the risk of esophageal cancer as a second primary, following first primary cancers of other sites., Methods: The present investigation is a multicenter study of 13 population-based cancer registries in Europe, Australia, Canada, and Singapore. To assess excess occurrence of second cancers after esophageal cancers, we calculated standardized incidence ratios (SIR) by dividing the observed numbers of second cancers by the expected number of cancers calculated from the accumulated person-years and the age-, sex-, calendar period-, and registry-specific first primary cancer incidence rates., Results: During the study period, 959 cases of second primary cancers occurred after an initial esophageal cancer, resulting in a SIR of 1.15 (95% confidence interval, 1.08-1.22). Second primary stomach cancers were associated with first primary esophageal adenocarcinomas (SIR, 2.13; 95% confidence interval, 1.26-3.37) and second primary cancers of the oral cavity and pharynx (6.68; 5.33-8.26), stomach (1.53; 1.14-2.01), larynx (3.24; 1.88-5.18), lung (1.55; 1.28-1.87), kidney (1.88; 1.18-2.85), and thyroid (2.92; 1.18-6.02) were associated with first primary squamous cell carcinomas of the esophagus. An excess of esophageal cancer as a second primary were observed following first primary cancers of the aerodigestive tract, female breast, cervix, testis, bladder, Hodgkin's lymphoma, and non-Hodgkin lymphoma., Conclusion: We observed associations of esophageal cancer with second primary head and neck cancers and lung cancer regardless of years of follow-up, which may suggest that common risk factors play a role in multiple tumor development.

The reasons for the high risk of contralateral breast cancer are not understood, although polygenic mechanisms have been suggested to be involved. The nationwide Swedish Family-Cancer Database was used to examine the interaction of the risks for contralateral and familial cancer. Relative risks were separately determined for contralateral and familial breast cancers, and these were tested for additive and multiplicative interactions. The Database contained information on 102,176 first breast cancers. Familial risk for breast cancer was 1.76 and the risk for contralateral breast cancer was 3.40, or 5.80 when extrapolated to two breasts. When women had a family history, the risk for contralateral breast cancer was remarkably high, 5.48, or 9.96 when the risk was extrapolated to two breasts, almost identical with 10.21, which was predicted by the multiplicative model. Although the data do not rule out polygenic mechanisms, they suggest that epigenetic imprinting events may be involved for the contralateral breast cancer.

The tumor necrosis factor-related apoptosis-inducing ligand receptor modulates apoptotic response by binding to the proapoptotic death receptor 4 (DR4). Perturbed apoptosis due to missense alterations in the candidate tumor suppressor gene DR4 leads to deregulated cell proliferation and cancer predisposition. Recent studies have discussed the association of DR4 variants with cancer risk. We evaluated, for the first time, the role of the Thr(209)Arg (626C>G) and Glu(228)Ala (683A>C) polymorphisms on colorectal cancer risk by genotyping 659 incident cases and 607 healthy controls drawn from the German population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study. Whereas DR4 Glu(228)Ala was not associated with colorectal cancer, Thr(209)Arg heterozygotes were at a significantly decreased colorectal cancer risk [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.97]. Stratification according to sex and age exhibited a significant association of Thr(209)Arg with a decreased risk for male heterozygotes (OR, 0.68; 95% CI, 0.46-0.99) and for Arg(209) carriers > or =65 years of age (OR, 0.65; 95% CI, 0.46-0.92) as well as an enhanced risk for female Ala(228) carriers in a allele dose-dependent manner (P(trend) = 0.01). Subsite analysis revealed a protective effect of Thr(209)Arg for rectal cancer risk (OR, 0.67; 95% CI, 0.48-0.95) and a significant risk increase for Ala(228) carriers with advanced colorectal cancer stages (P(trend) = 0.04). Haplotype analysis revealed a 2.4-fold risk for carriers of the rare 626C-683C haplotype (1% prevalence in the general population; OR, 2.37; 95% CI, 0.98-5.76). The score statistic yielded an empirical P of 0.03 of the haplotype-specific test for 626C-683C based on 20,000 simulations, suggesting that DR4 626C-683C may affect colorectal cancer predisposition.

Many studies have shown familial aggregation for cervical cancer, but they have been unable to distinguish between shared environmental and genetic effects. Full and half-siblings were identified from the nationwide Swedish Family-Cancer Database, including invasive and in situ cervical cancers in women up to age 70 years. Half-siblings were defined through a common father or mother. Standardized incidence ratios, adjusted for several variables, were calculated for proband-wise risks between full and half-siblings. The familial risk for full siblings was 1.84, compared with 1.40 for maternal and 1.27 for paternal half-siblings. These data were used to apportion familial risk for cervical tumors in full siblings into a heritable component, accounting for 64%, and an environmental component, accounting for 36% of the total risk. No evidence for gene-environment interactions was found. The intractable difficulty in separating cervical cancer causation will be an obstacle for a successful identification of susceptibility genes.

Epidemiologic evidence indicates that several markers of exposure to childhood infections are inversely associated with the risk of childhood leukemia and lymphomas. We used the Swedish Family-Cancer Database to assess the effects of number of siblings on the risk of non-Hodgkin's (n = 7,007) and Hodgkin's lymphomas (n = 3,115), leukemias (n = 7,650), and multiple myeloma (n = 1,492) by histopathology. Poisson regression models included terms for age, sex, family history, period, and socioeconomic index. Having four or more siblings compared with none was associated with an excess risk of childhood acute lymphoblastic leukemia [ALL; rate ratio (RR), 2.11; P(trend) = 0.001], acute monocytic leukemia (RR, 2.51; P(trend) = 0.002), and multiple myeloma (RR, 1.34; P(trend) = 0.006). Having three or more older siblings compared with none decreased the risk of acute monocytic leukemia (RR, 0.35; P(trend) = 0.001) and childhood ALL (RR, 0.69; P(trend) = 0.01). The risk of Hodgkin's lymphoma for five or more older siblings compared with none was 0.41 (P(trend) = 0.003). Acute myeloid leukemia, chronic lymphocytic leukemia, and other lymphoproliferative malignancies were not associated with number of siblings. In conclusion, we found an excess risk of childhood ALL and acute monocytic leukemia in large families. However, for ALL, acute monocytic leukemia, and Hodgkin's lymphoma, younger siblings were strongly protected compared with older siblings. The remarkable protective effect of number of older siblings on acute monocytic leukemia is a novel finding of potential interest. Possible interpretations of our findings in the context of a putative infectious etiology are discussed.

The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of familial breast cancer in patients with unknown p53 mutation status. Data from 549 women affected by familial breast cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of familial breast cancer. The data were also examined taking into account the presence of any additional cancer after breast cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable breast cancer.

High levels of DNA damage are induced in human skin following exposure to UV radiation. Cyclobutane thymidine dimer (T = T) is the most common of these lesions, which are enzymatically removed as oligonucleotides from DNA and further degraded before excretion in urine. Analysis of such repair products in the urine could serve as a biomarker of total body burden of UV exposure. The aim of this study was to examine the kinetics of T = T excretion following a single tanning session in a commercial solarium and to validate the method by delivering different doses. Ten individuals used the solarium for a total of 35 sessions of body tanning. Urine was collected before UV exposure and daily thereafter (up to 5 or 11 days) and T = T was analyzed using a very sensitive and quantitative (32)P-postlabeling technique combined with high-performance liquid chromatography. Following exposure, T = T levels increased dramatically and reached a peak 3 days later; afterwards, the T = T levels gradually decreased. The total amount of T = T excreted differed about 5-fold among subjects given an equal dose. A 50% excretion time was calculated using the excretion data for the first 5 days and it was found to be between 55 and 76 hours for different individuals. There was a good correlation between the amount of T = T excreted during days 1 to 5 and the delivered UV dose. Reducing exposure time to 50% lowered the amount of T = T to 47%; if half of the lamps were covered, T = T decreased to 44%. Our data show that urinary T = T could be a suitable noninvasive biomarker for UV exposure; a finding which could also be applicable to studies in children.

The importance of genetic factors in the etiology of non-Hodgkin lymphoma (NHL) is suggested by case-control and cohort studies. Most previous studies have been too small to estimate accurately risks of specific categories of lymphoproliferative malignancies in relatives of NHL cases or to quantify the contribution of NHL case characteristics to familial risk. We have overcome sample size limitations and potential recall bias by using large databases from Sweden and Denmark. Diagnoses of lymphoproliferative malignancies were compared in 70,006 first-degree relatives of 26,089 NHL cases (including 7,432 with subtype information) versus 161,352 first-degree relatives of 58,960 matched controls. Relatives of NHL cases were at significantly increased risk for NHL [relative risk (RR), 1.73; 95% confidence interval (95% CI), 1.39-2.15], Hodgkin lymphoma (RR, 1.41; 95% CI, 1.0-1.97), and nonsignificantly for chronic lymphocytic leukemia (CLL; RR, 1.31; 95% CI, 0.93-1.85). No increased risk was found for multiple myeloma among case relatives. Findings with respect to siblings compared with parents and offspring or with respect to age at diagnosis of proband were inconsistent. In both populations, relatives of cases with an aggressive NHL subtype were at substantially increased risk of NHL (combined RR, 3.56; 95% CI, 1.80-7.02). We conclude that NHL has an important familial component, which is shared with Hodgkin lymphoma and CLL. We estimate that the absolute lifetime risk for a first-degree relative of an NHL case to develop NHL is 3.6% (compared with a population risk of 2.1%) and higher if the index case had an aggressive subtype of NHL.

Background: Tobacco smoking is the principal cause of lung cancer. The risk of lung cancer in the offspring of lung cancer patients is about twice higher than the risk in the general population. The present study investigated the contribution of shared smoking habits to the familial clustering of lung cancer., Methods: We estimated the relative risk of lung cancer attributable to smoking according to the extent to which smokers transmit their smoking habits to the offspring (heritability of smoking), the prevalence of smoking in the general population, and the risk of lung cancer for smokers compared with nonsmokers., Findings: The relative risk of lung cancer for the offspring of lung cancer patients attributable to smoking was 1.19 when published data on smoking practice were modeled (i.e., assuming that the heritability of smoking was 0.5, the smoking prevalence 40%, and the odds ratio of lung cancer for smokers versus nonsmokers was 20)., Interpretation: Most familial cases of lung cancer cannot be attributed to shared smoking habits. The example of smoking can be used for other familial cancers, for which no strong environmental risk factors are usually known, to infer the primary role for heritable genes.

Genetic anticipation in familial non-Hodgkin's lymphoma, Hodgkin's lymphoma, and chronic lymphocytic leukemia (CLL) has been consistently reported in the literature. However, most of these findings were based on data from families ascertained for genetic studies. Fecundity bias, right censoring bias, and secular trends can lead to erroneous conclusions regarding the presence of anticipation. Our report investigates anticipation in four lymphoproliferative cancers, non-Hodgkin's lymphoma, Hodgkin's lymphoma, CLL, and multiple myeloma, drawn from Swedish and Danish population-based registries. We used marginal survival methods to test for a relative difference in age at diagnosis between parents and offspring and to account for other risk factors, staggered entries, censored data, and correlations among relatives. Changes in incidence rates of lymphoproliferative tumors were accommodated in the models by using time-varying covariates for different periods of diagnosis. Whereas no anticipation was observed for Hodgkin's lymphoma, CLL, and multiple myeloma, our initial model, which controlled for gender and country, suggested a significant difference (hazard ratio, 0.5; 95% confidence interval, 0.33-0.75) in age at diagnosis between the parents and offspring in the non-Hodgkin's lymphoma sample. However, once we accounted for the significant change in non-Hodgkin's lymphoma incidence over time, the statistical difference between parents and offspring disappeared (hazard ratio, 0.99; 95% confidence interval, 0.56-1.76). Our results emphasize the importance of considering secular trends when evaluating the possibility of anticipation in lymphoproliferative cancers. This is the first study to consider the changes of incidence over time as a source of bias when evaluating anticipation in lymphoproliferative cancers.

A family history is an identified risk factor for colorectal cancer (CRC). However, it is not known to what extent the risk is due to environmental or heritable genetic factors. We wanted to examine this question for familial CRC adenocarcinoma based on the nationwide Swedish Family-Cancer Database on 10.3 million individuals whose invasive cancers were followed up to year 2000. Standardized incidence ratios (SIRs) for offspring, siblings, and spouses were calculated based on 5-year age, sex, period (10-year bands), area (county), and socioeconomic status standardized rates. A significant risk was observed in the parent-offspring comparison among different subsites (left-sided and right-sided colon, rectum, and all CRC), the SIRs ranging from 1.74 to 1.84. When husbands were probands, the SIR in wives was 0.92 for colon cancer (left-sided 0.67 and right-sided 1.07), 0.98 for rectal cancer, and 0.96 for CRC. The risks for husbands when wives were probands were quite similar. None of the SIRs between spouses were significant, indicating lack of concordance between spouses that resided together for a minimum of 30 years. The risks between siblings were also increased particularly for cancer in the right-sided colon (SIR 6.89). The effect of shared childhood environmental effects were probed by analyzing the risks by age difference between the siblings. However, the risks were independent of the age difference. Data among spouses and siblings consistently point to the importance of heritable factors in familial CRC.

We used the nationwide Swedish Family-Cancer Database to analyze the risk for nervous system tumors in offspring through parental and sibling probands. Among 0-68-year-old offspring, close to 11000 patients with a nervous system tumor were identified in years 1961 to 2000, among whom 199 had a parent diagnosed with a nervous system tumor. Brain tumors constituted 86% of all tumors, and astrocytoma was the main histological type, representing half of all cases. Standardized incidence ratios (SIRs) for familial risk were only increased for brain tumors of meningioma, astrocytoma, and hemangioblastoma histology. When parents were diagnosed with tumors of the same histology, the SIRs for offspring were 3.06, 2.19, and 165 for meningioma, astrocytoma, and hemangioblastoma, respectively. Among siblings, the SIRs were 4.41, 3.20, and 61. Age-specific analysis of familial astrocytoma revealed three distinct components, one < 10 years, the second approximately age 30 years, and the third at age >60 years. The kappa test was used to assess the likelihood of an identical histology in two family members. The occurrence of hemangioblastoma was completely determined among the siblings, and the kappa value was 1.00. Meningiomas were also moderately ordered among the siblings, but astrocytomas were less determined. Many syndromes are known in which nervous system tumors are manifestations, including hemangioblastoma, recognized as part of von Hippel-Lindau disease. Yet, it is likely that many brain astrocytoma, meningioma, and mixed families represent yet unknown heritable conditions.

Limited data are available on the possible changes in cancer risk brought about by widowhood and divorce, an increasing segment of the population. We calculated standardized incidence ratios (SIRs) for cancer among 47,000 widows/widowers and 60,000 divorced people, based on the Swedish Family-Cancer Database. Persons had to be identified with the same civil status in the census of years 1960 and 1970; the comparison group was married people according to the same censuses. Cancers were followed from years 1971 to 1998. Both increased and decreased SIRs were found, and a consistent pattern emerged. The effects on the divorced were always stronger than those in widows/widowers, irrespective of the direction of the effect. Every significant SIR for a cancer site in widows/widowers was accompanied by a more deviant and significant SIR in the divorced. SIRs between divorced men and women (r=0.83, P<0.0001) and between widows and divorcees correlated (r=0.70, P<0.0001). The overall cancer risk for the divorced was 0.92-0.94, and it was a balance between increased risks at tobacco-, alcohol-, and human papilloma virus-related sites, and decreased risks at most other sites. The data suggest that the changes in lifestyle on the loss of a spouse impact on the incidence of almost every type of cancer. The effects were so large that a failure to consider marital status in epidemiological studies may be a source to bias. Understanding these lifestyle changes may provide new insight in cancer prevention.

It is well known that certain cancers have shown clusteringin educational and socioeconomic groups, but recent comprehensive data on clustering by education are limited. We determined standardized incidence ratios (SIRs), adjusted for several variables, for cancer among men and women in six educational groups based on the Swedish Family-Cancer Database. People were identified with a certain educational background in the census of year 1970; the comparison group was the largest group, those with <9 years of education. Cancers were followed from years 1971 to 1998. Total cancer risks did not differ much, but at individual sites, the trend was significant, either increasing or decreasing over all educational groups (for 27 of 29 male and 28 of 31 female cancers). University graduates had a decreased risk of tobacco-, alcohol-, and genital infection-related cancers, but male graduates had an excess of colon, prostate, squamous cell skin, nervous system cancer, and melanoma. Male graduates showed a low SIR of 0.50 for stomach cancer and a high SIR of 1.89 for melanoma; female graduates showed a low SIR of 0.43 for lung and cervical cancer and a high SIR of 1.57 for melanoma. The overall weighted population attributable fraction for educational level was 13.8% for men and 16.7% for women, and it was highest, >50%, for stomach cancer in both genders and for cervical and anal cancer in women.

Population attributable faction (PAF) shows the proportion of the disease that could be prevented if the cause could be removed. PAFs for most types of familial cancer have not been determined. We used the Swedish Family-Cancer Database on 10.2 million individuals and 688,537 parental and 116,741 offspring cancers to calculate familial risks, proportions of affected individuals, and familial PAFs for 28 neoplasms among 0-66-year-old offspring. The data were calculated by an exact proband status in the nuclear families. The familial risks for offspring cancer were increased at 23 of 28 sites from the same cancer in only the parent, at 17 sites from a sibling proband and at 12 sites from a parent and sibling proband. The highest PAFs by parent were for prostate (9.01%), breast (3.67%), and colorectal (5.15%) cancer. However, considering that in gender-specific cancers, the familial effect may originate from grandparents, the PAFs for prostate and breast cancer could be multiplied by 2. The PAFs for the sibling history of prostate, breast, and colorectal cancers were 1.55, 2.85, and 1.23% and for the parent and sibling history 0.99, 0.42, and 0.48%, respectively. Because of mutually exclusive proband definition, the PAFs were additive, giving a total PAF of 20.55% for prostate, 10.61% for breast, and 6.87% for colorectal cancer. The present PAF values give an estimate of the heritable single locus or additive effects for cancer in nuclear families. The data show that the familial PAF of prostate cancer was 20.55%, and breast cancer 10.61%, but for most other sites, it was between 1 and 3%.

Transplacental exposure to carcinogenic air pollutants from the combustion of fossil fuels is a growing health concern, given evidence of the heightened susceptibility of the fetus. These mutagenic/carcinogenic pollutants include aromatic compounds such as polycyclic aromatic hydrocarbons that bind to DNA, forming chemical-DNA adducts. We have investigated the genotoxic effects of transplacental exposure in humans by analyzing aromatic-DNA adducts and the frequency of gene mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in umbilical cord and maternal blood samples. Here we show, in a cross-sectional study of 67 mothers and 64 newborns from the Krakow Region of Poland, that aromatic-DNA adducts measured by (32)P-postlabeling are positively associated with HPRT mutant frequency in the newborns (beta = 0.56, P = 0.03) after controlling for exposure to tobacco smoke, diet, and socioeconomic status. In contrast to the fetus, HPRT mutations and DNA adducts do not reflect similar exposure periods in the mother, and the maternal biomarkers were not correlated. Adducts were higher in the newborn than the mother, indicating differential susceptibility of the fetus to DNA damage; but HPRT mutation frequency was 4-fold lower, consistent with the long lifetime of the biomarker. These results provide the first demonstration of a molecular link between somatic mutation in the newborn and transplacental exposure to common air pollutants, a finding that is relevant to cancer risk assessment.

Second cancers were studied among 68,104 cases of colorectal cancer (CRC) from the Swedish Family-Cancer Database. A total of 1,113 patients received a diagnosis of second CRC; 25 of them had a family history of CRC. Cases of second CRC with a family history were diagnosed up to 10 years before sporadic cases. The relative risk (RR) of all second CRCs was 2.21 compared with the first CRC. Familial second CRCs had a 2-fold risk compared with the sporadic forms. Age of onset was the most important covariate of second CRCs; the relative risk at ages 15-39 years was 27 compared with the first CRC. Familial CRC was associated with a high risk of small-intestinal, endometrial, and gastric cancers apart from CRC, all typical of hereditary nonpolyposis CRC (HNPCC). Among familial cases, 36% of second CRCs and 100% of endometrial cancers came from families that fulfilled the Bethesda criteria for HNPCC. Only 12 families conformed to the Amsterdam criteria; in family members, the risk of second CRC was 127-fold and that of endometrial cancer 257-fold. Other sites that were in excess among all second cancers were many cancers linked to HNPCC and, additionally, breast, prostate, thyroid and other endocrine, skin, and genital cancers. The high risk of second cancer after early-onset CRC calls for evaluation of family history and clinical surveillance.

Human and experimental evidence indicates that the developing fetus may be more susceptible than the adult to the effects of certain carcinogens, including some polycyclic aromatic hydrocarbons (PAHs). Factors that can modulate susceptibility include proliferation rates, detoxification capabilities, and DNA repair capacity. Biomarkers can facilitate quantification of age-related susceptibility among human populations. In this study, we report on three biomarkers measured in paired blood samples collected at birth from 160 Polish mothers and newborns: 70 pairs from Krakow (a city with high air pollution including PAHs) and 90 pairs from Limanowa (an area with lower ambient pollution but greater indoor coal use). Biomarkers were: WBC aromatic-DNA adducts by (32)P-postlabeling and PAH-DNA adducts by ELISA (as indicators of DNA damage from PAHs and other aromatics) and plasma cotinine (as an internal dosimeter of cigarette smoke). Correlations were assessed by Spearman's rank test, and differences in biomarker levels were assessed by the Wilcoxon signed-ranks test. A significant correlation between paired newborn/maternal samples was seen for aromatic-DNA adduct levels (r = 0.3; P < 0.001) and plasma cotinine (r = 0.8; P < 0.001) but not PAH-DNA adduct levels (r = 0.14; P = 0.13). Among the total cohort, levels of the three biomarkers were higher in newborn samples compared with paired maternal samples. The difference was significant for aromatic-DNA adduct levels (16.6 +/- 12.5 versus 14.21 +/- 15.4/10(8) nucleotides; P = 0.002) and plasma cotinine (14.2 +/- 35.5 versus 8.3 +/- 24.5 ng/ml; P < 0.001) but not for PAH-DNA adduct levels (7.9 +/- 9.9 versus 5.9 +/- 8.2/10(8) nucleotides; P = 0.13). When analyses were restricted to the 80 mother/newborn pairs from whom the blood sample was drawn concurrently (within 1 h of each other), levels of all of the three biomarkers were significantly higher in the newborn compared with paired maternal blood samples (P < 0.05). Results suggest reduced detoxification capabilities and increased susceptibility of the fetus to DNA damage, especially in light of experimental evidence that transplacental exposures to PAHs are 10-fold lower than paired maternal exposures. The results have implications for risk assessment, which currently does not adequately account for sensitive subsets of the population.

We have studied the influence of GSTM1 and NAT2 genotypes on aromatic DNA adduct level (AL) and HPRT mutant frequency (MF) in smokers with newly diagnosed lung cancer and matched population controls. AL was analyzed in relation to genotypes in 170 cases and 144 controls (113 current/recent smokers and 201 former/never smokers), and MF in 157 cases and 152 controls (155 ever smokers and 154 never smokers). Both genotypes exhibited the a priori expected effects on AL and MF among controls only, especially among smoking controls [significantly lower pack-years (a pack-year is defined as 1 pack of cigarettes/day for 1 year) than among cases]. Among the 42 currently smoking controls, the NAT2 slow genotype [odds ratio (OR), 7.5; 95% confidence interval (CI), 1.5-38.4], in particular in combination with the GSTM1 null genotype (OR, 19.3, 95% CI, 1.1-338.6 for null/slow versus positive/rapid) was strongly associated with high AL. The null/slow combination was also significantly associated with high MF among ever smokers (cases and controls pooled) with lower pack-years (OR, 3.7; 95% CI, 1.3-10.7 versus all of the other genotypes; OR, 5.1; 95% CI, 1.2-22.4 versus positive/rapid). In contrast, an antagonistic gene-gene interaction was seen among smoking cases for both AL and MF. Only currently smoking cases with the combined GSTM1 null and NAT2 rapid genotype showed a positive correlation between InAL and InMF (r, 0.64; P = 0.1), and an increase of AL with both age and daily cigarette use. This genotype combination was also associated with high MF among ever-smoking cases (OR, 4.0; 95% CI, 0.9-17.7 versus positive/rapid). There was a significant interaction between NAT2 genotype and pack-years of smoking among cases, so that the rapid genotype was associated with high MF among ever-smoking cases diagnosed at higher pack-years, whereas the slow genotype was associated with high MF at lower pack-years. These findings suggest that the influence of NAT2 genotype on AL and MF and its interaction with GSTM1 genotype may be dose dependent. The NAT2 slow genotype, in particular when combined with the GSTM1 null genotype, may confer increased susceptibility to adduct formation, gene mutation, and lung cancer when the smoking dose is low.

Endometrial cancer was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included over 20,000 cases of endometrial cancer. Seventy-six families were identified in which both the mother and the daughter had endometrial cancer, giving a familial standardized incidence ratio (SIR) of 3.19 for daughters and 2.78 for mothers. The risk depended inversely on the age at diagnosis, and the risk was almost 10 in daughters who were diagnosed before age 50 when their mothers were also diagnosed before that age. The discordant cancer site that associated with endometrial cancer between the two generations was colon, with a SIR of 1.44-1.68. However, when the maternal endometrial cancer was diagnosed before age 50, increased SIRs were observed in daughters or sons for rectal, pancreatic, nervous system, breast, and ovarian cancers. Second cancers were followed in females diagnosed with endometrial cancer, and the highest overall risks were observed for ovarian and connective tissue cancers; colorectal cancers were also clearly in excess. Among the other family members of the 76 families in which both mother and daughter were affected with endometrial cancer, there were 11 cases of colorectal cancer. When a sister was affected in such families, the SIR of endometrial cancer was 31.40, and the median diagnostic age was several years lower than in endometrial cancer families in which no colorectal cancers were found. Many of these families may have hereditary nonpolyposis colorectal carcinoma syndrome. However, the risk of endometrial cancer was increased even in families presenting no colorectal cancers.

We conducted a case-control study to assess the risk of lung cancer in relation to genetic polymorphisms of the detoxifying enzymes glutathione-S-transferase mu1 (GSTM1) and N-acetyl transferase 2 (NAT2), focusing on never-smokers, women, and older people. The study base consisted of persons > or =30 years of age in Stockholm County from 1992 to 1995. We recruited never-smoking lung cancer cases and a sex- and age-matched sample of ever-smoking cases at the three county hospitals mainly responsible for diagnosing and treating lung cancer. A total of 185 cases (25.4% men; 47.6% never-smokers) and 164 frequency-matched population controls (28.7% men; 48.2% never-smokers) supplied blood for genotyping. Detailed information was collected by interview on active and passive smoking, occupations, residences, and diet. The overall odds ratio (OR) for lung cancer associated with the GSTM1 null (GSTM1-) versus GSTM1+ genotype was 0.8 [95% confidence interval (CI), 0.5-1.2], with an OR close to unity among smokers, and lower ORs suggested among never-smokers. For NAT2 slow versus rapid acetylator genotypes, the OR was 1.0 (95% CI, 0.6-1.5) overall, which broke down into an increased risk for slow acetylators among never-smokers but an increased risk for rapid acetylators among smokers. Among never-smokers, a gene interaction was suggested, with combined slow acetylator and GSTM1+ genotype conferring particularly high risk (OR = 3.1; 95% CI, 1.1-8.6), but no clear pattern emerged among smokers. A detailed analysis among smokers showed no interaction between pack-years of smoking and the GSTM1 genotype but suggested a steeper increase in risk with increasing pack-years of smoking exposure for rapid than for slow acetylators. Our results do not support a major role for the GSTM1 genetic polymorphism as a risk factor for lung cancer among smokers or nonsmokers. There was, however, some suggestion that the slow acetylator genotype may confer an increased risk among never-smokers and that the rapid acetylator genotype interacts with pack-year dose to produce a steeper risk gradient among smokers.

The Swedish Family-Cancer Database was used to analyze relationships between parents and offspring with in situ cancers and between in situ cancers in one generation and invasive cancer in the other generation. A total of 130,000 in situ cancers and close to 400,000 invasive cancers were included from 1959 to 1994. The data on family relationships and cancers came from registered sources and should be free from bias. The offsprings' familial relative risks (FRRs) were calculated for concordant and discordant parental cancer sites. The most common male in situ site was skin (both melanoma and precancerous epithelial lesion), whereas cervix, breast, and skin were common female sites. Increased FRRs were observed for concordant sites: colon, breast, cervix, skin (melanoma), and, in males, precancerous epithelial lesions. The findings were consistent when in situ cancer-in situ cancer and in situ cancer-invasive cancer relationships were explored. FRRs were higher for in situ colon cancer and melanoma than the respective estimates in invasive cancers, and for the remaining sites, they were equal or somewhat lower. At discordant sites, increased FRRs of in situ cancers were observed for female breast and melanoma and, at many sites, implicated in tobacco and human papilloma virus carcinogenesis, together with cervix. Family histories of in situ cancers deserve clinical attention.

The UVB component of solar radiation is a risk factor for skin cancer, the most common cancer in the Western world. Yet little is known about the induction of DNA damage in human skin by UVB and its modulation by sunscreens. Here, we apply a novel postlabeling high-performance liquid chromatography technique to quantify UVB-induced photoproducts in skin biopsies with and without sunscreen. The results showed approximately 30-fold interindividual variations in levels of DNA damage in unprotected skin of the 14 subjects, probably relating to skin cancer susceptibility. On average, sunscreen guards against DNA damage as expected by the erythemal response, but some individuals are poorly protected.

UV light is considered an important contributor to skin cancer, but methods have been lacking to quantify specific UV-induced lesions in human skin in situ. We applied a newly developed 32P-postlabeling technique to measure specific UV-induced cyclobutane dimers and 6-4 dipyrimidine lesions in the skin of healthy volunteers. At a dose of 400 J/m2, solar-simulated radiation caused at least 20 cyclobutane dimers/10(6) nucleotides, which is much higher than any known DNA adducts induced by specific external chemical exposure in human target tissues. This may explain why patients with DNA repair syndromes, such as xeroderma pigmentosum, preferentially develop skin cancer. We applied the 32P-postlabeling technique to study rates of DNA repair in healthy individuals. The obtained data indicated a base sequence dependence of the repair process. The applied method has potential for the study of DNA repair as a determinant of individual susceptibility to skin cancer.

The Family-Cancer Database was constructed from the nationwide Swedish registries to include more than 30,000 cancers in offspring diagnosed at ages 15-51 years and their parents. Cancer risk in the offspring was increased about 1.10 times when the father had cancer, whereas no increase was noted when the mother had cancer. If both parents had cancer, the risk for sons was 1.39 and for daughters, 1.34. Familial aggregation between parents and offspring was observed for 5 concordant and 14 discordant cancer sites and 10 parental sites at which all cancer was increased in the offspring. The concordant sites between the parent and offspring were colorectum, breast, melanoma, skin (squamous cell carcinoma), and thyroid. The aggregation at discordant sites in the parents and the offspring included stomach-breast, colorectum-salivary glands, colorectum-breast, colorectum-lymphoma, colorectum-leukemia, liver-breast, pancreas-breast, breast-melanoma, ovary-breast, prostate-breast, prostate-cervix, prostate-multiple myeloma, kidney-melanoma, and nervous tissue-melanoma. In most of these combinations, cancer in the second parent increased the risk to the offspring. The present results on young and middle-aged adults suggest that cancer in both parents increases cancer risk in the offspring at many sites. Chance and environmental effects may explain some of the results, whereas true genetic factors probably contribute to most of the findings. The molecular genetic explanation may be that rare dominant single genes increase susceptibility at many sites or that overlapping sets of genes control susceptibility at multiple sites.

Tamoxifen-induced DNA adducts were analyzed with the (32)P-postlabeling method using high-performance liquid chromatography (HPLC)-radioactivity detection from endometrial tissue of breast cancer patients and controls. Liver DNA from tamoxifen-treated rats was used as a positive standard. In blind analysis, five of the seven samples from tamoxifen-treated patients showed DNA adducts; none of the five controls were positive. The identity of the tamoxifen adduct was confirmed by using different chromatographic systems, isolating the HPLC fractions and running them on TLC, with or without spiked rat liver samples. The level of adducts in the treated patients was 2.7 adducts/10(9) nucleotides in the HPLC analysis.

In an ongoing comprehensive evaluation of biological markers, workers in or near an iron foundry with varying exposure to polycyclic aromatic hydrocarbons (PAH) were analyzed for molecular response to this exposure. Exposure to benzo(a)pyrene, determined by personal monitors worn by the workers (2 to 60 ng/m3), was considerably lower than in a previous study at this foundry (< 50 to 200 ng/m3) (F.P. Perera et al., Cancer Res., 48: 2288-2291, 1988). Two biomarkers, 1-hydroxypyrene in urine measured by high-performance liquid chromatography with fluorescence detection (a measure of internal dose) and PAH-DNA adducts in WBC measured by immunoassay (a measure of biologically effective dose) were assessed to demonstrate their relationship to the lowest exposures yet analyzed in foundry workers. In addition, these markers were analyzed for dose response and interindividual variability. Cigarette smoking, but not age or charbroiled food, influenced the level of 1-hydroxypyrene but not PAH-DNA adducts. When workers were classified into three exposure categories (low, medium, and high), mean 1-hydroxypyrene levels were 2.7, 1.8, and 3.6 mumol/mol creatinine, respectively. Comparisons by analysis of variance showed a significant difference between the groups after controlling for smoking (P = 0.02), but a trend test using multivariate linear regression analysis was not significant (r = 0.27; P = 0.07). Substantial interindividual variation was demonstrated by the 19- to 20-fold range in the values within each of the three exposure groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding of the hepatocarcinogen 2-acetylaminofluorene (AAF) and two metabolites, 2-aminofluorene (AF) and N-hydroxy-2-acetylaminofluorene (N-OH-AAF), to the DNA and protein of rat hepatic nuclei was examined in vitro and in a cell-free system. Three and one-half hr following a single injection of each compound in equimolar amounts. DNA contained approximately 50% more of the compounds per mg than did protein. The amount of N-OH-AAF bound to DNA was 4 times greater than that of AAF, while AF bound in intermediate amounts. When incubated with nuclei in a cell-free system, AAF seldom bound in measurable amounts, while significant amounts of N-OH-AAF and AF bound to both DNA and protein. As occurred in vivo, DNA bound more of each per mg than did protein. The amount of N-OH-AFF bound to intranuclear DNA increased 54% when an aliquot of the postmicrosomal liver fraction was added to the incubation mixture, but maximum binding of AF occurred in the absence of any other liver fraction. Thus, it was shown that two AAF metabolites, AF and N-OH-AAF, bind covalently to the DNA and protein of hepatic nuclei more readily than does AAF itself and that binding in a cell-free system parallels binding in vivo. Additional evidence suggests that rat hepatic nuclei are capable of mediating the binding of AF and N-OH-AAF to macromolecules through distinct enzyme systems. This is the first demonstration that the nucleus is capable of metabolizing AF to an electrophile that can bind covalently to DNA.

Metabolic activation of benzo(a)pyrene (BP) to its ultimate carcinogenic form, 7 beta, 8 alpha-diol-9 alpha, 10 alpha-benzo(a)pyrene epoxide (BPDE), and the binding of BPDE to DNA are important steps in BP carcinogenicity in experimental animals. Since people of certain occupations are exposed to high concentrations of BP, we have used enzyme-linked immunosorbent assay and ultrasensitive enzymatic radioimmunoassay to measure BPDE:DNA adducts in white blood cells from 2 of these occupational groups. Seven of 28 samples from roofers and 7 of 20 samples from foundry workers were positive for BPDE:DNA adducts (range, 2 to 120 fmol BPDE/50 micrograms DNA). In a group of nine volunteers without these industrial exposures to BP, the two positive DNA samples were from cigarette smokers. Control DNA obtained from human lymphocyte cell line RPMI 4265 was negative. These results indicate that the metabolic activation of BP and formation of BPDE:DNA adducts occurs in humans.

Iron foundry workers, exposed to high levels of polycyclic aromatic hydrocarbons (PAHs), silica, and metal fumes and dusts, are at elevated risk of lung cancer. Benzo(a)pyrene and a number of structurally related PAHs are metabolically activated to diol epoxides (e.g., 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a) pyrene) which are mutagenic, carcinogenic in experimental animals, and form covalent adducts with DNA. The levels of these adducts were measured in an enzyme-linked immunosorbent assay using a polyclonal anti-benzo(a)pyrene diol epoxide-I-DNA antibody which cross-reacts with DNA modified by diol epoxides of structurally related PAHs. DNA was analyzed from peripheral blood cells of 35 Finnish foundry workers and 10 controls. Workers were classified as having low (less than 0.05 micrograms/m3), medium (0.05-0.2 micrograms/m3), or high (greater than 0.2 micrograms/m3) exposure to benzo(a)pyrene (as an indicator of PAH). When adjustment was made for cigarette smoking and time since vacation, benzo(a)pyrene exposure was significantly related to adduct levels (P = 0.0001). Each of the three exposure groups had significantly elevated adduct levels compared to controls. Among the exposed workers, the low group differed significantly from the high and medium categories. This study supports the usefulness of monitoring adduct formation in a population occupationally exposed to carcinogens.

The stability of phosphoramide mustard, a metabolite of cyclophosphamide was studied at pH 7.2 and 37 degrees C using 31P nuclear magnetic resonance. The phosphorus signal of phosphoramide mustard disappeared with a half-life of 8 min indicating rapid conversion to other species. The final product, inorganic phosphate, appeared with a half-life of 105 min indicating that phosphoramide mustard was easily dephosphoramidated. A rat liver microsomal system was used to study the binding of [chloroethyl-3H]cyclophosphamide to DNA. DNA was hydrolyzed in 0.1 N HCl:0.5 N NaCl at 80 degrees C for 20 min, conditions known to convert phosphoramide mustard to nornitrogen mustard with liberation of the phosphoramide residue. After such treatment three adducts were detected by high-performance liquid chromatography using several elution systems. They were all 7-substituted guanine adducts of nornitrogen mustard; two were monoalkylation products with an intact [N-(2-chloroethyl)-N-[2-(7-guaninyl)ethyl]amine] or an hydroxylated mustard arm [N-(2-hydroxyethyl)-N-[2-(7-guaninyl)ethyl]amine]; the third adduct was a cross-linked product [N,N-bis [2-(7-guaninyl)ethyl]-amine]. The relative abundance of these adducts depended on the length of the microsomal incubation. After 2 h, N-(2-chloroethyl)-N-[2-(guaninyl)ethyl]amine was the main product but after 6 h N-(2-hydroxyethyl)-N-[2-(7-guaninyl)ethyl]amine was most abundant, and at this time the cross-linked product represented 12% of the total adducts. The adducts in DNA depurinated readily and after 24 h at pH 7.0 and 37 degrees C 70% of them had been liberated. The rate of depurination was decreased in the presence of 0.5 N NaCl. After short-term depurination in 0.1 N HCl at 25 degrees C the primary alkylating species was phosphoramide mustard rather than nornitrogen mustard. In in vivo studies mice were given injections i.p. of 100 microCi of cyclophosphamide. Maximal levels of radioactivity had been incorporated into DNA between 2-7 h after injection; the specific activity of DNA from the kidney and lung exceeded that from the liver. While the level of radioactivity found in kidney DNA was rapidly reduced the rate of fall was lower in the lung. Between 24 and 72 h the specific activity of lung DNA exceeded that of kidney and liver DNA by a factor of 3:8. Lung is the principal target tissue for tumor formation in mice after an i.p. injection.