Pathological changes in basement membranes and dermal connective tissue of skin from patients with hereditary cystatin C amyloid angiopathy.

Hereditary cystatin C amyloid angiopathy (HCCAA) is a genetic disease caused by a mutation in the cystatin C gene. Cystatin C is abundant in cerebrospinal fluid and the most prominent pathology in HCCAA is cerebral amyloid angiopathy due to mutant cystatin C amyloid deposition with associated cerebral hemorrhages, typically in young adult carriers. Analyses of post-mortem brain samples shows that pathological changes are limited to arteries and regions adjacent to arteries. The severity of pathological changes at post-mortem has precluded the elucidation of the evolution of histological changes. Mutant cystatin C deposition in carriers is systemic and has, for example, been described in the skin, suggesting similar pathological mechanisms both in the brain and outside of the central nervous system. The aim of this study was to use skin biopsies from asymptomatic and symptomatic carriers to study intermediate events in HCCAA pathogenesis. We found that cystatin C deposition in minimally affected samples was limited to the basement membrane (BM) between the dermis and epidermis. When the deposits were more advanced, they extended to other BM regions in the skin. Our results showed that the immunoreactivity of the BM protein COLIV was increased to a similar extent in all carrier biopsies and cystatin C deposits were in close association with COLIV. The density of fibroblasts in the upper dermis of carrier skin was increased, whereas the distribution of other cell types examined did not differ compared with control biopsies. COLIV and cystatin C immunoreactivity in carrier biopsies was closely associated with the fibroblasts. The results of this study, in conjunction with our previous results regarding pathological BM changes in leptomeningeal arteries of patients, suggest that BM changes are early and important events in HCCAA pathogenesis that could facilitate cystatin C deposition and aggregation.

Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia.

BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.

Basal cells of the human airways acquire mesenchymal traits in idiopathic pulmonary fibrosis and in culture.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high morbidity and mortality. The cellular source of the fibrotic process is currently under debate with one suggested mechanism being epithelial-to-mesenchymal transition (EMT) in the alveolar region. In this study, we show that airway epithelium overlying fibroblastic foci in IPF contains a layer of p63-positive basal cells while lacking ciliated and goblet cells. This basal epithelium shows increased expression of CK14, Vimentin and N-cadherin while retaining E-cadherin. The underlying fibroblastic foci shows both E- and N-cadherin-positive cells. To determine if p63-positive basal cells were able to undergo EMT in culture, we treated VA10, a p63-positive basal cell line, with the serum replacement UltroserG. A sub-population of treated cells acquired a mesenchymal phenotype, including an E- to N-cadherin switch. After isolation, these cells portrayed a phenotype presenting major hallmarks of EMT (loss of epithelial markers, gain of mesenchymal markers, increased migration and anchorage-independent growth). This phenotypic switch was prevented in p63 knockdown (KD) cells. In conclusion, we show that airway epithelium overlying fibroblastic foci in IPF lacks its characteristic functional identity, shows increased reactivity of basal cells and acquisition of a partial EMT phenotype. This study suggests that some p63-positive basal cells are prone to phenotypic changes and could act as EMT progenitors in IPF.

A common variant associated with prostate cancer in European and African populations.

With the increasing incidence of prostate cancer, identifying common genetic variants that confer risk of the disease is important. Here we report such a variant on chromosome 8q24, a region initially identified through a study of Icelandic families. Allele -8 of the microsatellite DG8S737 was associated with prostate cancer in three case-control series of European ancestry from Iceland, Sweden and the US. The estimated odds ratio (OR) of the allele is 1.62 (P = 2.7 x 10(-11)). About 19% of affected men and 13% of the general population carry at least one copy, yielding a population attributable risk (PAR) of approximately 8%. The association was also replicated in an African American case-control group with a similar OR, in which 41% of affected individuals and 30% of the population are carriers. This leads to a greater estimated PAR (16%) that may contribute to higher incidence of prostate cancer in African American men than in men of European ancestry.

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.

Surgical lung biopsy for suspected interstitial lung disease with video-assisted thoracoscopic surgery is safe, providing exact histological and disease specific diagnosis for tailoring treatment.

Background: Surgical lung biopsy (SLB) is required for diagnosis in patients with suspected interstitial lung disease (ILD) if other less invasive diagnostic methods are non-conclusive. We evaluated the outcome of SLB by using centralized databases in a whole-nation patient-cohort. Methods: A population-based retrospective study on 68 consecutive patients (mean age 58 years, 58.8% males) that underwent SLB in Iceland between the years 2008 and 2020. Patient information was obtained from patient charts and peri- and postoperative complications were registered together with 30- and 90-day mortality. Computed tomography (CT) scans, histological biopsies and spirometry results were reviewed, and overall survival (Kaplan-Meier) estimated. Mean follow-up was 61.3 months (range, 3-155 months). Results: Out of 68 SLB-patients 41 (60.3%) had preoperatively undergone non-conclusive transbronchial biopsies (TBB) obtained with bronchoscopy. Spirometry showed forced vital capacity (FVC) 3.0 L and forced expiratory volume in 1 second (FEV1) 2.3 L, or 73.0% and 71.6% of predicted value, respectively. Video-assisted thoracoscopic surgery (VATS) technique was used in all cases and provided a histologic and disease specific diagnosis in 92.6% of cases; most often being nonspecific interstitial pneumonia (NSIP) (29.4%) and usual interstitial pneumonia (UIP) (23.5%). One patient (1.5%) sustained a major postoperative complication (excessive bleeding) and seven patients (10.3%) minor complications. Median chest tube time and length of stay was 1 and 2 days, respectively. No patients died <90 days postoperatively. Overall survival at 1 and 5 years was 95.6% and 73.5%, respectively, and 5-year survival for NSIP and UIP was 85% and 43.7%, respectively. Long-term mortality for UIP was four times higher when compared with NSIP and other diagnosis. Conclusions: Lung biopsy with VATS-technique provided a definitive histological and disease specific diagnosis in majority of cases. The procedure is safe, reflected in low complication-rates and short hospital stay, and can therefore be used to diagnose and tailor treatment of ILD patients.

NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients.

Hereditary cystatin C amyloid angiopathy is a dominantly inherited disease caused by a leucine to glutamine variant of human cystatin C (hCC). L68Q-hCC forms amyloid deposits in brain arteries associated with micro-infarcts, leading ultimately to paralysis, dementia and death in young adults. To evaluate the ability of molecules to interfere with aggregation of hCC while informing about cellular toxicity, we generated cells that produce and secrete WT and L68Q-hCC and have detected high-molecular weight complexes formed from the mutant protein. Incubations of either lysate or supernatant containing L68Q-hCC with reducing agents glutathione or N-acetyl-cysteine (NAC) breaks oligomers into monomers. Six L68Q-hCC carriers taking NAC had skin biopsies obtained to determine if hCC deposits were reduced following NAC treatment. Remarkably, ~50-90% reduction of L68Q-hCC staining was observed in five of the treated carriers suggesting that L68Q-hCC is a clinical target for reducing agents.

Pulmonary carcinoid tumours: incidence, histology, and surgical outcome. A population-based study.

BACKGROUND: Pulmonary carcinoids (PCs) represent only a minority of all primary pulmonary malignancies but they are the most common type of pulmonary malignancy diagnosed in children and adolescents. In this nationwide study, we analyzed data on all PC tumours in the Icelandic population over a 60-year period and concentrated especially on incidence and patient outcomes. METHODS: We studied all cases of PCs diagnosed in Iceland in the period 1955‒2015. Histological specimens were re-evaluated and the tumours were staged according to the TNM system (seventh edition). Survival was estimated using the Kaplan-Meier method, with a mean follow-up of 15.7 years. RESULTS: Altogether, 88 patients (median age 51.0 years, 65.9% women) were diagnosed with PCs in the study period. The incidence increased from 0.19/100,000/year in the first decade (1955‒1964) to 0.58/100,000/year in the last decade (2005‒2015), with a mean increase of 29.0% per decade of the study period (p < 0.001). The rise in incidental detection was, however, not significant. The median tumour diameter was 2.2 cm (range 0.4‒7.0) and typical histology was seen in 74 patients (84.1%). The other 14 patients (15.9%) had atypical histology. In all, 90.9% of the patients underwent pulmonary resection, 81.2% of them with lobectomy, with all of them surviving at least 30 days postoperatively. Most patients (n = 52, 62.7%) were stage IA at diagnosis, 15 (18.1%) were stage IB, nine (10.8%) were stage IIA, and three were stage IIIA (3.6%). Four patients (4.8%) had distant metastases (stage IV), two of whom had typical histology. Five-year survival was 89.8% for all patients: 93.2% for patients with typical histology and 70.7% for those with atypical histology. CONCLUSION: The incidence of PCs in Iceland has increased significantly over the last six decades, which cannot be explained by a rise in incidental detection at chest imaging. Most patients have localized disease and a favourable histology, where the long-term outcome is excellent.

Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.

Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are common conditions affecting the majority of elderly males. Here we report the results of a genome-wide association study of symptomatic BPH/LUTS in 20,621 patients and 280,541 controls of European ancestry, from Iceland and the UK. We discovered 23 genome-wide significant variants, located at 14 loci. There is little or no overlap between the BPH/LUTS variants and published prostate cancer risk variants. However, 15 of the variants reported here also associate with serum levels of prostate specific antigen (PSA) (at a Bonferroni corrected P < 0.0022). Furthermore, there is a strong genetic correlation, rg = 0.77 (P = 2.6 × 10-11), between PSA and BPH/LUTS, and one standard deviation increase in a polygenic risk score (PRS) for BPH/LUTS increases PSA levels by 12.9% (P = 1.6×10-55). These results shed a light on the genetic background of BPH/LUTS and its substantial influence on PSA levels.

Association of BRCA2 K3326* With Small Cell Lung Cancer and Squamous Cell Cancer of the Skin.

Background: Most pathogenic mutations in the BRCA2 gene carry a high risk of hereditary breast and ovarian cancer (HBOC). However, a stop-gain mutation, K3326* (rs11571833), confers risk of lung cancer and cancers of the upper-aero-digestive tract but only a modest risk of breast or ovarian cancer. The Icelandic population provides an opportunity for comprehensive characterization of the cancer risk profiles of K3326* and HBOC mutations because a single mutation, BRCA2 999del5, is responsible for almost all BRCA2-related HBOC in the population. Methods: Genotype information on 43 641 cancer patients and 370 971 control subjects from Iceland, the Netherlands, and the United States was used to assess the cancer risk profiles of K3326* and BRCA2 999del5. BRCA2 expression was assessed using RNAseq data from blood (n = 2233), as well as 52 tissues reported in the GTEx database. Results: The cancer risks associated with K3326* are fundamentally different from those associated with 999del5. We report for the first time an association between K3326* and small cell lung cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.35 to 3.16) and squamous cell carcinoma of the skin (OR = 1.69, 95% CI = 1.26 to 2.26). Individuals homozygous for K3326* reach old age and have children. Unlike BRCA2 999del5, the K3326* allele does not affect the level of BRCA2 transcripts, and the allele is expressed to the same extent as the wild-type allele. Conclusions: K3326* associates primarily with cancers that have strong environmental genotoxic risk factors. Expression of the K3326* allele suggests that a variant protein may be made that retains the DNA repair capabilities important to hormone-responsive tissues but may be less efficient in responding to genotoxic stress.

Primary adenocarcinoma of the lung--histological subtypes and outcome after surgery, using the IASLC/ATS/ERS classification of lung adenocarcinoma.

Adenocarcinoma is the most common histological type of lung carcinoma. Recently the histologic classification of adenocarcinomas in the lung was modified to better reflect biologic properties and prognosis. We reviewed the histology of all primary lung adenocarcinomas operated on in Iceland during a 20-year period and assessed the impact of histology on survival. This nationwide study included 285 patients (mean age 67 years, 57% female), who underwent resection in Iceland from 1991 to 2010. Tumors were reclassified according to the current IASLC/ATS/ERS classification system. Overall survival was estimated by the Kaplan-Meier method and Cox regression analysis used to evaluate prognostic factors of overall mortality. Acinar predominant adenocarcinoma was the most common histological subtype (46%) followed by solid-predominant (SPA) with mucin production comprised (23%). Non-invasive carcinomas were rare. A difference in survival between the histological adenocarcinoma subtypes was not seen (p = 0.32) and multivariate analysis showed that advanced stage and age predicted worse outcome, but histologic subtyping of adenocarcinoma did not. In this nation-wide study there was not a statistical difference in survival according to adenocarcinoma subtypes and the histological subtype did not predict mortality. Preinvasive and minimally invasive adenocarcinomas were rare.

[Outcome of surgical treatment for Pancoast lung carcinoma in Iceland]. / Árangur skurdmedfedar vid Pancoast-lungnakrabbameini á Íslandi.

OBJECTIVE: Pancoast tumors are lung carcinomas that invade the apical chest wall and surrounding structures. Treatment is complex and often involves surgery together with radio- and chemotherapy. We studied the outcome of surgical resection for Pancoast tumors in Iceland. MATERIALS AND METHODS: A retrospective study including all patients that underwent resection of a Pancoast tumor with curative intent in Iceland in the years 1991-2010. Data on symptoms, complications, TNM-stage, relapse and survival were analyzed. RESULTS: Twelve patients were operated on; 7 on the right lung. Shoulder pain (n=5) and/or chest pain (n=3), cough (n=6) and weight loss (n=5) were the most common presenting symptoms. Adenocarcinoma (n=5) and squamous cell carcinoma (n=4) were the most frequent histological types. Average tumor size was 5,9 cm (range: 2,8-15). Five cases were stage IIB and 7 stage IIIA according to operative staging. In 10 cases (83%) the surgical margins were free of tumor. All patients survived surgery and only one patient suffered a major operative complication, an intraoperative bleeding. In one case induction chemo-radiation prior to surgery was administrated, and 8 patients received postoperative radiotherapy. Recurrent disease was diagnosed in 9 patients; four had local or regional recurrence, four had distant metastases and one patient was diagnosed with both local and distant recurrences simultaneously. Survival at 5 years was 33% and median survival was 27,5 months (range: 4-181). CONCLUSIONS: Operative and short-term outcomes for patients with Pancoast tumors in Iceland are excellent. However, long-term outcomes are not as favorable and recurrence rate is high compared to other studies, possibly due to incomplete preoperative staging and less use of chemo-radiation therapy prior to surgery among these patients.

Parenchymal cystatin C focal deposits and glial scar formation around brain arteries in Hereditary Cystatin C Amyloid Angiopathy.

Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is an amyloid disorder in Icelandic families caused by an autosomal dominant mutation in the cystatin C gene. Mutant cystatin C forms amyloid deposits in brain arteries and arterioles which are associated with changes in the arterial wall structure, notably deposition of extracellular matrix proteins. In this post-mortem study we examined the neuroinflammatory response relative to the topographical distribution of cystatin C deposition, and associated haemorrhages, in the leptomeninges, cerebrum, cerebellum, thalamus, and midbrain of HCCAA patients. Cystatin C was deposited in all brain areas, grey and white matter alike, most prominently in arteries and arterioles; capillaries and veins were not, or minimally, affected. We also observed perivascular deposits and parenchymal focal deposits proximal to affected arteries. This study shows for the first time, that cystatin C does not exclusively form CAA and perivascular amyloid but also focal deposits in the brain parenchyma. Haemorrhages were observed in all patients and occurred in all brain areas, variable between patients. Microinfarcts were observed in 34.6% of patients. The neuroinflammatory response was limited to the close vicinity of affected arteries and perivascular as well as parenchymal focal deposits. Taken together with previously reported arterial accumulation of extracellular matrix proteins in HCCAA, our results indicate that the central nervous system pathology of HCCAA is characterised by the formation of a glial scar within and around affected arteries.

Familial risk of lung carcinoma in the Icelandic population.

CONTEXT: The dominant role of tobacco smoke as a causative factor in lung carcinoma is well established; however, an inherited predisposition may also be an important factor in the susceptibility to lung carcinoma. OBJECTIVE: To investigate the contribution of genetic factors to the risk of developing lung carcinoma in the Icelandic population. DESIGN, SETTING, AND PARTICIPANTS: Risk ratios (RRs) of lung carcinoma for first-, second-, and third-degree relatives of patients with lung carcinoma were estimated by linking records from the Icelandic Cancer Registry (ICR) of all 2756 patients diagnosed with lung carcinoma within the Icelandic population from January 1, 1955, to February 28, 2002, with an extensive genealogical database containing all living Icelanders and most of their ancestors since the settlement of Iceland. The RR for smoking was similarly estimated using a random population-based cohort of 10,541 smokers from the Reykjavik Heart Study who had smoked for more than 10 years. Of these smokers, 562 developed lung cancer based on the patients with lung cancer list from the ICR. MAIN OUTCOME MEASURES: Estimation of RRs of close and distant relatives of patients with lung carcinoma and comparison with RRs for close and distant relatives of smokers. RESULTS: A familial factor for lung carcinoma was shown to extend beyond the nuclear family, as evidenced by significantly increased RR for first-degree relatives (for parents: RR, 2.69; 95% confidence interval [CI], 2.20-3.23; for siblings: RR, 2.02; 95% CI, 1.77-2.23; and for children: RR, 1.96; 95% CI, 1.53-2.39), second-degree relatives (for uncles/aunts: RR, 1.34; 95% CI, 1.15-1.49; and for nephews/nieces: RR, 1.28; 95% CI, 1.10-1.43), and third-degree relatives (for cousins: RR, 1.14; 95% CI, 1.05-1.22) of patients with lung carcinoma. This effect was stronger for relatives of patients with early-onset disease (age at onset < or =60 years) (for parents: RR, 3.48; 95% CI, 1.83-8.21; for siblings: RR, 3.30; 95% CI, 2.19-4.58; and for children: RR, 2.84; 95% CI, 1.34-7.21). The hypothesis that this increased risk is solely due to the effects of smoking was rejected for all relationships, except cousins and spouses, with a single-sided test of the RRs for lung carcinoma vs RRs for smoking. CONCLUSIONS: These results underscore the importance of genetic predisposition in the development of lung carcinoma, with its strongest effect in patients with early-onset disease. However, tobacco smoke plays a dominant role in the pathogenesis of this disease, even among those individuals who are genetically predisposed to lung carcinoma.

Increased population use of medications for male lower urinary tract symptoms/benign prostatic hyperplasia correlates with changes in indications for transurethral resection of the prostate.

OBJECTIVE: The aim of this study was to determine whether there are correlations between medication use for lower urinary tract symptoms/benign prostate hypertrophy (LUTS/BPH) and alteration in incidence and indications for transurethral resection of the prostate (TURP). MATERIAL AND METHODS: The number of TURP patients between 1984 and 2008 in Iceland was obtained from hospital registries. The number of defined daily doses (DDDs) of 5-alpha-reductase inhibitors (5aRIs) and alpha-blockers (ABs) sold was obtained from the Icelandic Medicines Control Agency. Charts of all surgical BPH patients in Iceland from 1998 to 2008 were retrospectively reviewed. The main outcomes measures were: DDDs sold of 5aRIs and ABs, total numbers of TURP, indications for TURP and complications. RESULTS: After the introduction of ABs and 5aRIs, sales increased annually at a near linear rate. TURP rates peaked in 1992, then declined. In 2008, 81 and 3.4 of 1000 men over the age of 50 used LUTS/BPH medications or underwent TURP, respectively. There was an inverse correlation between LUTS/BPH medication use and (i) overall TURP (R(2) = 0.85), (ii) TURP done for absolute indications (R(2) = 0.91), and (iii) LUTS with (R(2) = 0.77) and (iv) without previous medical therapy (R(2) = 0.75). As medication use rose, fewer TURPs were performed for previous history of urinary retention, and more for recurrent urinary tract infections. CONCLUSION: Increased use of ABs and 5aRIs in the Icelandic population correlated with decreasing incidences of TURP procedures for both LUTS and absolute indications. The sequelae of BPH and indications for TURP are changing as medication use increases, although a clear causative link is hard to establish.

Deposition of collagen IV and aggrecan in leptomeningeal arteries of hereditary brain haemorrhage with amyloidosis.

Hereditary Cystatin C Amyloid Angiopathy (HCCAA) is a rare genetic disease in Icelandic families caused by a mutation in the cystatin C gene, CST3. HCCAA is classified as a cerebral amyloid angiopathy and mutant cystatin C forms amyloid deposits in cerebral arteries resulting in fatal haemorrhagic strokes in young adults. The aetiology of HCCAA pathology is not clear and there is, at present, no animal model of the disease. The aim of this study was to increase understanding of the cerebral vascular pathology of HCCAA patients with an emphasis on structural changes within the arterial wall of affected leptomeningeal arteries. Examination of post-mortem samples revealed extensive changes in the walls of affected arteries characterised by deposition of extracellular matrix constituents, notably collagen IV and the proteoglycan aggrecan. Other structural abnormalities were thickening of the laminin distribution, intimal thickening concomitant with a frayed elastic layer, and variable reduction in the integrity of endothelia. Our results show that excess deposition of extracellular matrix proteins in cerebral arteries of HCCAA is a prominent feature of the disease and may play an important role in its pathogenesis.

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.

We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.

Resection rate and outcome of pulmonary resections for non-small-cell lung cancer: a nationwide study from Iceland.

BACKGROUND: The proportion of patients with non-small-cell lung cancer (NSCLC) who undergo surgery with curative intent is one measure of effectiveness in treating lung cancer. To the best of our knowledge, surgical resection rate (SRR) for a whole nation has never been reported before. We studied the SRR and surgical outcome of NSCLC patients in Iceland during a recent 15-year period. METHODS: This was a retrospective study of all pulmonary resections performed with curative intent for NSCLC in Iceland from 1994 to 2008. Information was retrieved from medical records and from the Icelandic Cancer Registry. Patient demographics, postoperative tumor, node, metastasis stage, overall survival, and complication rates were compared over three 5-year periods. RESULTS: Of 1530 confirmed cases of NSCLC, 404 were resected, giving an SRR of 26.4%, which did not change significantly during the study period. Minor and major complication rates were 37.4% and 8.7%, respectively. Operative mortality rates were 0.7% for lobectomy, 3.3% for pneumonectomy, and 0% for lesser resection. Five-year survival after all procedures was 40.7% and improved from the first to the last 5-year period (34.8% versus 43.8%, p = 0.04). Five-year survival for stages I and II together was 46.8%, with no significant change in stage distribution between periods. Five-year survival after pneumonectomy was 22.0%, which was significantly lower than for lobectomy (44.6%) and lesser resection (40.7%) (p < 0.005). Unoperated patients had a 5-year survival of 4.8%, as compared to 12.4% for all the NSCLC patients together. CONCLUSION: Compared with most other published studies, the SRR of NSCLC in Iceland is high. Short-term outcome is good, with a low rate of major complications and an operative mortality of only 1.0%. Five-year survival improved significantly over the study period.

[Sublobar resection for non-small cell lung cancer in Iceland]. / Arangur fleyg- og geiraskurda vid lungnakrabbbameini á Islandi.

INTRODUCTION: A sublobar resection is performed on patients with non-small cell lung cancer (NSCLC) who are not candidates for a lobectomy due to reduced pulmonary function or comorbid disease. The aim of this study was to investigate the outcomes of these operations in Iceland. MATERIAL AND METHODS: A retrospective study of all patients with NSCLC who underwent wedge resection or segmentectomy with curative intent during 1994-2008. Data on indication, pathological TNM-stage, complications and overall survival was analyzed. All histological samples were re-evaluated. RESULTS: Forty four patients underwent 42 wedge and 5 segmental resections (age 69.1 yrs, 55.3% female), with 38.3% of cases detected incidentally. The majority of patients (55.3%) had a history of coronary artery disease and 40.4% had chronic obstructive pulmonary disease. Mean operative time was 83 minutes (range 30-131), mean intraoperative bleeding was 260 ml (range 100-650) and median hospital stay was 9 days (range 4-24). Pneumonia (14.9%) and prolonged air leakage (12.8%) were the most common complications. Two patients had major complications and 36.2% stayed in the intensive care unit overnight. No deaths occurred within 30 days of surgery. Adenocarcinoma was the most common histological type (66.7%). Most cases were stage IA/IB (78.7%), 17.0% were stage IIA/IIB and 4.3% were stage IIIA. One and 5 year survival was 85.1% and 40.9% respectively. CONCLUSION: In Iceland, both survival and complication rate after sublobar resection for NSCLC are comparable to results published for lobectomies, even though a higher percentage of patients have underlying cardiopulmonary disease.

Genome-wide significant association between a sequence variant at 15q15.2 and lung cancer risk.

Genome-wide association studies (GWAS) have identified 3 genomic regions, at 15q24-25.1, 5p15.33, and 6p21.33, which associate with the risk of lung cancer. Large meta-analyses of GWA data have failed to find additional associations of genome-wide significance. In this study, we sought to confirm 7 variants with suggestive association to lung cancer (P < 10(-5)) in a recently published meta-analysis. In a GWA dataset of 1,447 lung cancer cases and 36,256 controls in Iceland, 3 correlated variants on 15q15.2 (rs504417, rs11853991, and rs748404) showed a significant association with lung cancer, whereas rs4254535 on 2p14, rs1530057 on 3p24.1, rs6438347 on 3q13.31, and rs1926203 on 10q23.31 did not. The most significant variant, rs748404, was genotyped in an additional 1,299 lung cancer cases and 4,102 controls from the Netherlands, Spain, and the United States and the results combined with published GWAS data. In this analysis, the T allele of rs748404 reached genome-wide significance (OR = 1.15, P = 1.1 × 10(-9)). Another variant at the same locus, rs12050604, showed association with lung cancer (OR = 1.09, 3.6 × 10(-6)) and remained significant after adjustment for rs748404 and vice versa. rs748404 is located 140 kb centromeric of the TP53BP1 gene that has been implicated in lung cancer risk. Two fully correlated, nonsynonymous coding variants in TP53BP1, rs2602141 (Q1136K) and rs560191 (E353D) showed association with lung cancer in our sample set; however, this association did not remain significant after adjustment for rs748404. Our data show that 1 or more lung cancer risk variants of genome-wide significance and distinct from the coding variants in TP53BP1 are located at 15q15.2.