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David C Christiani

Publications and source records attributed to David C Christiani.

At least 19 recordsLinked to original sources
PubMed2026

Germline determinants of risk and molecular subtype in young-onset lung cancer.

Young-onset lung cancer is enriched for never-smoking and oncogene-driven tumors, yet its inherited genetic basis remains poorly defined. We performed germline whole-genome sequencing in 251 young-onset lung cancer cases (median age 37), which we jointly analyzed with never-smoking cases (n=196; median age 68) and cancer-free controls (n=1,883). We identified enrichments of rare deleterious coding variants across 55 cancer-related gene sets, including EGFR/ERBB2 signaling and genes implicated by prior lung cancer GWAS. Exome-wide analyses of rare coding variants affirmed TP53 as a penetrant lung cancer predisposition gene (odds ratio [OR]=36.1, p=1.02x10-7) and discovered two novel exome-wide significant tumor subtype-dependent associations: IREB2 in cases with fusion-driven tumors (p=1.39x10-6) and SMAD6 in fusion-negative tumors (p=2.05x10-6). Structural variants contributed distinct risk, with enrichment in constrained, lung-expressed genes (OR=5.79, p=5.8x10-5) and very large germline deletions being markedly enriched in cases with fusion-driven tumors. Polygenic risk scores for lung cancer were inversely correlated with rare variant burden, consistent with additive risk from rare and common variants. Collectively, these findings delineate a complex germline architecture underlying susceptibility and molecular subtype in young-onset lung cancer.

Journal Article↗
PubMed2026

Telomere Length Dynamics as a Biomarker of Individual Radiation Sensitivity and Pneumonitis in Lung Cancer Patients Receiving Thoracic Radiation Therapy.

PURPOSE: Telomere shortening is a biomarker for genome instability and aging, and the vulnerability of telomeric DNA to oxidative damage suggests its potential role in mediating radiation therapy (RT) side effects. This study evaluates telomere length (TL) as a biomarker for clinical radiosensitivity and adverse outcomes in thoracic RT-treated patients. METHODS AND MATERIALS: Patients with cancer receiving thoracic RT (2019-2022) were prospectively enrolled at Brigham and Women's Hospital, Boston, Massachusetts. Peripheral blood mononuclear cells (PBMCs) were collected pre-RT and ≤12 months post-RT. TL was measured using quantitative PCR, and multipathway DNA repair capacity (DRC) was simultaneously assessed by fluorescence multiplex host cell reactivation assays. RT outcomes included patient-reported quality of life and radiation pneumonitis. Linear mixed-effects models were used to analyze TL dynamics; risk prediction models for RT outcomes were evaluated using area under the curve. RESULTS: Pre-RT TL decreased with age (0.44% lower per year; 95% CI, 0.12%-0.77%) and advanced cancer stage (6.87% lower per step increase of stage; 95% CI, 3.45%-10.16%). Radical RT was associated with telomere shortening (3.7% lower; 95% CI, 0.27%-7.07%) in PBMCs, detectable ≤6 months post-RT. Pre-RT TL strongly predicted post-RT changes, and TL dynamics outperformed static measures in predicting symptom burden and radiation pneumonitis. Positive associations were observed between TL and DRC against oxidative lesions, with A:8-oxoG repair capacity mediating 12.8% of RT-induced TL shortening. CONCLUSIONS: Lymphocyte TL can reflect individual radiosensitivity and interact with oxidative damage repair. Longitudinal assessment of TL dynamics provides additional predictive value for adverse RT outcomes compared with static measures. Further studies are needed to fully determine the clinical utility of TL.

Humans↗
PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗
PubMed2025

A prognostic signature for lung adenocarcinoma in people who have never smoked.

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes' alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings.

Journal Article↗
PubMed2007

Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome.

OBJECTIVE: The variant alleles in the mannose binding lectin-2 (MBL-2) gene have been associated with MBL deficiency and increased susceptibility to sepsis. We postulate that the variant MBL-2 genotypes are associated with increased susceptibility to and mortality in acute respiratory distress syndrome (ARDS). DESIGN: Nested case-control study. SETTING: Tertiary academic medical center. PATIENTS: Two hundred and twelve Caucasians with ARDS and 442 controls genotyped for the variant X, D, B, and C alleles of codon -221, 52, 54, and 57, respectively. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients homozygous for the variant codon 54B allele (54BB) had worse severity of illness on admission (p = .007), greater likelihood of septic shock (p = .04), and increased odds of ARDS (adjusted odds ratio, 6.7; 95% confidence interval, 1.5-31) when compared with heterozygotes and homozygotes for the wild-type allele. This association with ARDS was especially strong among the 311 patients with septic shock (adjusted odds ratio, 12.0; 95% confidence interval, 1.9-74). Among the patients with ARDS, the 54BB genotype was associated with more daily organ dysfunction (p = .01) and higher mortality (adjusted hazard rate, 4.0; 95% confidence interval, 1.6-10). Development of ARDS and outcomes in ARDS did not vary significantly with variant alleles of codon -221, 52, and 57, but the power to detect an effect was limited secondary to the low allele frequencies. CONCLUSIONS: The MBL-2 codon 54BB genotype may be important in ARDS susceptibility and outcome. Additional studies are needed to confirm these findings in other populations.

Adolescent↗
PubMed2006

Second hand smoke exposure and survival in early-stage non-small-cell lung cancer patients.

PURPOSE: Second hand smoke (SHS) exposure is associated with higher risk of lung cancer. However, the role of SHS in lung cancer survival is not clear. EXPERIMENTAL DESIGN: We examined the association between self-reported SHS exposure before diagnosis and overall survival and recurrence-free survival in 393 early-stage non-small-cell lung cancer patients. SHS exposure was analyzed by both duration and location of exposure using log-rank test and Cox proportional hazard models, adjusting for covariates including pack-years of smoking. RESULTS: The median follow-up time was 66 months (range, 0.2-140 months). There were 135 recurrences and 213 deaths. The 5-year overall survival rates were 71% [95% confidence interval (95% CI), 62-81%], 61% (51-72%), 49% (38-60%), and 47% (37-58%), respectively, for patients with the lowest to highest quartile of SHS exposure durations (P < 0.001, log-rank test), with the adjusted hazard ratio (AHR) of 1.57 (95% CI, 1.02-2.41) for the highest versus lowest quartile of SHS exposure durations (P(trend) = 0.04). For different SHS exposure locations, a stronger association was found for SHS exposure at work (AHR of the highest versus lowest quartile, 1.71; 95% CI, 1.12-2.61; P(trend) = 0.03) than for exposure at home (AHR, 1.26; 95% CI, 0.86-1.86; P(trend) = 0.20) or leisure places (AHR, 1.28; 95% CI, 0.83-1.95; P(trend) = 0.16). Similar associations were observed when SHS exposure durations were dichotomized into two or three groups and between SHS exposure and recurrence-free survival. CONCLUSIONS: SHS exposure is associated with worse survival in early-stage non-small-cell lung cancer patients, especially for SHS exposure at the work.

Adult↗
PubMed2006

An association between glutathione S-transferase P1 gene polymorphism and younger age at onset of lung carcinoma.

BACKGROUND: Among the genes that encode the glutathione S-transferase (GST) superfamily of Phase 2 metabolizing enzymes, GSTP1 has the highest expression in the lung. The polymorphic GSTP1 gene encodes glutathione S-transferase pi, which is an enzyme that detoxifies cigarette carcinogens, such as benzo-[a]-pyrene. The variant GSTP1 GG genotype is associated with lower enzymatic activity and higher DNA adduct levels in human lymphocytes compared with the AA genotype. METHODS: The authors evaluated the association of GSTP1 genotypes with lung cancer in 1921 cases and 1343 controls of Caucasian descent by using polymerase chain reaction-restriction fragment length polymorphism techniques. The results were analyzed with multiple logistic regression adjusting for age, gender, smoking status, and pack-years. To investigate specifically the subset of younger lung cancer patients and controls, the effect of age (either as a dichotomous or continuous variable in separate models) was analyzed as a modifying factor of the association between the GSTP1 polymorphism and lung cancer. RESULTS: The GSTP1 GG genotype was not associated with an overall increased risk of lung cancer (adjusted odds ratio, 1.02; 95% confidence interval [95% CI], 0.78-1.34) compared with the GSTP1 AA genotype. In both models that evaluated the gene-age interaction, an overall statistically significant interaction (P < .01) was observed between age and the GG genotype. However, for the model that included age as a dichotomous variable, the odds ratio of lung cancer risk with the GG genotype compared with the AA among individuals age </=50 years was 2.67 (95% CI, 1.36-5.22); in older individuals, the risk was 0.87 (95% CI, 0.65-1.2). CONCLUSIONS: The GSTP1 GG genotype was associated with increased lung cancer susceptibility among younger study participants.

Adult↗
PubMed2006

Matrix metalloproteinase polymorphisms and survival in stage I non-small cell lung cancer.

PURPOSE: The matrix metalloproteinases (MMP) are a family of enzymes that can degrade extracellular matrix and facilitate invasion through the basement membrane. Several polymorphisms in MMP-1, MMP-2, MMP-3, and MMP-12 have been described, some of which lead to differential transcription. We hypothesized that polymorphisms in these MMP genes may be associated with survival outcomes in early-stage non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: We evaluated the relationship between MMP-1, MMP-2, MMP-3, and MMP-12 polymorphisms and both recurrence-free survival (RFS) and overall survival (OS) among 382 patients with stage I NSCLC. Analyses of genotype associations with survival outcomes were done using Cox proportional hazards models and Kaplan-Meier methods and the log-rank test. RESULTS: Patients carrying the variant G allele of the MMP-12 1082A/G polymorphism had significantly worse outcomes [crude hazard ratio (HR) for OS 1.74; 95% confidence interval (95% CI), 1.18-2.58, P=0.006; crude HR for RFS, 1.53; 95% CI, 1.05-2.23, P=0.03]. After adjusting for age, sex, stage, pack-years of smoking, and histologic subtype, the MMP-12 1082A/G polymorphism remained significantly associated with survival outcomes [adjusted HR (AHR) for OS, 1.94; 95% CI, 1.28-2.97, P=0.002; AHR for RFS, 1.61; 95% CI, 1.07-2.41, P=0.02]. None of the other MMP polymorphisms was significantly associated with survival. CONCLUSIONS: Our results show that patients with stage I NSCLC carrying the variant G allele of the MMP-12 1082A/G polymorphism have worse survival.

Adult↗
PubMed2006

Smoking cessation before diagnosis and survival in early stage non-small cell lung cancer patients.

Smoking cessation decreases the risk of lung cancer. However, little is known about how smoking cessation affects lung cancer survival. We examined the association between smoking cessation and overall survival (OS) and recurrence-free survival (RFS) in 543 early stage non-small cell lung cancer (NSCLC) patients. The data were analyzed using log-rank test and Cox proportional hazard models, adjusting for age, gender, stage, and smoking intensity. The median follow-up time was 57 months (range 0.2-140 months). There were 191 recurrences and 285 deaths. The 5-year OS rates were 50% (95% confidence interval (CI), 43-58%) for current smokers, 54% (44-65%) for ex-smokers who quit 1-8 years, 59% (49-70%) for ex-smokers who quit 9-17 years, 58% (47-69%) for ex-smokers who quit > or =18 years prior to diagnosis, and 76% (63-90%) for never smokers (P=0.09, log-rank test). The adjusted hazard ratios for ex-smokers who quit 1-8, 9-17, > or =18 years, and never smokers were 0.82 (95% CI, 0.59-1.13), 0.69 (0.49-0.97), 0.66 (0.45-0.95), and 0.54 (0.29-0.996), respectively, when compared with current smokers (P(trend)=0.004). Similar associations were found among ever smokers-only, when smoking cessation time was treated as a continuous variable, and for RFS. The significantly beneficial effects of smoking cessation on OS and RFS were observed among women only, while not among men (P=0.01 for interactions between gender and smoking cessation). In conclusion, smoking cessation is associated with improved survival in early stage NSCLC patients. The longer the time since cessation of smoking, the better the survival outcome.

Adult↗
PubMed2006

Residential exposure to petrochemicals and the risk of leukemia: using geographic information system tools to estimate individual-level residential exposure.

The authors conducted a population-based, case-control study in Kaohsiung, southern Taiwan, Republic of China, to investigate the association between residential petrochemical exposure and leukemia risk among subjects 29 years of age and younger. Between November 1997 and June 2003, 171 cases and 410 controls matched for age and sex were recruited. Since assessment of petrochemical impacts depends on accurate exposure estimates, the authors developed a procedure using geographic information system tools to assign subjects' exposure. The resulting individual-level exposure estimates (the exposure opportunity score) are an integrated exposure measure that accounts for subjects' mobility, length of stay at each residence, distance to petrochemical plant(s), monthly prevailing wind direction, and multiple petrochemical pollution sources. Different conditional logistic regression models were fitted for subjects aged 0-19 and 20-29 years to evaluate separately childhood versus adulthood leukemia. No overall association was observed for the younger age group. However, residential petrochemical exposure was a significant risk factor for leukemia for the older age group. For one unit of increase in the log-transformed exposure opportunity score, the adjusted odds ratio was 1.54 (95 percent confidence interval: 1.14, 2.09). This study illustrates the utility of geographic information system tools for providing refined exposure estimates for residential exposure to petrochemical pollution.

Adolescent↗
PubMed2006

Modeling, estimation and validation of cotton dust and endotoxin exposures in Chinese textile operations.

In support of an epidemiological study of cancer incidence among cotton textile workers in Shanghai, PRC, historical estimates of exposure to cotton dust and endotoxin were developed for subjects drawn from a cohort of 267,400 female textile workers. A large dataset of historical cotton dust measurements were available from 56 of the study factories. Using these data, a series of models were developed to estimate cotton dust exposure by year, factory and process. Model estimates were validated by comparing with independently collected measurements gathered over a 15 year period and indicated a low relative bias (< 2%) and relative accuracy (+/- 61%). Endotoxin exposures were estimated using the endotoxin content of cotton dust by major processes obtained in five separate surveys in these factories. The validated exposures were assigned to the 7,242 jobs held by the 3,812 study subjects. Among the exposed workers, the mean cumulative exposure levels were 113.8 mg m(-3)*years for cotton dust and 6,707.7 EU m(-3)*years for endotoxin, respectively. The overall correlation among cotton dust and endotoxin exposures for these subjects was r = 0.58. Using an unusually rich set of historical cotton dust measurements, along with independently collected exposure measurements for validation and conversion to endotoxin levels, validated estimates of cumulative exposure were constructed for this large case-cohort study in the textile industry.

China↗
PubMed2006

Adverse effects of asbestos exposure and smoking on lung function.

BACKGROUND: Exposure to asbestos is a well-recognized cause of both malignant and nonmalignant diseases of lung parenchyma and pleura. This study was conducted to determine the adverse effects of exposure to asbestos and smoking on pulmonary function. METHODS: Four hundred and sixty-eight workers who were occupationally exposed to asbestos for an average of 13 years were selected from an asbestos-product factory in China. Of them, 85 workers were diagnosed with asbestosis. Additionally, 282 workers who had no experience of exposure to industrial dust were included as a control group. A questionnaire was administered during a face-to-face interview and spirometric maneuvers and single-breath CO diffusing capacity (DL(CO)) were performed. RESULTS: Multivariate regression analysis showed that exposure to asbestos was more strongly associated with decreased forced vital capacity (FVC) and DL(CO), and asbestosis more strongly associated with decreased FVC, while smoking was a major contributing factor to reduced FEV1/FVC. The results were confirmed by a further analysis where the subjects were grouped exclusively by smoking, asbestos exposure, and chest radiographic changes. No interaction or joint effect was observed between asbestos exposure and smoking. CONCLUSIONS: This analysis suggested that asbestos and smoking might play independent roles, in which asbestos caused mainly a restrictive impairment, and smoking was a major causal factor for airway obstruction in the workers who were intensively exposed to asbestos.

Adult↗
PubMed2006

pH increase observed in exhaled breath condensate from welding fume exposure.

OBJECTIVES: We sought to investigate changes in exhaled breath condensate (EBC) pH in healthy workers exposed to welding fumes. METHODS: Fourteen exposed participants (median age 39 years, 5 smokers) and 8 nonexposed controls (median age 44 years, 1 smoker) were monitored at an apprentice welding school. Exposure to fine particulate matter less than 2.5 microm (PM2.5) was assessed using cyclone samplers. EBC samples were collected at baseline and at the end of the work shift. EBC samples were deaerated using argon and pH values were measured using standard pH microelectrodes. RESULTS: Mean +/- SEM PM2.5 levels were 1.17 +/- 0.18 mg/m for exposed subjects and 0.03 +/- 0.01 mg/m for controls. Baseline median (range) EBC pH values for the control and exposed group were similar (P = 0.86), 7.21 (4.91 to 8.26), and 7.39 (4.85 to 7.79), respectively. The exposed subjects had a small-but-marginally significant (P = 0.07) pre- to post-work shift increase in pH of 0.28, whereas the control group showed a minimal increase of only 0.03 (P = 0.56). Compared with the control group, the exposed group had a median cross-shift pH increase of 0.25 (P = 0.49). CONCLUSIONS: The aerosolized fine particulate matter contained in metal fumes may be associated with an acute increase in EBC pH values. Further study is necessary to investigate the acute rise in EBC pH after acute exposure to welding fume.

Adult↗
PubMed2006

Survey of acute low back pain management by specialty group and practice experience.

OBJECTIVE: The objective of this study was to explore concurrence with evidence-based management of acute back pain by primary care specialty and years in practice groups. METHODS: Participants randomly selected from five American Medical Association physician groups were surveyed asking their initial care recommendations for case scenarios with and without sciatica. Response differences were compared among groups and with the Agency for Health Research Quality's guideline. RESULTS: Response rate was 25%. Emergency physicians were least likely to order diagnostic studies for both cases but more often made recommendations likely to promote inactivity. Occupational physicians were less likely to order diagnostic studies and more likely choose treatments conducive to increasing activity. The longer physicians were in practice, the less likely they were to follow recommendations. All specialty groups selected more nonevidence-based interventions for the patient with sciatica. General practitioners were least likely to follow the guidelines in either case. CONCLUSIONS: Despite widespread dissemination of acute low back pain guidelines, the study suggests a lack of adherence by certain primary care groups, physicians with more practice experience, and in specific areas of management.

Adult↗
PubMed2006

Cancer mortality among textile workers in Shanghai, China: a preliminary study.

OBJECTIVE: We assessed the association between cotton textile work and cancer mortality. METHODS: The cancer mortality experience of 912 (444 cotton, 468 silk) textile workers in Shanghai, China, was compared. Workers were followed from 1981 to 2003. The associations between cotton textile work and death due to all cancers combined (with and without lung cancer) and to gastrointestinal cancers were estimated with Cox models, adjusting for age, work years, and pack-years. RESULTS: There were 69 deaths. The adjusted hazard rate ratio (HR) was 2.10 (95% confidence interval [CI], 0.98-4.47) for all cancers combined and 2.56 (95% CI, 1.14-5.74) after excluding lung cancer. For gastrointestinal cancers, the adjusted HR was 2.09 (95% CI, 0.83-5.27). CONCLUSIONS: These preliminary data suggest that, with the exception of lung cancer, cotton workers have significantly higher cancer mortality rates than silk workers.

Adult↗
PubMed2006

Personal coronary risk profiles modify autonomic nervous system responses to air pollution.

OBJECTIVE: We investigated whether PM2.5-mediated autonomic modulation depends on individual coronary risk profiles. METHODS: Five-minute average heart rate (HR) and heart rate variability (HRV, including standard deviation of normal-to-normal intervals [SDNN], square root of the mean squared differences of successive NN intervals [rMSSD], high frequency [HF]) were measured from 24-hour ambulatory electrocardiograms, and personal PM(2.5) exposures were monitored in a prospective study of 10 male boilermakers (aged 34.3 +/- 8.1 years). We used the Framingham score to classify individuals into low (score = 1-3) and high (score = 5-6) risk categories. Mixed-effect models were used for statistical analyses. RESULTS: Each 1-mg/m(3) increase in the preceding 4-hour moving average PM(2.5) was associated with HR increase (5.3 beats/min) and HRV reduction (11.7%, confidence interval [CI] = 6.2-17.1% for SDNN; 11.1%, CI = 3.1-19.1% for rMSSD; 16.6%, CI = 1.5-31.7% for HF). Greater responses (2- to 4-fold differences) were observed in high-risk subjects than in low-risk subjects. CONCLUSIONS: Our study suggests that adverse autonomic responses to metal particulate are aggravated in workers with higher coronary risk profiles.

Adult↗
PubMed2006

Gender-specific protective effect of hemoglobin on arsenic-induced skin lesions.

Chronic arsenic poisoning remains a public health crisis in Bangladesh. As arsenic has been shown to bind to human hemoglobin (Hb), hematologic mechanisms may play a role in the pathway through which arsenic exerts its toxicity. Two separate studies, a case-control and a cohort, were conducted to investigate the role of Hb in the development of arsenic-induced skin lesions. In the first, conditional logistic regression was used to investigate the effect of Hb on skin lesions among 900 case-control pairs from Pabna, Bangladesh, in which individuals were matched on gender, age, and location. In the second, mixed linear regression models were used to examine the association between toenail arsenic, urinary arsenic, and Hb within a cohort of 184 individuals from 50 families in the same region who did not have arsenic-induced skin lesions. Hb was significantly associated with skin lesions but this association was gender specific. In males, a 40% reduction in the odds of skin lesions occurred for every 1 g/dL increase in Hb (odds ratio, 0.60; 95% confidence interval, 0.49-0.73). No effect was observed for females (odds ratio, 1.16; 95% confidence interval, 0.92-1.46). In the cohort of 184 individuals, no associations between toenail arsenic or urinary arsenic species and Hb levels were observed. Low Hb levels may exacerbate the detrimental health effects of chronic arsenic poisoning. Whereas providing clean water remains the optimal solution to Bangladesh's problem of arsenic poisoning, improving nutrition and reducing iron-deficiency anemia may ameliorate negative health effects, such as skin lesions in individuals who have been exposed.

Arsenic↗