Relationships Between Patient Race and Residential Race Context With Missed Human Immunodeficiency Virus Care Visits in the United States, 2010-2015.

BACKGROUND: Racial inequities exist in retention in human immunodeficiency virus (HIV) care and multilevel analyses are needed to contextualize and address these differences. Leveraging data from a multisite clinical cohort of people with HIV (PWH), we assessed the relationships between patient race and residential characteristics with missed HIV care visits. METHODS: Medical record and patient-reported outcome (PRO; including mental health and substance-use measures) data were drawn from 7 participating Center for AIDS Research Network of Integrated Clinical Systems (CNICS) sites including N = 20 807 PWH from January 2010 through December 2015. Generalized estimating equations were used to account for nesting within individuals and within census tracts in multivariable models assessing the relationship between race and missed HIV care visits, controlling for individual demographic and health characteristics and census tract characteristics. RESULTS: Black PWH resided in more disadvantaged census tracts, on average. Black PWH residing in census tracts with higher proportion of Black residents were more likely to miss an HIV care visit. Non-Black PWH were less likely to miss a visit regardless of where they lived. These relationships were attenuated when PRO data were included. CONCLUSIONS: Residential racial segregation and disadvantage may create inequities between Black PWH and non-Black PWH in retention in HIV care. Multilevel approaches are needed to retain PWH in HIV care, accounting for community, healthcare setting, and individual needs and resources.

Acceleration of cervical cancer diagnosis with human papillomavirus testing below age 30: Observational study.

Several international cervical screening guidelines advise against using high-risk human papillomavirus (HR-HPV) testing in women younger than 30. The rationale for this in young women, lies in the potential for additional detection of both low-grade and high-grade cervical intraepithelial neoplasia (CIN) leading to unnecessary treatments without reducing the burden of cervical cancer. We studied 56 544 women screened at 24 to 29 with HR-HPV testing and 116 858 screened with liquid-based cytology (LBC) in the English HPV screening pilot. They were compared to 528 460 women screened at the age of 30 to 49. We studied the detection of cervical cancer and CIN2/3 across two consecutive screening rounds 3 years apart. At 24 to 29, a positive HR-HPV test detected more cases of cervical cancer in the prevalence round than did a positive LBC test (1.36/1000 screened vs 0.82/1000, ORadj : 1.61, 95% CI: 1.18-2.19). In women with a negative HR-HPV test, cervical cancer was diagnosed before or at the incidence round in 0.07/1000. After a negative LBC test, cancer detection reached 0.47/1000 and 40% of these cases were diagnosed at FIGO stage IB+. HR-HPV testing increased the detection of CIN2/3 diagnoses in two consecutive rounds combined by 30% (71.9/1000 vs 55.2/1000). The patterns of detection of cervical cancer and CIN2/3 were almost identical at older ages. These data support using HR-HPV testing for screening of women younger than 30, which not only accelerates the diagnosis of cervical cancer but leads to a similar relative increase in CIN2/3 diagnosis to that found in women aged 30 to 49.

The impact of catch-up bivalent human papillomavirus vaccination on cervical screening outcomes: an observational study from the English HPV primary screening pilot.

BACKGROUND: In England, bivalent vaccination (Cervarix) against high-risk human papillomavirus (HR-HPV) genotypes 16/18 was offered in a population-based catch-up campaign in 2008-2010 to girls aged 14-17 years. These women are now entering the national cervical screening programme. We determined the impact of catch-up bivalent vaccination on their screening outcomes. METHODS: We studied the overall and genotype-specific screening outcomes in 108,138 women aged 24-25 (offered vaccination) and 26-29 years (not offered vaccination) included in the English HPV screening pilot between 2013 and 2018. RESULTS: At 24-25 years, the detection of high-grade cervical intraepithelial neoplasia (CIN2+) associated with HPV16/18 decreased from 3 to 1% (p < 0.001), with estimated vaccine effectiveness of 87% (95% CI: 82-91%). The detection of any CIN2+ halved from 6 to 3% (p < 0.001), with an estimated vaccine effectiveness of 72% (95% CI: 66-77%). The positive predictive value of a colposcopy for CIN2+ decreased for both low-grade (p < 0.001) and high-grade (p = 0.02) abnormalities on triage cytology. The decreases in screen-detected abnormalities at age 26-29 were of a substantially smaller magnitude. CONCLUSIONS: These data confirm high effectiveness of bivalent HPV vaccination delivered through a population-based catch-up campaign in England. These findings add to the rationale for extending screening intervals for vaccinated cohorts.

Impact of changes to the interscreening interval and faecal immunochemical test threshold in the national bowel cancer screening programme in England: results from the FIT pilot study.

INTRODUCTION: The NHS Bowel Cancer Screening Programme (BCSP) faces endoscopy capacity challenges from the COVID-19 pandemic and plans to lower the screening starting age. This may necessitate modifying the interscreening interval or threshold. METHODS: We analysed data from the English Faecal Immunochemical Testing (FIT) pilot, comprising 27,238 individuals aged 59-75, screened for colorectal cancer (CRC) using FIT. We estimated screening sensitivity to CRC, adenomas, advanced adenomas (AA) and mean sojourn time of each pathology by faecal haemoglobin (f-Hb) thresholds, then predicted the detection of these abnormalities by interscreening interval and f-Hb threshold. RESULTS: Current 2-yearly screening with a f-Hb threshold of 120 µg/g was estimated to generate 16,092 colonoscopies, prevent 186 CRCs, detect 1142 CRCs, 7086 adenomas and 4259 AAs per 100,000 screened over 15 years. A higher threshold at 180 µg/g would reduce required colonoscopies to 11,500, prevent 131 CRCs, detect 1077 CRCs, 4961 adenomas and 3184 AAs. A longer interscreening interval of 3 years would reduce required colonoscopies to 10,283, prevent 126 and detect 909 CRCs, 4796 adenomas and 2986 AAs. CONCLUSION: Increasing the f-Hb threshold was estimated to be more efficient than increasing the interscreening interval regarding overall colonoscopies per screen-benefited cancer. Increasing the interval was more efficient regarding colonoscopies per cancer prevented.

Age-specific outcomes from the first round of HPV screening in unvaccinated women: Observational study from the English cervical screening pilot.

OBJECTIVE: To report detailed age-specific outcomes from the first round of an English pilot studying the implementation of high-risk human papillomavirus (HR-HPV) testing in primary cervical screening. DESIGN: Observational study with screening in 2013-2016, followed by two early recalls and/or colposcopy until the end of 2019. SETTING: Six NHS laboratory sites. POPULATION: A total of 1 341 584 women undergoing screening with HR-HPV testing or liquid-based cytology (LBC). METHODS: Early recall tests and colposcopies were recommended, depending on the nature of the screening-detected abnormality. MAIN OUTCOME MEASURES: We reported standard screening process indicators, e.g. proportions with an abnormality, including high-grade cervical intraepithelial neoplasia (CIN2+) or cancer, and the positive predictive value (PPV) of colposcopy for CIN2+, by screening test and age group. RESULTS: Among unvaccinated women screened with HR-HPV testing at age 24-29 years, 26.9% had a positive test and 10.4% were directly referred to colposcopy following cytology triage, with a PPV for CIN2+ of 47%. At 50-64 years of age, these proportions were much lower: 5.3%, 1.2% and 27%, respectively. The proportions of women testing positive for HR-HPV without cytological abnormalities, whose early recall HR-HPV tests returned negative results, were similar across the age spans: 54% at 24-29 years and 55% at 50-64 years. Two-thirds of infections at any age were linked to non-16/18 genotypes. Among women with CIN2, CIN3 or cervical cancer, however, the proportion of non-16/18 infections increased with age. As expected, the detection of abnormalities was lower following screening with LBC. CONCLUSIONS: These data provide a reliable reference for future epidemiological studies, including those concerning the effectiveness of HPV vaccination. TWEETABLE ABSTRACT: Data from the English pilot study provide a comprehensive overview of abnormalities detected through HPV screening.

Supporting the implementation of new healthcare technologies by investigating generalisability of pilot studies using area-level statistics.

BACKGROUND: Implementation of new technologies into national health care systems requires careful capacity planning. This is sometimes informed by data from pilot studies that implement the technology on a small scale in selected areas. A critical consideration when using implementation pilot studies for capacity planning in the wider system is generalisability. We studied the feasibility of using publicly available national statistics to determine the degree to which results from a pilot might generalise for non-pilot areas, using the English human papillomavirus (HPV) cervical screening pilot as an exemplar. METHODS: From a publicly available source on population indicators in England ("Public Health Profiles"), we selected seven area-level indicators associated with cervical cancer incidence, to produce a framework for post-hoc pilot generalisability analysis. We supplemented these data by those from publicly available English Office for National Statistics modules. We compared pilot to non-pilot areas, and pilot regimens (pilot areas using the previous standard of care (cytology) vs. the new screening test (HPV)). For typical process indicators that inform real-world capacity planning in cancer screening, we used standardisation to re-weight the values directly observed in the pilot, to better reflect the wider population. A non-parametric quantile bootstrap was used to calculate 95% confidence intervals (CI) for differences in area-weighted means for indicators. RESULTS: The range of area-level statistics in pilot areas covered most of the spectrum observed in the wider population. Pilot areas were on average more deprived than non-pilot areas (average index of multiple deprivation 24.8 vs. 21.3; difference: 3.4, 95% CI: 0.2-6.6). Participants in HPV pilot areas were less deprived than those in cytology pilot areas, matching area-level statistics. Differences in average values of the other six indicators were less pronounced. The observed screening process indicators showed minimal change after standardisation for deprivation. CONCLUSIONS: National statistical sources can be helpful in establishing the degree to which the types of areas outside pilot studies are represented, and the extent to which they match selected characteristics of the rest of the health care system ex-post. Our analysis lends support to extrapolation of process indicators from the HPV screening pilot across England.

Attendance at early recall and colposcopy in routine cervical screening with human papillomavirus testing.

Attendance at early recall and colposcopy is crucial to attaining the benefits of primary high-risk human papillomavirus (HR-HPV)-based screening. Within the English HPV pilot, we analysed deprivation- and age-related patterns of attendance at colposcopy and 12- and 24-month early recall of HR-HPV positive women screened in 2013 to 2015 (N = 36 466). We fitted logistic regression models for adjusted odds ratios (OR). Despite high overall attendance, area deprivation had a small but significant impact at both early recalls, for example, attendance at 24 months was 86.3% and 83.0% in less vs more deprived areas, respectively (ORadj : 0.76; 95% CI: 0.67-0.87). Older women (≥30 years) were more likely to attend early recall than younger women (<30 years), for example, attendance at 24 months was 86.1% vs 82.3%, respectively (ORadj : 1.32, 95% CI: 1.16-1.51). Most women attended colposcopy following a baseline referral, with 96.9% attendance among more deprived and 97.8% among less deprived areas (ORadj : 0.70; 95% CI: 0.55-0.88). Differences in colposcopy attendance by deprivation level at 12 and 24 months were of approximately the same magnitude. In conclusion, attendance at early recall and colposcopy was reassuringly high. Although there were statistically significant differences by deprivation and age group, these were small in absolute terms.

Deoxyribonucleotide salvage falls short in whole animals.

Ribonucleotide reductase (RNR) catalyzes the first committed reaction in DNA synthesis. Most of what we know about RNR regulation comes from studies with cultured cells and with purified proteins. In this study, Tran et al. use Cre-Lox technology to inactivate RNR large subunit expression in heart and skeletal muscle of mouse embryos. Analysis of these mutants paints a picture of dNTP regulation in whole animals quite different from that seen in studies of purified proteins and cultured cells.

Impact of screening on cervical cancer incidence: A population-based case-control study in the United States.

Cervical cancer is widely preventable through screening, but little is known about the duration of protection offered by a negative screen in North America. A case-control study was conducted with records from population-based registries in New Mexico. Cases were women diagnosed with cervical cancer in 2006-2016, obtained from the Tumor Registry. Five controls per case from the New Mexico HPV Pap Registry were matched to cases by sex, age and place of residence. Dates and results of all cervical screening and diagnostic tests since 2006 were identified from the pap registry. We estimated the odds ratio of nonlocalized (Stage II+) and localized (Stage I) cervical cancer associated with attending screening in the 3 years prior to case-diagnosis compared to women not screened in 5 years. Of 876 cases, 527 were aged 25-64 years with ≥3 years of potential screening data. Only 38% of cases and 61% of controls attended screening in a 3-year period. Women screened in the 3 years prior to diagnosis had 83% lower risk of nonlocalized cancer (odds ratio [OR] = 0.17, 95% CI: 0.12-0.24) and 48% lower odds of localized cancer (OR = 0.52, 95% CI: 0.38-0.72), compared to women not screened in the 5 years prior to diagnosis. Women remained at low risk of nonlocalized cancer for 3.5-5 years after a negative screen compared to women with no negative screens in the 5 years prior to diagnosis. Routine cervical screening is effective at preventing localized and nonlocalized cervical cancers; 3 yearly screening prevents 83% of nonlocalized cancers, with no additional benefit of more frequent screening. Increasing screening coverage remains essential to further reduce cervical cancer incidence.

Impact of first-line antiretroviral therapy regimens on the restoration of the CD4/CD8 ratio in the CNICS cohort.

BACKGROUND: The CD4/CD8 ratio is an indicator of immunosenescence and a predictor of all-cause mortality in HIV-infected patients. The effects of different ART regimens on CD4/CD8 ratio recovery remain unclear. METHODS: Clinical cohort study of ART-treated patients from the CFAR Network of Integrated Clinical Systems (CNICS). We included ART-naive adults with HIV infection who achieved undetectable HIV RNA during the first 48 weeks of treatment and had additional follow-up 48 weeks after virological suppression (VS). Primary endpoints included increase in CD4/CD8 ratio at both timepoints and secondary endpoints were CD4/CD8 ratio recovery at cut-offs of ≥0.5 or ≥1.0. RESULTS: Of 3971 subjects who met the study criteria, 1876 started ART with an NNRTI, 1804 with a PI and 291 with an integrase strand transfer inhibitor (INSTI). After adjusting for age, sex, race, year of entry, risk group, HCV serostatus, baseline viral load and baseline CD4/CD8 ratio, subjects on an NNRTI showed a significantly greater CD4/CD8 ratio gain compared with those on a PI, either 48 weeks after ART initiation or after 48 weeks of HIV RNA VS. The greater CD4/CD8 ratio improvement in the NNRTI arm was driven by a higher decline in CD8 counts. The INSTI group showed increased rates of CD4/CD8 ratio normalization at the ≥1.0 cut-off compared with the PI group. CONCLUSIONS: NNRTI therapy was associated with a greater increase in the CD4/CD8 ratio compared with PIs. NNRTI- and INSTI-based first-line ART were associated with higher rates of CD4/CD8 ratio normalization at a cut-off of 1.0 than a PI-based regimen, which might have clinical implications.

A state-wide population-based evaluation of cervical cancers arising during opportunistic screening in the United States.

OBJECTIVE: Despite widespread cervical screening, an estimated 13,800 women will be diagnosed with cervical cancer in the United States in 2020. To inform improvements, the screening histories of women diagnosed with cervical cancer in New Mexico were assessed. METHODS: Data were collected on all cervical screening, diagnostic tests and treatment procedures for all women diagnosed with cervical cancer aged 25-64 yrs. in New Mexico from 2006 to 2016. Women were categorized by their screening attendance in the 5-40 months (screening interval) and 1-4 months (peri-diagnostic interval) prior to cancer diagnosis. RESULTS: Of the 504 women diagnosed between May 2009-December 2016, 64% were not screened or had only inadequate screening tests in the 5-40 months prior to diagnosis, and 90 of 182 screened women (49%) had only negative screens in this period. Only 32% (N = 162) of cervical cancers were screen-detected. Women with adenocarcinomas were more likely to have had a recent negative screen (41/57 = 722%) than women with squamous cancers (50/112 = 45%). Both older women (aged 45-64 years) and women with more advanced cancers were less likely to have been screened, and if screened, were more likely to have a false-negative outcome. Only 9% of cancers were diagnosed in women who did not attend biopsy or treatment after positive tests requiring clinical management. Screening currently prevents 35% of cancers, whereas full screening coverage could prevent 61% of cervical cancers. CONCLUSION: Improved screening coverage has the largest potential for reducing cervical cancer incidence, though there is also a role for improved recall procedures and screening sensitivity.

16/18 genotyping in triage of persistent human papillomavirus infections with negative cytology in the English cervical screening pilot.

BACKGROUND: In the English pilot of primary cervical screening with high-risk human papillomavirus (HR-HPV), we exploited natural viral clearance over 24 months to minimise unnecessary referral of HR-HPV+ women with negative cytology. Three laboratories were permitted to use 16/18 genotyping to select women for referral at 12-month recall. We estimated the clinical impact of this early genotyping referral. METHODS: The observed numbers of women referred to colposcopy and with detected high-grade cervical intraepithelial neoplasia (CIN2+), and of women who did not attend early recall in the three laboratories were compared with those estimated to represent a situation without an early genotyping referral. The 95% confidence intervals (CI) for the differences between the protocols were calculated by using a parametric bootstrap. RESULTS: Amongst 127,238 screened women, 16,097 (13%) had HR-HPV infections. The genotyping protocol required 5.9% (95% CI: 4.4-7.7) additional colposcopies and led to a detection of 1.2% additional CIN2+ (95% CI: 0.6-2.0), while 2.3% (95% CI: 2.1-2.5) fewer HR-HPV+/cytology- women did not attend the early recall compared with the non-genotyping protocol. CONCLUSIONS: In a screening programme with high quality of triage cytology and high adherence to early recall,16/18 genotyping of persistent HPV infections does not substantially increase CIN2+ detection.

Risk-adjusted colorectal cancer screening using the FIT and routine screening data: development of a risk prediction model.

BACKGROUND: The faecal immunochemical test (FIT) is replacing the guaiac faecal occult blood test in colorectal cancer screening. Increased uptake and FIT positivity will challenge colonoscopy services. We developed a risk prediction model combining routine screening data with FIT concentration to improve the accuracy of screening referrals. METHODS: Multivariate analysis used complete cases of those with a positive FIT (⩾20 µg g-1) and diagnostic outcome (n=1810; 549 cancers and advanced adenomas). Logistic regression was used to develop a risk prediction model using the FIT result and screening data: age, sex and previous screening history. The model was developed further using a feedforward neural network. Model performance was assessed by discrimination and calibration, and test accuracy was investigated using clinical sensitivity, specificity and receiver operating characteristic curves. RESULTS: Discrimination improved from 0.628 with just FIT to 0.659 with the risk-adjusted model (P=0.01). Calibration using the Hosmer-Lemeshow test was 0.90 for the risk-adjusted model. The sensitivity improved from 30.78% to 33.15% at similar specificity (FIT threshold of 160 µg g-1). The neural network further improved model performance and test accuracy. CONCLUSIONS: Combining routinely available risk predictors with the FIT improves the clinical sensitivity of the FIT with an increase in the diagnostic yield of high-risk adenomas.

Influence of Substance Use Disorders on 2-Year HIV Care Retention in the United States.

Substance use disorders (SUDs) are thought to predict care discontinuity, though magnitude and substance-specific variance of effects are unclear. This report of analytic work undertaken with a multi-regional American cohort of 9153 care enrollees addresses these gaps. Care retention was computed from 24-month post-linkage clinic visit documentation, with SUD cases identified from patient-report screening instruments. Two generalized estimating equations tested binary and hierarchial SUD predictors of retention, and potential effect modification by patient age-group, sex, and care site. Findings demonstrate: (1) detrimental SUD effect, equivalent to a nine percentage-point decrease in retention, with independent effects of age-group and care site; (2) substance-specific effect of marijuana UD associated with lower retention; and (3) age-modification of each effect on care discontinuity, with SUDs serving as a risk factor among 18-29 year-olds and protective factor among 60+ year-olds. Collective findings document patient attributes as influences that place particular subgroups at-risk to discontinue care.

Increased uptake and improved outcomes of bowel cancer screening with a faecal immunochemical test: results from a pilot study within the national screening programme in England.

BACKGROUND: The National Health Service Bowel Cancer Screening Programme (BCSP) in England uses a guaiac-based faecal occult blood test (gFOBt). A quantitative faecal immunochemical test (FIT) for haemoglobin (Hb) has many advantages, including being specific for human blood, detecting Hb at a much lower concentration with a single faecal sample and improved uptake. METHODS: In 2014, a large comparative pilot study was performed within BCSP to establish the acceptability and diagnostic performance of FIT. Over a 6-month period, 40 930 (1 in 28) subjects were sent a FIT (OC-SENSOR) instead of a gFOBt. A bespoke FIT package was used to mail FIT sampling devices to and from FIT subjects. All participants positive with either gFOBt or FIT (cut-off 20 µg Hb/g faeces) were referred for follow-up. Subgroup analysis included cut-off concentrations, age, sex, screening history and deprivation quintile. RESULTS: While overall uptake increased by over 7 percentage points with FIT (66.4% vs 59.3%, OR 1.35, 95% CI 1.33 to 1.38), uptake by previous non-responders almost doubled (FIT 23.9% vs gFOBt 12.5%, OR 2.20, 95% CI 2.10 to 2.29). The increase in overall uptake was significantly higher in men than women and was observed across all deprivation quintiles. With the conventional 20 µg/g cut-off, FIT positivity was 7.8% and ranged from 5.7% in 59-64-year-old women to 11.1% in 70-75-year-old men. Cancer detection increased twofold and that for advanced adenomas nearly fivefold. Detection rates remained higher with FIT for advanced adenomas, even at 180 µg Hb/g. CONCLUSIONS: Markedly improved participation rates were achieved in a mature gFOBt-based national screening programme and disparities between men and women were reduced. High positivity rates, particularly in men and previous non-respondents, challenge the available colonoscopy resource, but improvements in neoplasia detection are still achievable within this limited resource.

Maternal VDR variants rather than 25-hydroxyvitamin D concentration during early pregnancy are associated with type 1 diabetes in the offspring.

AIMS/HYPOTHESIS: We investigated whether single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentration in the metabolic pathway of vitamin D show different genotype distributions between Finnish families with an offspring with type 1 diabetes (cases) and families with a healthy offspring (controls). METHODS: A total of 31 SNPs in eight genes were studied in case and control mothers and family members (offspring with type 1 diabetes and healthy siblings, healthy control children and fathers) (n = 2,854). The 25-hydroxyvitamin D concentration was studied in 474 case and 348 matched control mothers during pregnancy. RESULTS: The genotype distributions of 13 SNPs (in the following genes: 7-dehydrocholesterol reductase NADSYN1/DHCR7, vitamin D receptor VDR, group-specific component GC and CYP27A1) that showed a nominal association with 25-hydroxyvitamin D concentration (p < 0.05) were compared between case and control families. SNPs in VDR had different genotype distributions between the case and control mothers (rs1544410, p = 0.007; rs731236, p = 0.003; rs4516035, p = 0.015), two SNPs (rs1544410 and rs731236) remaining significant after correction for multiple testing using a false discovery rate. The mean 25-hydroxyvitamin D concentrations during pregnancy did not differ between the case and control mothers. CONCLUSIONS/INTERPRETATION: Our preliminary results suggest that the maternal genotypes of SNPs in VDR may influence the in utero environment and thus contribute to the early programming of type 1 diabetes in the fetus. It is possible that the effects are only relevant in the presence of vitamin D insufficiency.

Deoxyribonucleotides as genetic and metabolic regulators.

For >35 yr, we have known that the accuracy of DNA replication is controlled in large part by the relative concentrations of the 4 canonical deoxyribonucleoside 5'-triphosphates (dNTPs) at the replisome. Since this field was last reviewed, ∼8 yr ago, there has been increased understanding of the mutagenic pathways as they occur in living cells. At the same time, aspects of deoxyribonucleotide metabolism have been shown to be critically involved in processes as diverse as cell cycle control, protooncogene expression, cellular defense against HIV infection, replication rate control, telomere length control, and mitochondrial function. Evidence supports a relationship between dNTP pools and microsatellite repeat instability. Relationships between dNTP synthesis and breakdown in controlling steady-state pools have become better defined. In addition, new experimental approaches have allowed definitive analysis of mutational pathways induced by dNTP pool abnormalities, both in Escherichia coli and in yeast. Finally, ribonucleoside triphosphate (rNTP) pools have been shown to be critical determinants of DNA replication fidelity. These developments are discussed in this review article.

Initiation of genome instability and preneoplastic processes through loss of Fhit expression.

Genomic instability drives tumorigenesis, but how it is initiated in sporadic neoplasias is unknown. In early preneoplasias, alterations at chromosome fragile sites arise due to DNA replication stress. A frequent, perhaps earliest, genetic alteration in preneoplasias is deletion within the fragile FRA3B/FHIT locus, leading to loss of Fhit protein expression. Because common chromosome fragile sites are exquisitely sensitive to replication stress, it has been proposed that their clonal alterations in cancer cells are due to stress sensitivity rather than to a selective advantage imparted by loss of expression of fragile gene products. Here, we show in normal, transformed, and cancer-derived cell lines that Fhit-depletion causes replication stress-induced DNA double-strand breaks. Using DNA combing, we observed a defect in replication fork progression in Fhit-deficient cells that stemmed primarily from fork stalling and collapse. The likely mechanism for the role of Fhit in replication fork progression is through regulation of Thymidine kinase 1 expression and thymidine triphosphate pool levels; notably, restoration of nucleotide balance rescued DNA replication defects and suppressed DNA breakage in Fhit-deficient cells. Depletion of Fhit did not activate the DNA damage response nor cause cell cycle arrest, allowing continued cell proliferation and ongoing chromosomal instability. This finding was in accord with in vivo studies, as Fhit knockout mouse tissue showed no evidence of cell cycle arrest or senescence yet exhibited numerous somatic DNA copy number aberrations at replication stress-sensitive loci. Furthermore, cells established from Fhit knockout tissue showed rapid immortalization and selection of DNA deletions and amplifications, including amplification of the Mdm2 gene, suggesting that Fhit loss-induced genome instability facilitates transformation. We propose that loss of Fhit expression in precancerous lesions is the first step in the initiation of genomic instability, linking alterations at common fragile sites to the origin of genome instability.