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Abstract: A single founder mutation in each of the BRCA genes has been identified in Iceland. The frequency of the BRCA1 G5193A and BRCA2 999del5 mutations in all ovarian cancer patients diagnosed over the period 1991–2000 was determined. Mutation status was correlated with family history, tumour morphology and age at diagnosis. Samples from 86% of cases (179 carcinomas and 74 borderline tumours) were available. In the carcinomas, BRCA1 and BRCA2 mutations were present in 1.2% and 6% of cases, respectively. No BRCA mutations were found in the borderline tumours. Odds Ratio (OR) of developing ovarian cancer was 20.65 for BRCA2 carriers. Family history of breast/ovarian cancer was present for 70% of BRCA2 carriers and approximately 14% for non-carriers with carcinoma. In conclusion, BRCA2 999del5 is present in 6% of ovarian cancer cases in Iceland and is associated with a 20-fold increase in the risk of the disease. The BRCA1 G5193A mutation is too rare to contribute significantly to ovarian cancer in Iceland. [Copyright &y& Elsevier]

: ObjectiveCervical cancer is a disease caused in part by an infection with an oncogenic subtype of human papillomavirus (HPV). In this study we analysed all cervical cancer samples diagnosed in Iceland during two periods, 1958–1960 and 1995–1996, and asked whether significant changes in viral or immunological parameters had occurred over a period that spanned both significant changes in sexual attitude and the implementation of organized screening for cervical cancer.: MethodsSamples from 47 patients (46 squamous cell carcinomas (SCC) and 1 adenosquamous carcinoma (ASC)) in the first period and 30 patients (20 SCC, 4 ASC, and 6 adenocarcinomas (AC)) in the later period were analysed for viral subtype and expression of Fas, FasL, MHC class I, p53 and apoptosis.: ResultsAC and ASC are proportionately much more common today than 40 years ago (30% vs 2%). The distribution of HPV in cervical cancer is similar in both periods, with HPV16 found in 75% and HPV18 in 13% of cases. Other HPV types found were 31,33,45, and 59. No significant differences were found in the immunological profiles of tumors from the two periods except that a higher fraction of SCC in the later period stained positive for FasL. When SCC are compared with AC/ASC, the latter have less expression of MHC class I, less expression of Fas, and stronger FasL expression.: ConclusionAC/ASC tumors show some immunological features that suggest that they are more resistant to immune attack than SCC. [Copyright &y& Elsevier]

We report a middle aged smoker with recurrent pneumonia caused by endobronchial actinomycosis secondary to a tooth aspiration. Unlike previously reported cases, our patient was not chronically debilitated. The case suggests that a follow-up bronchoscopy is beneficial after the initiation of antibiotic therapy for endobronchial actinomycosis. [ABSTRACT FROM AUTHOR]

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; Pcombined = 6.2 × 10?34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r2 ? 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. [ABSTRACT FROM AUTHOR]

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10?17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10?20). rs78378222 is in the 3? untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3?-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10?6), glioma (OR = 2.35, P = 1.0 × 10?5) and colorectal adenoma (OR = 1.39, P = 1.6 × 10?4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27). [ABSTRACT FROM AUTHOR]

Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five—one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes—have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site. [ABSTRACT FROM AUTHOR]

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 × 10−10) on 3q21.3; two moderately correlated (r2 = 0.07) variants, rs16902094[G] (OR = 1.21, P = 6.2 × 10−15) and rs445114[T] (OR = 1.14, P = 4.7 × 10−10), on 8q24.21; and rs8102476[C] (OR = 1.12, P = 1.6 × 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 × 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. [ABSTRACT FROM AUTHOR]

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 × 10−9). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 × 10−9), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 × 10−10). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma. [ABSTRACT FROM AUTHOR]

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 × 10−12) and rs801114 on 1q42 (OR = 1.28, P = 5.9 × 10−12). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers. [ABSTRACT FROM AUTHOR]

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 × 10−9) and BCC (OR = 1.33, P = 1.2 × 10−6). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 × 10−7) and BCC (OR = 1.14, P = 6.1 × 10−4). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.6 × 10−4). The association of all three variants is robust with respect to adjustment for the effect of pigmentation. [ABSTRACT FROM AUTHOR]

Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions—four not previously implicated in the normal variation of human pigmentation—and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R. [ABSTRACT FROM AUTHOR]

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1β), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes. [ABSTRACT FROM AUTHOR]

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 (∼42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis. [ABSTRACT FROM AUTHOR]

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 × 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 ∼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. [ABSTRACT FROM AUTHOR]

Objective: To investigate quantitative aberrations involving p53 copy numbers in eutopic endometrial and endometriotic tissue from two populations. Design: Comparative analysis of normal and diseased tissue. Setting: Tissue specimens collected in Iceland and USA. Patient(s): Subjects with moderate/severe endometriosis (Iceland, n = 26; USA, n = 45). Paraffin-embedded tissue from 19 matched Icelandic cases and seven unaffected controls. American cases were fresh surgical tissue from 17 matched cases and 28 unaffected controls. DNA isolation and real-time polymerase chain reaction (PCR) with TaqMan assay were performed. Main Outcome Measure(s): The frequency of p53 loss and/or gain based on quantitative differences for copy numbers of p53 located on chromosome (17p) and GAPDH on a control locus (chromosome 12p). Result(s): Among American cases, significant p53 gain (n = 13) or loss (n = 4) was observed in 17 of 21 cases. In Icelandic cases this was not seen to the same degree. Mean normalized p53 values were 3.46 and 1.16 copies per reaction, respectively. Significant differences were observed between normalized p53 in the control blood and affected tissue for the American and Icelandic cases compared to standard GAPDH control but not in normal Icelandic and American endometrium. Conclusion(s): The results continue to support a role for nonrandom somatic p53 locus alterations in the pathogenesis of late or severe-stage endometriosis. Differences between Icelandic and American subjects have implications for generalization of genome-wide approaches. [Copyright &y& Elsevier]

We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R. [ABSTRACT FROM AUTHOR]

We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 × 10−13 and 7.7 × 10−9, respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease. [ABSTRACT FROM AUTHOR]

A correction to the article "ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma," that was published in the May 18, 2008 issue is presented.