Occupation as a risk factor for renal cell cancer: a nationwide, prospective epidemiological study.

Objective Using centralized registries in Iceland, the aim of this study was to prospectively investigate multiple risk factors for renal cell carcinoma (RCC), including occupational history. Materials and methods From the Reykjavik study database, 18,840 men and women born in the period 1907-1935 were linked with a population-based registry containing all RCCs diagnosed in Iceland from 1971 to 2005 (n = 910). From this cross-reference, altogether 225 cases were identified. A prospective analysis of the risk factors for RCC was performed using Cox regression analysis, from the time of entry into the Reykjavik study to the diagnosis of RCC, death or end of follow-up, with a median follow-up time of 25 years. The hazard ratio (HR) was then calculated for multiple risk factors including occupational history. Results Male gender [HR 1.65, 95% confidence interval (CI) 1.14-2.38], body mass index (BMI) over 25 kg/m² (HR 1.41, 95% CI 1.06-1.88) and age (HR 1.04, 95% CI 1.03-1.07) increased the risk of RCC, as did severe hypertension (>160/100 mmHg) (HR 1.46, 95% CI 1.05-2.03) and history of kidney disease (HR 1.55, 95% CI 1.11-2.16); however, smoking and type 2 diabetes were not significantly associated with the disease. The risk of RCC was significantly increased in painters (HR 2.97, 95% CI 1.31-6.74), aircraft mechanics (HR 4.51, 95% CI 1.11-18.28) and shipbuilders (HR 2.03, 95% CI 1.06-3.84). Conclusions Together with male gender, advanced age, hypertension, BMI over 25 kg/m² and history of kidney disease, the risk of RCC was significantly increased in painters, aircraft mechanics and shipbuilders, suggesting a link to occupational exposure.

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).

The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study.

BACKGROUND: The observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry. METHODS: Retrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival. RESULTS: The probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM. CONCLUSION: Tumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.

A common variant at 8q24.21 is associated with renal cell cancer.

Renal cell carcinoma (RCC) represents between 80 and 90% of kidney cancers. Previous genome-wide association studies of RCC have identified five variants conferring risk of the disease. Here we report the results from a discovery RCC genome-wide association study and replication analysis, including a total of 2,411 patients and 71,497 controls. One variant, rs35252396[CG] located at 8q24.21, is significantly associated with RCC after combining discovery and replication results (OR=1.27, P(combined)=5.4 × 10(-11)) and has an average risk allele frequency in controls of 46%. rs35252396[CG] does not have any strongly correlated variants in the genome and is located within a region predicted to have regulatory functions in several cell lines, including six originating from the kidney. This is the first RCC variant reported at 8q24.21 and it is largely independent (r(2)≤0.02) of the numerous previously reported cancer risk variants at this locus.

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer.

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 × 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Chromophobe renal cell carcinoma in Iceland: an epidemiological and clinicopathological study.

OBJECTIVE: Numerous studies have suggested that the rare chromophobe renal cell carcinoma (CRCC) has a more favourable prognosis than the other more common subtypes of RCC, clear cell RCC (CCRCC) and papillary RCC (PRCC). These studies have, however, usually involved selected patient cohorts and not whole populations. This study compared CRCC patients with patients with the other two major histological subtypes and established a population-based age-standardized incidence rate (ASR). MATERIAL AND METHODS: Of 828 histopathologically confirmed RCCs diagnosed between 1971 and 2005 in Iceland, 15 CRCC cases were identified. Histological material was reviewed, the TNM system was used for staging and cancer-specific survival was estimated. Univariate and multivariate analysis was used to compare CRCC to both CCRCC (n = 740) and PRCC (n = 66). Mean follow-up was 6.7 years. RESULTS: CRCC accounted for 1.8% of RCCs, the ASR being 0.17/100,000 per year. Compared to other subtypes, CRCC was detected incidentally less often (7% vs 29%, p = 0.02), but was more often diagnosed at lower stages (73% vs 45% at stage I + II, p < 0.001). One patient had synchronous metastasis and another developed recurrent CRCC; both died of CRCC. Five-year survival for CRCC, CCRCC and PRCC was 86%, 59% and 50%, respectively (p = 0.004). After correcting for TNM stage (odds ratio 1.98), multivariate analysis did not indicate that CRCC subtype was an independent predictive factor for survival. CONCLUSION: CRCC is a rare neoplasm with an ASR of 0.17/100,000 per year. These tumours often present with symptoms despite being at lower stages than the other RCC subtypes. The more favourable survival of the CRCC subtype appears to be explained by these tumours being diagnosed at low stages. These findings may suggest that CRCC has a different biological behaviour.

Genetic correction of PSA values using sequence variants associated with PSA levels.

Measuring serum levels of the prostate-specific antigen (PSA) is the most common screening method for prostate cancer. However, PSA levels are affected by a number of factors apart from neoplasia. Notably, around 40% of the variability of PSA levels in the general population is accounted for by inherited factors, suggesting that it may be possible to improve both sensitivity and specificity by adjusting test results for genetic effects. To search for sequence variants that associate with PSA levels, we performed a genome-wide association study and follow-up analysis using PSA information from 15,757 Icelandic and 454 British men not diagnosed with prostate cancer. Overall, we detected a genome-wide significant association between PSA levels and single-nucleotide polymorphisms (SNPs) at six loci: 5p15.33 (rs2736098), 10q11 (rs10993994), 10q26 (rs10788160), 12q24 (rs11067228), 17q12 (rs4430796), and 19q13.33 [rs17632542 (KLK3: I179T)], each with P(combined) <3 × 10(-10). Among 3834 men who underwent a biopsy of the prostate, the 10q26, 12q24, and 19q13.33 alleles that associate with high PSA levels are associated with higher probability of a negative biopsy (odds ratio between 1.15 and 1.27). Assessment of association between the six loci and prostate cancer risk in 5325 cases and 41,417 controls from Iceland, the Netherlands, Spain, Romania, and the United States showed that the SNPs at 10q26 and 12q24 were exclusively associated with PSA levels, whereas the other four loci also were associated with prostate cancer risk. We propose that a personalized PSA cutoff value, based on genotype, should be used when deciding to perform a prostate biopsy.

Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility.

We report a prostate cancer genome-wide association follow-on study. We discovered four variants associated with susceptibility to prostate cancer in several European populations: rs10934853[A] (OR = 1.12, P = 2.9 x 10(-10)) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 x 10(-15)) and rs445114[T] (OR = 1.14, P = 4.7 x 10(-10)), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 x 10(-11)) on 19q13.2. We also refined a previous association signal on 11q13 with the SNP rs11228565[A] (OR = 1.23, P = 6.7 x 10(-12)). In a multivariate analysis using 22 prostate cancer risk variants typed in the Icelandic population, we estimated that carriers in the top 1.3% of the risk distribution are at a 2.5 times greater risk of developing the disease than members of the general population.

Simultaneous bilateral spontaneous pneumothorax in metastatic testicular cancer.

Simultaneous bilateral spontaneous pneumothorax (SBSP) is a very rare condition, mainly detected in patients with underlying pulmonary disease. This study reports a case of SBSP following chemotherapy for metastatic testicular cancer.

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

[Pulmonary resections for metastatic renal cell carcinoma in Iceland]. / Skurdadgerdir vegna lungnameinvarpa frá nýrnafrumukrabbameini á Islandi.

OBJECTIVE: At the time of diagnosis, approximately 20% of renal cell carcinoma (RCC) patients have pulmonary metastasis. These patients have poor survival with less than 10% of the patients being alive 5 years after diagnosis. However, recent studies have reported 30-49% 5-year survival in selected patients that underwent pulmonary resection for RCC metastases. The aim of this study was to analyse the outcome of this patient group in Iceland over a 23 year period. MATERIALS AND METHODS: This is a retrospective population-based study including all patients in Iceland that underwent pulmonary resection for RCC metastasis between 1984 and 2006. Complications were tabulated and the histology of all tumors reviewed by a pathologist. The renal tumors were classified and staged according to the TNM staging system (WHO). Crude survival was calculated using 1st of March 2007 as an endpoint, with mean follow up of 82 months. RESULTS: A total of 14 patients were identified, 10 males and 4 females with an average age of 59 years (range 45-78). One patient had pulmonary metastases at the diagnosis of RCC. In the other patients, metastasectomy was performed on average 39 months after the nephrectomy (range 1-132 months). Most of these patients (n=11) had a single metastasis, with an average size of 27 mm (range 8-50). Lobectomy was the most common procedure (n=7), wedge resection and pulmectomy were performed in three cases each, and one patient underwent both lobectomy and wedge resection. There were no major surgical complications. and all patients survived surgery. Today, four of the 14 patients (29%) are alive with 2- and 5-year survival of 64% and 29%, respectively. CONCLUSION: In this retrospective study, every third patient survived five years after pulmonary resection of RCC metastases. This is a favorable survival-rate when compared to patients with metastases not operated on (9.8% survival). These operations seem to be safe and complications are most often minor. It should be kept in mind, however, that a selected cohort was studied and a well defined control group was absent.

[Renal cell carcinoma diagnosed at autopsy in Iceland 1971-2005]. / Nýrnafrumukrabbamein greind vid krufningu á Islandi 1971-2005: Samanburdur vid aexli greind í sjúklingum á lífi.

INTRODUCTION: The incidence of renal cell carcinoma (RCC) is rising in Iceland. This has been attributed to increased diagnostic activity, such as abdominal imaging of unrelated diseases, rather than changes in the behavior of the disease. The aim of this study was to compare RCCs diagnosed in living patients and at autopsy, but also to investigate the relationship between the incidence of RCC and autopsy findings. MATERIAL AND METHODS: RCC found incidentally in individuals at autopsy was compared to patients diagnosed alive over three decades in Iceland (1971-2005). Stage at diagnosis and tumor histology was reviewed. RESULTS: 110 tumors were diagnosed at autopsy with a rate of 7.1/1000 autopsies. When compared to patients diagnosed alive (n = 913) the mean age at diagnosis was higher in the autopsy group (74.4 vs. 65 yrs.) while male to female ratio and laterality was similar. Tumors found at autopsy were smaller (3.7 vs. 7.3 cm), at lower stage (88% at stage I+II vs. 42%) and at lower tumor grade (85% at grade I+II vs. 56%). A difference, although smaller, is present when the autopsy detected cases are compared to only incidentally detected RCCs in living patients. Furthermore the autopsy detected tumors were more frequently of papillary cell type (21% vs. 8%). After correcting for declining autospy rate (>50%), a slight trend for a reduced rate of autopsy dectected RCC cases was seen during the last 10 years of the period but the difference was not significant. CONCLUSION: RCCs diagnosed at autopsy are at a lower stage and tumor grade than in patients diagnosed alive. The autopsy-rate is declining in Iceland with fewer RCCs found per autopsy. After correcting for the decline in autopsy rate, the rate of RCC detected at autopsy is relatively unchanged. The increase in incidence of RCC is therefore not explained by findings at autopsy.

Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

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.

Effect of incidental detection for survival of patients with renal cell carcinoma: results of population-based study of 701 patients.

OBJECTIVES: To conduct a population-based study to evaluate the effect of incidental detection of renal cell carcinoma (RCC) on survival. Incidental detection of RCC has increased significantly in recent years because of widespread use of abdominal imaging. The patients with incidentally diagnosed RCC have better survival; however, because of possible "lead time" bias and stage migration, the real implications of incidental detection on survival have been a matter of debate. METHODS: All living patients diagnosed with RCC in Iceland between 1971 and 2000 were included (n = 701). The histologic findings were verified, the stage (extent) of the disease was determined, and the incidence, mortality, and survival were evaluated. RESULTS: The strongest predictors of mortality were stage and nuclear grade. After correcting for these factors in the multivariate analysis, incidental diagnosis, histologic subtype, and gender lost their significance as independent prognostic factors of death. However, the incidentally diagnosed tumors were 2.3 cm smaller on average and at a lower stage and grade than symptomatic tumors, with significantly better patient survival than those with symptomatic tumors on univariate analysis (76% versus 44% 5-year disease-specific survival). An increased incidence of RCC was only seen in men, but incidental detection increased threefold during the study period in both sexes, with significant improvement in survival for the whole group as a result. CONCLUSIONS: The increased frequency of incidental detection has improved the survival of patients with RCC in Iceland. Incidental detection was not an independent prognostic factor of death, indicating that these tumors are of a similar biologic nature as symptomatic RCCs, only diagnosed earlier.

Renal oncocytoma: a clinicopathological analysis of 45 consecutive cases.

OBJECTIVE: To evaluate the clinical behaviour and pathology of renal oncocytoma in a well-defined population over a 30-year period. PATIENTS AND METHODS: In a retrospective population-based study we assessed relevant clinical and pathological factors in 45 patients (31 men and 14 women) diagnosed with renal oncocytoma in Iceland between 1971 and 2000. Clinical presentation, pathology, survival and causes of death were evaluated. RESULTS: The age-standardized incidence was 0.3 per 100,000 per year for both men and women, the incidence of oncocytomas being 5.5% of renal cell carcinomas (RCCs) diagnosed during the same period in Iceland. Fourteen patients were diagnosed at autopsy for an unrelated disease. Of 31 living patients (mean age 70.5 years), seven were diagnosed incidentally (23%), and the others had presented with haematuria (32%), abdominal pain (29%), and weight loss (10%). All the patients had a radical nephrectomy, except for one with bilateral oncocytoma who had a partial nephrectomy. The mean (range) tumour size was 5.7 (0.9-12) cm. Eighteen patients (58%) were diagnosed at Tumour-Node-Metastasis stage I, 10 at stage II (32%) and three at stage III (10%), all of those at stage III having renal capsular penetration or tumour invasion into perirenal fat tissue (T3aN0M0). No patients were diagnosed with lymph node or distant metastasis. Two cases of coexisting RCC were detected. After a median follow-up of 8.3 years there were no recurrences or deaths from oncocytoma (100% disease-specific survival). The overall 5-year survival was 63%, with most patients dying from cardiovascular diseases or nonrenal cancers. CONCLUSIONS: In most cases renal oncocytoma behaves like a benign tumour; the long-term prognosis is excellent. Thus, in the present patients, radical nephrectomy could be regarded as an over-treatment and nephron-sparing surgery as more appropriate, especially in patients with small tumours. However, both coexisting RCC and perirenal fat invasion, a hallmark of malignant behaviour, might indicate that more radical surgery is warranted in some of these patients.

Histological subtyping and nuclear grading of renal cell carcinoma and their implications for survival: a retrospective nation-wide study of 629 patients.

OBJECTS: The aim of this study was to evaluate the prognostic significance of the current WHO histological subtyping and Fuhrman nuclear grading on the survival of patients with renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective population-based study was carried out on all patients with a histopathologically confirmed diagnosis of RCC in Iceland between 1971 and 2000. Fuhrman grade, TNM stage, and survival were evaluated and multivariate analysis applied in order to determine prognostic factors. RESULTS: Out of 629 patients (387 males, 242 females, mean age 64 years), 558 (88.7%) had clear cell, 53 (8.4%) papillary, and 13 (2.1%) chromophobe RCC. Patient demographics were comparable for the two major subtypes, but chromophobe RCCs were larger in size and were diagnosed at a younger age. Clear cell RCCs were more often of higher grades (G3+G4, 48.4%) and at advanced TNM stages (III+IV, 59.3%) than papillary RCCs (22.6% and 34% respectively, p<0.001). Linear regression analysis showed a strong correlation between grade, tumor size, and stage (p<0.001). Chromophobe RCCs had a better survival in univariate analysis than both papillary and clear cell RCCs (84.6% vs. 66.5% and 54.9% 5-year disease specific survival, p<0.001). However, in the multivariate analysis, only the patient's age, calendar year of diagnosis, TNM stage, and nuclear grade were independent prognostic factors of survival. CONCLUSION: In this complete nation-wide series nuclear grading is important in predicting survival of patients with RCC. It is strongly related to both tumor size and stage, with stage being by far the strongest prognostic factor. Different histological subtypes confer different survival. However, in spite of the distinctive cytogenetic and molecular characteristics of the subtypes, the survival difference is to a large extent due to differences in grade and particularly stage.

A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas.

The etiology of RCC is incompletely understood and the inherited genetic contribution uncertain. Although there are rare mendelian forms of RCC stemming from inherited mutations, most cases are thought to be sporadic. We sought to determine the extent of familial aggregation among Icelandic RCC patients in general. Medical and pathologic records for all patients diagnosed with RCC in Iceland between 1955 and 1999 were reviewed. This included a total of 1,078 RCC cases, 660 males and 418 females. With the use of an extensive computerized database containing genealogic information on 630,000 people in Iceland during the past 11 centuries, several analyses were conducted to determine whether the patients were more related to each other than members drawn at random from the population. Patients with RCC were significantly more related to each other than were subjects in matched groups of controls. This relatedness extended beyond the nuclear family. RRs were significantly greater than 1.0 for siblings, parents and cousins of probands. RRs were 2-3 for first-degree relatives and 1.6 for third-degree relatives. The risk of RCC is significantly higher for members of the extended family of an affected individual, as well as the nuclear family. Our results indicate that germline mutations are significantly involved in what has been defined as sporadic RCC.

[Two cases of spontaneous regression of metastasis secondary to renal cell carcinoma.].

Spontaneous regression of metastatic renal cell carcinoma is a rare but well documented event, most often involving pulmonary metastasis. Two cases involving brain and pleural metastasis are presented. In both cases nephrectomy was the only treatment.