Increased Risk of Internal Tumors in DNA Repair-Deficient Xeroderma Pigmentosum Patients: Analysis of Four International Cohorts

Abstract Background Xeroderma pigmentosum (XP) is a rare, autosomal, recessive DNA repair-deficiency disorder with a frequency of 1-3 per million livebirths in Europe and USA but with higher frequencies in isolated islands or in countries with a high level of consanguinity. XP is characterized by high incidence of skin cancers on sun-exposed sites. Recent improvement in life expectancy of XP patients suggests an increased risk of frequently aggressive and lethal internal tumors. Our purpose was to quantify relative risks of internal tumor development for XP patients by tumor type, XP-subtype, patients’ ages and ethnicity through comparison with the US general population. Methods We analyzed four independent international well-characterized XP cohorts (from USA, UK, France and Brazil) with a total of 434 patients, where 11.3% developed internal tumors and compared them to the American general population. We also compiled, through PubMed/Medline, a dataset of 89 internal tumors in XP patients published between 1958 and 2020. Results In the combined 4-XP cohort, relative risk of internal tumors was 34 (95% confidence interval (CI) 25-47) times higher than in the general population (p-value=1.0E-47) and tumor arose 50 years earlier. The XP-C group was at the highest risk for the 0-20 years old-patients (OR=665; 95% CI 368-1200; p-value=4.3E-30). The highest risks were observed for tumors of central nervous system (OR=331; 95% CI 171-641; p-value=2.4E-20), hematological malignancies (OR=120; 95% CI 77-186; p-value=3.7E-36), thyroid (OR=74; 95% CI 31-179; p-value=1.2E-8) and gynecological tumors (OR=91; 95% CI 42-193; p-value=3.5E-12). The type of mutation on the XPC gene is associated with different classes of internal tumors. The majority of French XP-C patients (80%) are originated from North Africa and carried the XPC delTG founder mutation specific from the South Mediterranean area. The OR is extremely high for young (0-20 years) patients with more than 1,300-fold increase for the French XPs carrying the founder mutation. Conclusion Because the age of XP population is increasing due to better sun-protection and knowledge of the disease, these results are of particular importance for the physicians to help in early prevention and detection of internal tumors in their XP patients. Few preventive blood analyses or simple medical imaging may help to better detect early cancer appearance in this population.

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Analysis of second primary cancers in gastroinstestinal stromal tumor patients using SEER database.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.327 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 327-327

Author(s):

Krishna Bilas Ghimire ◽

Barsha Nepal ◽

Binay Kumar Shah

Keyword(s):

General Population ◽

Solid Tumors ◽

Stromal Tumor ◽

P Value ◽

Second Primary ◽

Seer Database ◽

Second Primary Cancers ◽

Increased Risk ◽

Second Primary Malignancies ◽

End Results

327 Background: Development of second primary cancers among gastrointestinal stromal tumor (GIST) patients is not very well studied. This study was conducted to evaluate second primary malignancies in GIST patients using U.S. Surveillance, Epidemiology, and End Results (SEER) cancer registry database. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER Stat) database: Incidence - SEER 13 Regs Research Data, Nov 2011 Sub, Vintage 2009 Pops (1992-2009) using MP-SIR session. We analysed secondary cancer rate among adult GIST patients during the period 1992-2009. We also compared the risk of secondary malignancies in pre- (1992-2001) to post-imatinib (2002-2009) eras. We used SEER MP-SIR session and Graph pad scientific software to calculate p value. Results: There were 2,436 (693 in pre-imatinib era and 1,743 in post-imatinib era) GIST patients reported during 1992-2009 period in SEER database. Among them, 163 GIST patients developed second primary malignancy, which is significantly higher than expected in general population, with observed/expected (O/E) ratio: 1.31, p value = <0.05, (95% CI: 1.11-1.52) and excess risk of 39.76 per 10,000 population. The total number of second primary cancers in GIST in pre- and post-imatinib eras were 69 and 94, p value = <0.0001 with observed/expected (O/E) ratio of 29.18 and 48.22 respectively. The total number of second primary solid tumors in pre- and post-imatinib era was: 59 and 84, p value=0.0008 and O/E ratio: 20.18 vs 43.32 respectively. Conclusions: This study showed overall increased risk of second primary malignancies among GIST patients as compared to general population. There was significantly increased risk of second primary malignancies, especially solid tumors in post-imatinib era. [Table: see text]

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XRCC3 Thr241Met polymorphism is not associated with lung cancer risk in a Romanian population

Medicine and Pharmacy Reports ◽

10.15386/cjmed-523 ◽

2016 ◽

Vol 89 (1) ◽

pp. 89-93 ◽

Cited By ~ 2

Author(s):

Andreea Catana ◽

Monica Pop ◽

Dragos Horea Marginean ◽

Ioana Cristina Blaga ◽

Mihai Dumitru Porojan ◽

...

Keyword(s):

Lung Cancer ◽

Dna Repair ◽

Critical Role ◽

Recessive Model ◽

Tumor Type ◽

Increased Risk ◽

Pcr Rflp ◽

Repair Mechanisms ◽

Xrcc3 Thr241met ◽

Xrcc3 Gene

Background and aims. Deoxyribonucleic Acid (DNA) repair mechanisms play a critical role in protecting the cellular genome against carcinogens. X-ray cross-complementing gene 3 (XRCC3) is involved in DNA repair and therefore certain genetic polymorphisms that occur in DNA repair genes may affect the ability to repair DNA defects and may represent a risk factor in carcinogenesis. The purpose of our study was to investigate the association between XRCC3 gene substitution of Threonine with Methionine in codon 241 of XRCC3 gene (Thr241Met) polymorphism and the risk of lung cancer, in a Romanian population.Methods. We recruited 93 healthy controls and 85 patients with lung cancer, all smokers. Thr241Met, XRCC3 gene genotyping was determined by multiplex Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR–RFLP).Results. Statistical analysis (OR, recessive model), did not revealed an increased risk for lung cancer, for the variant 241Met allele and Thr241Met genotypes (p=0.138, OR=0.634, CI=0.348-1.157; p=0.023, OR=0.257, CI=0.085-6.824). Also, there were no positive statistical associations between Thr241Met polymorphism of XRCC3 gene, gender, tobacco and various histopathological tumor type of lung cancer.Conclusion. In conclusion, the results of the study suggest that the XRCC3 gene Thr241Met polymorphism is not associated with an increased risk for the development of lung cancer in this Romanian group.

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Abstract 3603: Extreme Lipoprotein(a) Levels Predict a 3–4 Fold Increase in Risk of Myocardial Infarction in the General Population

Circulation ◽

10.1161/circ.116.suppl_16.ii_817-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Pia R Kamstrup ◽

Marianne Benn ◽

Anne Tybjćrg Hansen ◽

Børge G Nordestgaard

Keyword(s):

Myocardial Infarction ◽

General Population ◽

Fold Increase ◽

Threshold Effect ◽

Lipoprotein A ◽

Hazard Ratios ◽

Heart Study ◽

Increased Risk ◽

Increase In Risk

Background: Elevated lipoprotein(a) levels associate with increased risk of myocardial infarction in some, but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) levels, measurements in long-term frozen samples and no correction for regression dilution bias. We tested the hypothesis that extreme lipoprotein(a) levels predict myocardial infarction in the general population, measuring levels shortly after sampling and correcting for regression dilution bias. Methods and Results: We examined 9330 men and women from the Danish general population, The Copenhagen City Heart Study. During 10 years follow-up, 498 participants developed myocardial infarction. In women, multifactorially adjusted hazard ratios for myocardial infarction for elevated lipoprotein(a) levels were 1.1(95% confidence interval 0.6 –1.9) for 5–29 mg/dL, 1.7(1.0 –3.1) for 30 – 84 mg/dL, 2.6(1.2–5.9) for 85–119 mg/dL (>90 th percentile), and 3.6(1.7–7.7) for ≥120 mg/dL (>95 th percentile) versus levels <5 mg/dL (figure , p-values are test for trend of hazard ratios). Equivalent values in men were 1.5(0.9 –2.3), 1.6(1.0 –2.6), 2.6(1.2–5.5), and 3.7(1.7– 8.0). Conclusions: We observed a stepwise increase in risk of myocardial infarction with increasing levels of lipoprotein(a) in both genders, with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3– 4 fold increase in risk of myocardial infarction in the general population. Figure. Risk of myocardial infarction by levels of lipoprotein(a)

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Exploring the association between renal cell carcinoma (RCC) and myeloid malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13073 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13073-e13073

Author(s):

Niraj Konchady Shenoy ◽

Mythri Mudireddy ◽

Nelson Leung ◽

Brian Addis Costello ◽

Bradley C. Leibovich ◽

...

Keyword(s):

General Population ◽

Mayo Clinic ◽

Myelogenous Leukemia ◽

P Value ◽

Epigenetic Landscape ◽

Myeloid Malignancy ◽

Myeloid Malignancies ◽

Increased Risk ◽

History Of ◽

Medicare Database

e13073 Background: We observed several patients with a personal history of both RCC and myeloid malignancy, and aimed to explore a possible association, especially given the similarity in their epigenetic landscape, with both being characterized by widespread aberrant hypermethylation (Hu C et al, CCR 2014; Jiang Y et al, Blood 2009). Methods: Mayo Clinic’s ‘Advanced Cohort Explorer’ database was used to identify patients with a history of both RCC and a myeloid malignancy - Acute Myelogenous Leukemia (AML), Myeloproliferative Neoplasms (MPN), Myelodysplastic syndromes (MDS) - and to determine the clinical characteristics. The incidence of MDS in patients ≥65 years with a history of RCC was compared to that in the general population ≥65 years (SEER- Medicare database) as well as the general patient population at Mayo Clinic, using one sample test of proportions. Results: A total of 59 patients were identified, with both biopsy proven RCC and a myeloid malignancy during their life time (12 AML, 9 MPN, 9 low risk MDS and 29 intermediate- high risk MDS). The cohort was characterized by marked male predominance (4.4: 1). Median age at RCC diagnosis was 64 years (range 37-87) and myeloid malignancy was 75 years (range 44-90). 46/59 patients had the RCC antecedent, 10/59 concurrent and 3/59 subsequent to the myeloid malignancy with a median time of myeloid malignancy diagnosis after RCC diagnosis of 7.7 years. For patients ≥65 years, the risk of developing MDS with a history of stage I/II RCC and nephrectomy was 5.26 times that of the general population based on the SEER-Medicare database (Cogle, Blood 2011)(395/100,000 vs 75/100,000; p value < 0.001), and 3.07 times that of the general population at Mayo Clinic (395/100,000 vs 128.4/100,000; p value < 0. 001). Conclusions: We observed an association between RCC and myeloid malignancies, particularly MDS; with a history of RCC conferring a substantially increased risk of developing MDS. We hypothesize that the perturbation of epigenetic landscape in the form of widespread hypermethylation may explain, in part, the association between the two malignancies; and aim to explore the potential aberrancy of epigenetic regulators in our patient cohort with a genomic, epigenomic and transcriptomic analysis.

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Hospitalizations and mortality among patients with fetal alcohol spectrum disorders: a prospective study

Scientific Reports ◽

10.1038/s41598-020-76406-6 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Sarah Soyeon Oh ◽

Young Ju Kim ◽

Sung-in Jang ◽

Sohee Park ◽

Chung Mo Nam ◽

...

Keyword(s):

Nervous System ◽

General Population ◽

Fetal Alcohol Spectrum Disorders ◽

Fold Increase ◽

Fetal Alcohol ◽

Common Cause ◽

Increased Risk ◽

Study Population ◽

Spectrum Disorders ◽

Fetal Alcohol Spectrum

Abstract With nearly 10% of women consuming alcohol during pregnancy, fetal alcohol spectrum disorders (FASDs) are becoming an increasing concern for clinicians and policymakers interested in the field of healthcare. Known as the range of mental and/or physical disabilities that occur among individuals with prenatal alcohol exposure, FASDs can result in dysmorphic features, problems with physical growth, neurobehavioral and cognitive problems that not only increase risk of various diseases, but also premature mortality. We investigated whether the diagnosis of FASDs result in increased risk of hospitalizations and mortality, with respect to FASD domains and relative diseases, when age effects are controlled for. The data for this study was taken from the National Health Insurance Service – National Sample Cohort (NHIS-NSC) between 2003 and 2013. The population attributable risk (PAR) statistic was used to estimate the percentage of hospitalizations and mortality attributable to FASDs and other factors. A time-dependent Cox proportional hazards model with age of diagnosis as the time-scale was employed to calculate adjusted hazard ratios and 95% CIs for hospitalizations and mortality among FASD populations compared to their general population peers. Among the 3,103 FASD cases, 27.5% experienced hospitalizations and 12.5% died. Overall, FASDs accounted for 853 FASD-attributable hospitalizations (51.0% of all hospitalizations in the study population) and 387 mortality events (34.5% of all deaths in the study population). 20.52% of hospitalizations and 21.35% of mortalities were attributable to FASDs in this population. Compared to the control group, FASD patients had a 1.25-fold (HR: 1.25, 95% CI: 1.05–1.49, p = 0.0114) increased risk of hospitalizations and a 1.33-fold (HR: 1.33, 95% CI: 1.07–1.67, p = 0.0118) increased risk of all-cause mortality. The most common cause for hospitalization was diseases of the nervous system, which accounted for 450 FASD-attributable hospitalizations (96.2% of all nervous system hospitalizations in the study population). In fact, FASD patients were 52 times more likely to be hospitalized for nervous system diseases than their peers (HR: 51.78, 95% CI: 29.09–92.17, p < .0001). The most common cause for mortality was neoplasms, which accounted for 94 FASD-attributable deaths (28.7% of all neoplasm deaths in the study population). However, FASD patients did not have increased risk of neoplasm mortality than the general population (HR: 0.88, 95% CI: 0.59–1.32, p < .0001). Overall, this study found that individuals diagnosed with FASDs have increased risk of both hospitalizations and mortality, compared to their general population peers. This is particularly so for diseases of the nervous system, which showed a 52-fold increase in hospitalizations and four-fold increase in mortality for FASD patients in our study. Likewise, while the association between FASDs and neoplasm mortality was not significant in our investigation, more attention by neurologists and related healthcare providers regarding the link between these two factors is necessary. Trial Registration: Institutional Review Board of Yonsei University’s Health System: Y-2019-0174.

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Assessing the relationship between monoallelic PRKN mutations and Parkinson’s risk

Human Molecular Genetics ◽

10.1093/hmg/ddaa273 ◽

2021 ◽

Author(s):

Steven J Lubbe ◽

Bernabe I Bustos ◽

Jing Hu ◽

Dimitri Krainc ◽

Theresita Joseph ◽

...

Keyword(s):

Meta Analysis ◽

Copy Number Variant ◽

Fold Increase ◽

Preliminary Evidence ◽

P Value ◽

Biallelic Mutation ◽

Mutation Status ◽

Increased Risk ◽

Biallelic Mutations

Abstract Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson’s disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.

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Abstract P325: Cardiometabolic Factors Associated With Alcohol Use; The New Orleans Alcohol Use In Hiv Study

Circulation ◽

10.1161/circ.141.suppl_1.p325 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Tekeda F Ferguson ◽

Liz Simon ◽

Katherine Theall ◽

David Welsh ◽

Patricia E Molina

Keyword(s):

Alcohol Use ◽

New Orleans ◽

Fold Increase ◽

High Density Lipoproteins ◽

P Value ◽

Study Cohort ◽

People Living With Hiv ◽

Lifestyle Choice ◽

Increased Risk ◽

Drinking History

As people living with HIV (PLWH) live longer, morbidity and mortality related to chronic illness specifically, cardiovascular disease (CVD) has increased. HIV disease has been associated with hypertension (HTN) and dyslipidemia, which are risk factors for developing CVD. The objective of this study was to determine whether heavy alcohol use among PLWH is associated with increased risk of HTN, dyslipidemia, and metabolic syndrome (MS). To investigate this hypothesis we analyzed data from the New Orleans Alcohol Use in HIV (NOAH) Study. Alcohol use was assessed with the Alcohol Use Disorders Identification Test (AUDIT), the Timeline Follow Back (TLFB) Calendar, a Lifetime Drinking History, and the biomarker, Phosphatidylethanol (PEth). HTN stage 1, was defined as a mean systolic 130-139 or diastolic blood pressure 80-89 mmHg; HTN stage 2 as a systolic ≥140 or diastolic ≥ 90 mmHg. MS was defined as having 3 of 5 conditions: HTN, low high-density lipoproteins (≤40 (men)/50 (women)), high triglycerides (≥ 150mg/dl), high glucose (≥100 mg/dl), waist circumference >88(women)/102(men). The NOAH study cohort (n=365) is majority African American (83.6%), mean age 48.2 ±10.4, 68.8% male and 31.2% female. Descriptive statistics and multivariable linear and logistic regression analyses were performed stratifying by sex and adjusting for age, race, smoking, and viral load. Approximately, 41.3% had an AUDIT ≥8 and 14.0% were hazardous drinkers (greater than 40 (women)/60 (men) grams of alcohol per day). MS was prevalent in 36.1%, stage 2 HTN 66.0%, 9.3% with hyperglycemia (>125mg/dl), 23.0% had elevated creatinine, and 27.4% were obese. Creatinine was positively associated with LDH and PEth (p-value <0.04). TLFB grams of alcohol had a positive linear association with glucose among men (beta=0.0033; p=0.0035). LDH was associated with two-fold increase odds of MS (OR=2.69; 95% C.I.: 1.18 - 9.58) with sex as an effect modifier. AUDIT score ≥8 was not a significant predictor of hypertension, dyslipidemia, or MS in adjusted models. Our preliminary results indicate that lifetime drinking history was more associated with increased cardiometabolic risk than recent drinking. As PLWH are living longer, hazardous and chronic alcohol use is a lifestyle choice that has clinical relevance and has to be addressed in the chronic care model of treatment in PLWH. (Supported by: NIH P60AA009803)

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OP0192 INCIDENT GOUT AND RISK OF FIRST-TIME ACUTE CORONARY SYNDROME: A PROSPECTIVE, POPULATION-BASED, COHORT STUDY IN SWEDEN

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3256 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 115.1-116

Author(s):

P. Drivelegka ◽

L. T. H. Jacobsson ◽

U. Lindström ◽

K. Bengtsson ◽

M. Dehlin

Keyword(s):

Risk Factors ◽

Acute Coronary Syndrome ◽

Cardiovascular Risk ◽

General Population ◽

Cardiovascular Risk Factors ◽

Population Based ◽

P Value ◽

Coronary Syndrome ◽

Increased Risk ◽

First Time

Background:Gout is associated with an increased risk of cardiovascular disease (CVD), but it is not clear whether this risk is intrinsic to gout itself or to underlying comorbidities. Although the impact of gout on CVD has been studied previously, the results have been conflicting and studies from European countries are scarce.Objectives:To investigate the risk of first-time acute coronary syndrome (ACS) in patients with incident gout in western Sweden, compared to the general population.Methods:Using data from the population-based health care database VEGA, we identified all patients with incident gout diagnosis at either primary or specialized health care units in western Sweden, in the period 2007– 2017 (20,287 cases; mean age, 65.6 years; 67.4% males). Cases regarded as incident, if they did not have any recorded diagnosis of gout in the previous seven years. For each case, up to five controls matched on age, sex, and county at the date of first gout diagnosis were identified from the census register (84,240 controls). Cases and controls with prior history of ischemic heart disease were excluded. The follow-up began at the first diagnosis of gout, and ended at the earliest of an ACS event, emigration, death, or 31 December 2017. To estimate the risk of first-time ACS, we used incident rate (IR) and univariable and multivariable Cox regression analysis with adjustments for the following cardiovascular risk factors: the diagnoses of hypertension, diabetes, hyperlipidemia, obesity, renal disease, heart failure, cardiomyopathy, psoriasis, chronic obstructive pulmonary disease, alcoholism, cancer, cerebrovascular, and atherosclerotic disease, as well as for the dispensed prescriptions of statins, anticoagulants, anti-hypertensive, anti-diabetic, anti-hyperlipidemic, anti-obesity, and vasodilator drugs.Results:The IR of first-time ACS was 9.0 events per 1,000 person-years in the gout cohort, compared to 6.3 in the control cohort. The IRs were lower for women than men, both in the gout (IR, 8.2 vs 9.4) and in the control cohort (IR, 5.0 vs 7.0). Univariable analysis showed that patients with gout have a higher risk of first-time ACS, as compared to the general population (Figure 1, Table 1), but the increased risk is largely diminished after adjustments for cardiovascular risk factors (Table 1).Table 1.Risk of first-time ACS in patients with incident gout, as compared to the general population.Unadjusted HR95% CIp-valueAdjusted HR95% CIp-valueACS Overall1.431.32-1.55<.00011.151.05-1.240.0013 Men1.351.23-1.48<.00011.121.02-1.230.0230 Women1.631.41-1.89<.00011.211.03-1.410.0207Figure 1.Event-free survival curve for patients with gout and controls during the follow-up, where event is first-time acute coronary syndrome.Conclusion:Patients with incident gout have a 43% higher risk of first-time ACS, as compared to the general population. This increased risk is largely explained by the increased occurrence of comorbidities in gout, but there is still a modestly increased risk that may be due to gout related factors. Our results underline the importance of cardiovascular risk assessment and the need for appropriate management of the underlying cardiovascular risk factors in patients with gout.Disclosure of Interests:None declared

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A kórházi és az ambuláns kemoterápiában részesülő onkológiai betegek vénásthromboembolia-profilaxisának aktuális kérdései

Orvosi Hetilap ◽

10.1556/650.2016.30357 ◽

2016 ◽

Vol 157 (6) ◽

pp. 203-211

Author(s):

Hajna Losonczy ◽

Ágnes Nagy ◽

Attila Tar

Keyword(s):

Venous Thromboembolism ◽

General Population ◽

Cancer Patients ◽

Current Knowledge ◽

Fold Increase ◽

Increased Risk ◽

Venous Thromboembolism Prevention ◽

Breast And Prostate Cancer ◽

Underlying Mechanisms ◽

Current Guidelines

Cancer patients have a 2–7 fold increased risk of venous thromboembolism compared with the general population and, since 1990, this is associated with significant morbidity and mortality. This review summarizes the current knowledge on venous thromboembolism and cancer. Notably, the risk of venous thromboembolism varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of venous thromboembolism than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors, cytokines and growth factors may directly and indirectly enhance venous thromboembolism. Chemotherapy produces ~6,5 fold increase in venous thromboembolism incidence in cancer patients compared to the general population. Prevention of this complication is challenging. The authors review the development of guidelines concerning venous thromboembolism prevention in hospitalized and also in ambulatory cancer patients treated with chemotherapy. Current guidelines recommend the use of low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent venous thromboembolism in cancer patients. Orv. Hetil., 2016, 157(6), 203–211.

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Cancer in Heterozygote Carriers of Fanconi Anemia Genes

Blood ◽

10.1182/blood-2018-99-116458 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3868-3868

Author(s):

Blanche P. Alter ◽

Neelam Giri ◽

Lisa James McReynolds ◽

Philip S. Rosenberg

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Dna Repair ◽

Missing Data ◽

General Population ◽

Fanconi Anemia ◽

Family Members ◽

Repair Pathway ◽

Increased Risk ◽

Risk Of Cancer

Abstract Background: Fanconi anemia (FA) is an inherited bone marrow failure syndrome, characterized by a defect in DNA repair, increased frequency of birth defects, and high risks of malignancies. Relatives of patients with FA are concerned about the risk of cancer in themselves or other family members. Carrier grandparents with mutations in genes for FA were reported in 2007 to have no increase in overall cancer incidence, except for a higher rate of breast cancer among FANCC carrier grandmothers (Berwick et al, Cancer Research 67:9591, 2007); this study included 944 relatives among 312 families. Tischkowitz et al also did not find increased risks of cancer in 575 relatives among 36 families, except for prostate cancer (Tischkowitz et al, BMC Cancer 8:257, 2008). The relative risk of breast cancer associated with germline mutations in genes in the BRCA/FA DNA repair pathway in the general population not due to BRCA1 or BRCA2 is 5 to 10 fold (Couch et al, JAMA Oncology 3:1190, 2017), suggesting that heterozygotes for FA might be at increased risk. The FA cohort at the National Cancer Institute (NCI) is sufficiently large to again address the question of cancer in FA heterozygotes. Hypothesis: Patients heterozygous for a mutated gene in the BRCA/FA DNA repair pathway have an increased risk of cancer. Identification of FA genes with increased cancer risk in heterozygotes, and specific cancer types in relatives of patients with FA, would guide screening recommendations for these categories of family members, and studies to determine whether FA heterozygotes with cancer should be managed with modifications of drug or radiation doses. Methods: We evaluated cancer risks in relatives of probands in the NCI FA cohort. We collected self-report or proxy report data on the presence or absence of cancer, cancer type, age at cancer diagnosis for individuals with a history of cancer, and age at death from other causes or current age. We studied obligate heterozygotes (parents and offspring of probands with FA), relatives with a 50% probability of heterozygosity (grandparents), and relatives with a 2/3 probability of being carriers (siblings without FA). We determined the ratio of observed/expected cases (O/E) using data from SEER cancer registries, with adjustment for age, sex, and birth cohort. Confirmatory genotyping is being done by targeted panel next-generation sequencing for participants with DNA available. Results and Discussion: Our study includes 94 families. Twenty-one cancers were reported in 188 parents, with 24 expected (O/E 0.86, 95% CI [confidence interval] 0.53-1.31). Three hundred and twenty-seven grandparents had 89 cases with cancer, expected 125 (O/E 0.71, CI 0.57-0.88). There were 122 siblings, with 1 cancer case and 4 expected (O/E 0.26, CI 0.01-1.46). Among 12 offspring there was 1 case of leukemia (O/E 1:0.12, CI 0.2-44.64). Specific cancers had increased O/E in parents (2 cases of salivary gland cancer, O/E 27.3, CI 3.31-98.66), grandparents (5 with liver cancer O/E 4.7, CI 1.53-10.96; 9 with leukemia O/E 2.42, CI 1.11-4.59), and a single case of acute myeloid leukemia in an offspring (O/E of 402.44, CI 10.19-2242.85). Four cases of prostate cancer in parents (O/E of 1.47, CI 0.4-3.76) and 8 in grandparents (O/E 0.47, CI 0.2-0.93) failed to support the suggestion by Tischkowitz et al that prostate cancer was significantly increased in male relatives (5 cases, O/E 3.1, CI 1.1-8.8). Missing data include birth dates, death dates, or cancer dates for 44 grandparents and 2 siblings. Our results suggest that heterozygotes for mutations in FA genes do not appear to have an increased risk of cancer compared with the general population, in agreement with data from other cohorts. Further analyses will be done after completion of genotyping the relatives, with the caveat that DNA may not be available from some of the grandparents. The NCI FA study is limited by the numbers of participants, and the missing data, particularly in the grandparent generation. In addition, data are reported by the individuals or their proxies, and medical record validation may not be possible; the types and ages of cancers cannot be confirmed. Although the types of cancer and risks in FA heterozygotes are similar to those in the general population, the potential concern that management of patients who are carriers of a defect in DNA repair may need to be modified requires future investigation. Disclosures No relevant conflicts of interest to declare.

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