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PubMed1994

Alcohol consumption and breast cancer: estrogen receptor status and histology.

Data from a case-control study conducted in New York State during 1982-1984 were used to evaluate the relation between alcohol consumption and estrogen receptor-positive and estrogen receptor-negative breast cancers and alcohol and various histologic subtypes. The cases were women between 20 and 79 years of age with a diagnosis of primary breast cancer. A total of 794 estrogen receptor-positive and 358 estrogen receptor-negative breast cancer cases were available for study. Controls (n = 1,617) were selected from driver's license files of the New York State Department of Motor Vehicles. Information on estrogen receptor status and histology was obtained from hospital records. The risk of estrogen receptor-positive breast cancer was shown to increase with increasing amounts of alcohol consumption in grams per day (odds ratio (OR) = 1.18 (95% confidence interval (CI) 0.88-1.57) for < 1.5 g/day, 1.28 (95% CI 0.91-1.80) for 1.5-4.9 g/day, 1.28 (95% CI 0.96-1.70) for 5.0-14.9 g/day, and 1.35 (95% CI 0.99-1.85) for > or = 15.0 g/day). There was no relation between alcohol consumption and estrogen receptor-negative tumors (OR = 0.92 (95% CI 0.62-1.36) for < 1.5 g/day, 1.19 (95% CI 0.77-1.83) for 1.5-4.9 g/day, 0.94 (95% CI 0.64-1.35) for 5.0-14.9 g/day, and 1.05 (95% CI 0.70-1.59) for > or = 15.0 g/day). The risk for each of the histologic subtypes studied increased with increasing daily alcohol consumption. These findings suggest that alcohol may only increase a woman's risk of estrogen receptor-positive breast cancers.

Adult↗

PubMed2026

Mitotic microhomology-mediated break-induced replication promotes chromoanasynthesis.

Chromoanasynthesis is a form of complex chromosomal rearrangement (CCR) commonly detected in cancers and congenital disorders, but the mechanism underlying its generation remain elusive. Here we develop a single-molecule long-read DNA sequencing approach to characterise ultra-complex mutational events, consistent with chromoanasynthesis, occurring at shortened telomeres and sub-telomeric DNA double-strand breaks in human cells. Our data reveal that chromoanasynthesis is generated by microhomology-mediated break-induced replication (MM-BIR), occurring specifically in mitosis. Surprisingly, this mitotic pathway involves a collaboration between microhomology-mediated end-joining (MMEJ) and BIR, where MMEJ proteins initiate a Polδ-dependent BIR pathway that is regulated by PIF1, POLD3 and PCNA. This pathway is highly prone to template switching and can generate dramatic amplification of genomic loci in a single event. Our findings help explain the extreme mutagenic nature of chromoanasynthesis and establish mitotic MM-BIR as a key driver of CCRs, with important implications for the origin of cancers and congenital disorders.

Humans↗

PubMed1992

Passive smoking and lung cancer in nonsmoking women.

OBJECTIVES: The causes of lung cancer among nonsmokers are not clearly understood. To further evaluate the relation between passive smoke exposure and lung cancer in nonsmoking women, we conducted a population-based, case-control study. METHODS: Case patients (n = 618), identified through the Missouri Cancer Registry for the period 1986 through 1991, included 432 lifetime nonsmokers and 186 ex-smokers who had stopped at least 15 years before diagnosis or who had smoked for less than 1 pack-year. Control subjects (n = 1402) were selected from driver's license and Medicare files. RESULTS: No increased risk of lung cancer was associated with childhood passive smoke exposure. Adulthood analyses showed an increased lung cancer risk for lifetime nonsmokers with exposure of more than 40 pack-years from all household members (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 1.0, 1.8) or from spouses only (OR = 1.3; 95% CI = 1.0, 1.7). When the time-weighted product of pack-years and average hours exposed per day was considered, a 30% excess risk was shown at the highest quartile of exposure among lifetime nonsmokers. CONCLUSIONS: Ours and other recent studies suggest a small but consistent increased risk of lung cancer from passive smoking. Comprehensive actions to limit smoking in public places and worksites are well-advised.

Adult↗

PubMed1990

An epidemiological case-control study of breast cancer and alcohol consumption.

A case-control study of breast cancer and alcohol consumption was conducted with 1617 patients diagnosed with a primary cancer of the breast between 1982 and 1984 in 18 New York State counties. For each case, one control, matched for year of birth and county of residence, was selected from the driver's license files of the New York State Department of Motor Vehicles. Breast cancer risk was shown to increase as daily consumption of alcohol increased, with a risk of 1.37 (95% Cl = 1.07, 1.75) observed among women who consumed 15 or more grams of alcohol per day. Breast cancer risk did not appear to be related to the total number of years a woman drank or to be restricted to specific types of alcoholic beverages. The data suggest that this may be higher in women who began drinking at a later age. The increased risk associated with alcohol consumption, observed in the current study, persisted within strata of various breast cancer risk factors.

Adult↗

PubMed1997

Body size and risk of breast cancer.

The relation between body size and breast cancer remains uncertain, particularly with regard to differences between pre- and postmenopausal women. The authors examined whether height, weight, body mass index, and weight change were associated with breast cancer risk among pre- and postmenopausal women. This population-based case-control study included women aged 20-74 years (n = 6,548) who were diagnosed with invasive breast cancer during 1988-1991 in Maine, Massachusetts, New Hampshire, and Wisconsin. Similarly aged control women (n = 9,057) were selected at random from driver's license files and Health Care Financing Administration files. Height, weight, and information on other breast cancer risk factors were ascertained by telephone interview, and logistic regression was used to estimate multivariate-adjusted odds ratios and 95% confidence intervals. Among premenopausal women, the adjusted odds ratio for the upper quintile group of height relative to the lowest was 1.36 (95% confidence interval (CI) 1.05-1.76). The heaviest premenopausal women had a lower risk (odds ratio (OR) = 0.87, 95% CI 0.70-1.10). Among postmenopausal women, the adjusted odds ratios were higher for the upper quintile categories of both height (OR = 1.27, 95% CI 1.11-1.45) and weight (OR = 1.57, 95% CI 1.37-1.79). Weight gain since ages 18 and 35 years was associated with increased postmenopausal breast cancer risk, and risk was lower in women who had lost weight. These findings suggest that programs to avoid weight gain merit study as a means to reduce risk of postmenopausal breast cancer.

Adult↗

PubMed1999

Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification.

CpG island methylation has been linked to tumor suppressor gene inactivation in neoplasia and may serve as a useful marker to clone novel cancer-related genes. We have developed a novel PCR-based method, methylated CpG island amplification (MCA), which is useful for both methylation analysis and cloning differentially methylated genes. Using restriction enzymes that have differential sensitivity to 5-methyl-cytosine, followed by adaptor ligation and PCR amplification, methylated CpG rich sequences can be preferentially amplified. In a model experiment using a probe from exon 1 of the p16 gene, signal was detected from MCA products of a colorectal cancer cell line but not in normal colon mucosa. To identify novel CpG islands differentially methylated in colorectal cancer, we have applied MCA coupled with representational difference analysis to the colon cancer cell line Caco2 as a tester and normal colon mucosa as a driver. Using this strategy, we isolated 33 differentially methylated DNA sequences, including fragments identical to several known genes (PAX6, Versican, alpha-tubulin, CSX, OPT, and rRNA gene). The association of hypermethylation of the clones obtained and transcriptional suppression in colorectal cancer was confirmed by examining the Versican gene, which we found to be silenced in methylated cell lines and reactivated by the methylation inhibitor 5-aza-2'-deoxycytidine. We therefore propose that MCA is a useful technique to study methylation and to isolate CpG islands differentially methylated in cancer.

5-Methylcytosine↗

PubMed2026

STK11 Mutations and Deletions Define an Aggressive Molecular Subgroup of Cervical Adenocarcinoma.

Cervical adenocarcinoma accounts for 15%-20% of cervical cancers and is associated with poorer survival and reduced response to screening and immunotherapy compared with squamous cell carcinoma (SCC). The genomic drivers underlying this molecular subgroup remain incompletely characterized. Whole-exome sequencing was performed on 302 invasive cervical cancers from Guatemala and Venezuela. Structural variation analysis was conducted using SNP-array and whole-genome sequencing data. Findings were replicated in more than 4600 additional cervical cancer samples from TCGA, AACR Project GENIE, MSKCC, and Caris datasets. TP53 mutations were more frequent in adenocarcinoma than SCC, particularly in HPV-negative tumors. STK11 alterations, including mutations and focal deletions, were significantly enriched in HPV-positive adenocarcinomas compared with SCC and affected 23% of adenocarcinomas overall. Whole-genome analyses identified recurrent focal deletions, inversions, chromosomal rearrangements, and breakage-fusion-bridge events involving chromosome 19p and STK11 that were not detected by exome sequencing alone. STK11 alterations were associated with younger age at diagnosis, poorer overall survival, and inferior outcomes following immune checkpoint inhibitor (ICI) therapy. STK11 alterations significantly co-occurred with YAP1 amplification but were largely mutually exclusive with PIK3CA mutation. Cervical adenocarcinomas also demonstrated significantly lower CD274 (PD-L1) expression than SCC. STK11 alterations define a distinct molecular subgroup of cervical adenocarcinoma characterized by structural disruption of chromosome 19p, younger age at onset, and poorer clinical outcomes. These findings have implications for molecular classification and future targeted therapeutic approaches in cervical cancer.

Humans↗

PubMed1991

Breast cancer risk and oral contraceptive use: results from a large case-control study.

The association between oral contraceptive use and breast cancer risk was examined using data from a case-control study of breast cancer in Long Island, New York. Cases were defined as female residents of Nassau and Suffolk Counties between the ages of 20 and 79, diagnosed with breast cancer between January 1, 1984 and December 31, 1986. Age- and county-matched controls were selected from driver's license files. Among all women under age 70 at diagnosis, there was no association between oral contraceptive use and breast cancer; there was, however, a positive association in the subgroup ages 20-49 (adjusted odds ratio = 1.68, 95% CI: 1.16-2.42). Risk increased with increasing duration of use, but did not differ between women who first used oral contraceptives before the first pregnancy and those who first used them later, or between women who first used oral contraceptives before age 25 and those who first used them at a later age. Risk also appeared to increase with number of years of use before the first pregnancy or before age 25, although numbers were small. History of benign breast disease did not influence risk. The association of breast cancer risk with oral contraceptive use appeared stronger in women from Suffolk County than Nassau County.

Adult↗

PubMed1993

[Investigation on the incidence of genital herpes in different professional groups in Qingdao].

Genital herpes is one of 8 legally reportable sexually transmitted diseases (STD) in China. Using a HSV antigen ELISA kit we detected and typed HSV antigen in 1,148 clinical specimens collected from the genital organs (penis, cervix, vagina and vulva) of 446 men and 702 women in Qindao and divided into 11 different professional and 2 special groups (patients with cervical cancer and pregnant women). The highest positive rate of HSV antigen was found among long-distance transport drivers (48.0%). The second and third high positive rates were among waiters and waitresses in private, restaurants (39.2%) and patients with cervical cancer (38.2%). The positive rates among self-employed retailers and employees in private inns and restaurants were notably higher than those among employees in state-run shops, restaurants and hotels. And, the positive rate among workers was higher than that among peasants. There was no notable difference between the positive rate of HSV antigen among men (24.2%) and that among women (21.5%). But the incidence of HSV-2 infection was much higher than that of HSV-1 infection. The results indicate that some special professional groups have high rates of genital HSV infection. More attention needs to be paid to these special groups in order to control sexually transmitted herpes diseases.

Adolescent↗

PubMed2025

Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets.

BACKGROUND: The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS: Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS: The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS: This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.

Humans↗

PubMed1984

Occupational causes of laryngeal cancer.

In a case-control study of all new cases of laryngeal cancer in Denmark from 1980 to 1982, 326 cases and 1134 community selected controls participated. Questionnaires were used to obtain information on education, occupation, and number of occupational exposures as well as smoking and drinking habits. High risk ratios for laryngeal cancer were found for semiskilled and unskilled workers, workers exposed to dust, out of doors workers, drivers, and people working in the cement industries and port services. The study hypothesis was that exposure to chromium or nickel increases the incidence rate of laryngeal cancer. No support for this was found concerning chromium, but exposure to nickel had a statistically significant risk ratio of 1.7.

Chromium↗

PubMed2026

In vivo CRISPR screening links NFKB1 to endocrine resistance in ER+ breast cancer.

Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. Despite the bottlenecks inherent to in vivo pooled screening, recurrent enrichment analysis identified NFKB1 as a candidate regulator of estrogen-independent tumor progression. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 deficiency activated canonical NF-κB signaling, leading to inflammatory gene induction and enhanced ER signaling. Furthermore, pharmacologic inhibition of NF-κB signaling restored ET sensitivity in NFKB1-deficient cells. Analysis of TCGA breast cancer datasets revealed reduced NFKB1 expression in luminal breast tumors, whereas expression of other NF-κB family members was largely unchanged. Further analysis showed that low NFKB1 expression was associated with poorer clinical outcomes in patients with ER+ breast cancer. Collectively, these findings identify NFKB1 as a negative regulator of NF-κB signaling and endocrine resistance in ER+ breast cancer and provide mechanistic evidence linking NF-κB activation to ligand-independent ER signaling. Our results support further investigation of NFKB1 as a candidate biomarker and of NF-κB pathway inhibition as a potential therapeutic strategy in endocrine therapy-resistant breast cancer. These findings also illustrate the utility of in vivo CRISPR screening for identifying candidate regulators of endocrine resistance in breast cancer.

ER+ breast cancer↗

PubMed2002

A validation of information on occupation--data from a nested case-control study.

OBJECTIVES: To evaluate the validity of information about employment obtained from self-respondents and proxies in a nested case-control study. METHODS: We interviewed 230 self-respondents and 652 proxies covering 237 cancer cases and 645 controls. Questions about employment as a bus driver, other jobs, and residence were asked. Golden standard was employment data obtained from personnel records. RESULTS: All categories of respondents tended to over-report the length of employment, and respondents aged above 70 years had significantly decreased odds ratio for disagreement between interview and company files compared with respondents below the age of 60 years. There were no significant differences in whether the respondent was a case or control as there were no differences in whether the respondent was a self-respondent or a proxy. The validity of the reported employment time was statistically independent of the interval between death and proxy contact. Compared with the self-responders, the proxies reported significantly fewer jobs and residential areas. CONCLUSIONS: In general, data obtained from cases and controls not knowing that the study was about cancer and without the interviewer's knowing who were cases and who were controls appeared good. The quality of information obtained from proxies appeared good as well. There seems to be no problem in interviewing very old people about a specific job when they are mentally prepared for it. The time interval between death and proxy contact was without importance.

Adult↗

PubMed1999

Lung cancer risk in male workers occupationally exposed to diesel motor emissions in Germany.

BACKGROUND: Although in several epidemiological studies exposure to diesel motor emissions (DME) shows an elevated lung cancer risk, it is still controversial whether DME is a human carcinogen. METHODS: In a pooled analysis of two case-control studies on lung cancer in Germany a total of 3498 male cases with histologically or cytologically ascertained lung cancer and 3541 male population controls were included. Information about lifelong occupational and smoking history was obtained by questionnaire. Drivers of lorries, buses, taxies, diesel locomotives and forklift trucks, bulldozers, graders, excavators, and tractors, were considered as exposed to DME and their cumulative exposure was estimated. All odds ratios were adjusted for smoking and asbestos exposure. RESULTS: The evaluation of lung cancer risk for all jobs with DME-exposure combined showed an odds ratio of OR=1.43 (95%-CI: 1.23-1.67). Most pronounced was the increase in lung cancer risk in heavy equipment operators (OR=2. 31 95%-CI: 1.44-3.70). The risk of tractor drivers increased with length of employment and reached statistical significance for exposures longer than 30 years (OR=6.81, 95%-CI: 1.17-39.51). The group of professional drivers (e.g., trucks, buses, and taxies), showed an increased risk only in West Germany (OR=1.44, 95%-CI: 1. 18-1.76), but not in East Germany (OR=0.83, 95%-CI: 0.60-1.14). DME-exposure in other traffic related jobs (e.g., diesel engine locomotive drivers, switchmen, forklift operators) was associated with an odds ratio of OR=1.53 (95%-CI: 1.04-2.24). CONCLUSIONS: The study provides further evidence that occupational exposure to diesel motor emissions is associated with an increased lung cancer risk.

Aged↗

PubMed2004

Urinary 1-hydroxypyrene and mutagenicity in bus drivers and mail carriers exposed to urban air pollution in Denmark.

BACKGROUND: Previous studies in Denmark have shown that bus drivers and tramway employees were at an increased risk for developing several types of cancer and that bus drives from central Copenhagen have high levels of biomarkers of DNA damage. AIMS: The present study evaluates 1-hydroxypyrene concentrations and mutagenic activity in urine as biomarkers of exposure in non-smoking bus drivers in city and rural areas on a work day and a day off and in non-smoking mail carriers working outdoors (in the streets) and indoors (in the office). METHODS: Twenty-four hour urine samples were collected on a working day and a day off from 60 non-smoking bus drivers in city and rural areas and from 88 non-smoking mail carriers working outdoors (in the streets) and indoors (in the office). The concentration of 1-hydroxypyrene was measured by means of HPLC and the mutagenic activity was assessed by the Ames assay with Salmonella tester strain YG1021 and S9 mix. The N-acetyltransferase (NAT2) phenotype was used as a biomarker for susceptibility to mutagenic/carcinogenic compounds. RESULTS: Bus drivers excreted more 1-hydroxypyrene in urine than did mail carriers. The differences were slightly smaller when NAT2 phenotype, cooking at home, exposure to vehicle exhaust, and performing physical exercise after work were included. The NAT2 slow acetylators had 29% (1.29 [CI: 1.15-1.98]) higher 1-hydroxypyrene concentrations in urine than the fast acetylators. Male bus drivers had 0.92 revertants/mol creatinine [CI: 0.37-1.47] and female bus drivers 1.90 revertants/mol creatinine [CI: 1.01-2.79] higher mutagenic activity in urine than mail carriers. CONCLUSION: The present study indicates that bus drivers are more exposed to polycyclic aromatic hydrocarbons (PAH) and mutagens than mail carriers. Mail carriers who worked outdoors had higher urinary concentration of 1-hydroxypyrene, a marker of exposure to PAH, than those working indoors. The individual levels of urinary mutagenic activity were not correlated to excretion of 1-hydroxypyrene. This might be due to the fact that the most potent mutagenic compounds in diesel exhaust are not PAH but dinitro-pyrenes. Among bus drivers, fast NAT2 acetylators had higher mutagenic activity in urine than slow NAT2 acetylators and female bus drivers had higher mutagenic activity than male bus drivers.

Adult↗

PubMed2025

In vivo CRISPR screening links NFKB1 to endocrine resistance in ER⁺ breast cancer.

Resistance to endocrine therapy (ET) remains a major clinical challenge in the treatment of estrogen receptor-positive (ER⁺) breast cancer, underscoring the need for novel therapeutic targets. To identify genetic drivers of ET resistance, we conducted an in vivo genome-wide CRISPR-Cas9 screen in MCF7 cells implanted into ovariectomized nude mice under estrogen-deprived conditions. NFKB1 emerged as a top candidate whose loss promoted estrogen-independent tumor growth and recurrence. Functional studies confirmed that NFKB1 deficiency enhanced tumorigenicity and conferred resistance to tamoxifen and fulvestrant both in vitro and in vivo. Mechanistically, transcriptomic and biochemical analyses revealed that NFKB1 loss activated canonical NF-κB signaling, leading to inflammatory gene induction and hyperactivation of ER signaling. Importantly, pharmacologic inhibition of NF-κB signaling restored ET sensitivity in NFKB1-deficient cells. Clinically, NFKB1 downregulation was enriched in ER⁺ breast tumors and associated with poor patient outcomes. Collectively, these findings establish NFKB1 as a key suppressor of ET resistance, uncover a mechanistic link between inflammation and ER reactivation, and highlight NF-κB signaling as a therapeutic vulnerability in NFKB1-deficient ER⁺ breast cancer.

Journal Article↗

PubMed1987

[Cancer mortality according to occupation].

The 55 profession groups, fully enclosing the male population of Switzerland, can be adjoined to a cancer risk category, according to their absolute and proportional mortality rate from 1979 to 1983 (age standardized for 35- to 74-years old). Lung-cancer mortality is for all building trade professions, even for building engineer and truck drivers, three times higher as for professions asking school-leaving examination. The carcinoma of the superior digestion tract and the bladder follow this falling incidence, while the opposite, profession specific falling incidence being shown by colon and rectum cancers and by the tumours of the lymphatic tissue and the prostata. Deduction of the results is cancer prevention: this should be carried out by a general, profession-orientated furtherance.

Adult↗

PubMed1989

Lung cancer in motor exhaust-related occupations.

The association between employment in motor exhaust-related occupations and the risk for lung cancer was examined in 2,291 male cases of lung cancer and 2,570 controls in data pooled from three U.S. case control studies carried out by the National Cancer Institute between 1976 and 1983. Most analyses were limited to subjects providing direct, in-person interviews, including 1,444 cases and 1,893 controls. For those providing direct interviews and employed 10 years or more in motor exhaust-related (MER) occupations, the age, smoking, and study area adjusted odds ratio (OR) for lung cancer was 1.5 (95% CI = 1.2-1.9). Risk was elevated for truck drivers (OR = 1.5; 95% CI = 1.1-1.9) and for other MER occupations (OR = 1.4; 95% CI = 1.1-2.0). The odds ratios associated with MER employment of 10+ years were 1.6 (95% CI = 1.2-2.1) for whites and 1.4 (95% CI = 0.9-2.1) for nonwhites; 1.2 (95% CI = 0.7-2.0) [corrected] for those with possible exposure to other recognized or reported lung carcinogens; and 1.6 (95% CI 1.2-2.1) for those without such exposure. The 50% excess risk for lung cancer associated with employment in motor exhaust-related occupations could not be explained by greater use of cigarettes or by other occupational exposures among these workers.

Aged↗