Kristin Alexiusdottir

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10−12 for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer

Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 × 10−12). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.

Ancestry-shift refinement mapping of the C6orf97-ESR1 breast cancer susceptibility locus.

We used an approach that we term ancestry-shift refinement mapping to investigate an association, originally discovered in a GWAS of a Chinese population, between rs2046210[T] and breast cancer susceptibility. The locus is on 6q25.1 in proximity to the C6orf97 and estrogen receptor α (ESR1) genes. We identified a panel of SNPs that are correlated with rs2046210 in Chinese, but not necessarily so in other ancestral populations, and genotyped them in breast cancer case∶control samples of Asian, European, and African origin, a total of 10,176 cases and 13,286 controls. We found that rs2046210[T] does not confer substantial risk of breast cancer in Europeans and Africans (OR = 1.04, P = 0.099, and OR = 0.98, P = 0.77, respectively). Rather, in those ancestries, an association signal arises from a group of less common SNPs typified by rs9397435. The rs9397435[G] allele was found to confer risk of breast cancer in European (OR = 1.15, P = 1.2×10−3), African (OR = 1.35, P = 0.014), and Asian (OR = 1.23, P = 2.9×10−4) population samples. Combined over all ancestries, the OR was 1.19 (P = 3.9×10−7), was without significant heterogeneity between ancestries (Phet = 0.36) and the SNP fully accounted for the association signal in each ancestry. Haplotypes bearing rs9397435[G] are well tagged by rs2046210[T] only in Asians. The rs9397435[G] allele showed associations with both estrogen receptor positive and estrogen receptor negative breast cancer. Using early-draft data from the 1,000 Genomes project, we found that the risk allele of a novel SNP (rs77275268), which is closely correlated with rs9397435, disrupts a partially methylated CpG sequence within a known CTCF binding site. These studies demonstrate that shifting the analysis among ancestral populations can provide valuable resolution in association mapping.

Loss-of-function variants in ATM confer risk of gastric cancer

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10−12; odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.

Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

Oestrogen receptor status, treatment and breast cancer prognosis in Icelandic BRCA2 mutation carriers.

Background:The impact of an inherited BRCA2 mutation on the prognosis of women with breast cancer has not been well documented. We studied the effects of oestrogen receptor (ER) status, other prognostic factors and treatments on survival in a large cohort of BRCA2 mutation carriers.Methods:We identified 285 breast cancer patients with a 999del5 BRCA2 mutation and matched them with 570 non-carrier patients. Clinical information was abstracted from patient charts and pathology records and supplemented by evaluation of tumour grade and ER status using archived tissue specimens. Univariate and multivariate hazard ratios (HR) were estimated for breast cancer-specific survival using Cox regression. The effects of various therapies were studied in patients treated from 1980 to 2012.Results:Among mutation carriers, positive ER status was associated with higher risk of death than negative ER status (HR=1.94; 95% CI=1.22–3.07, P=0.005). The reverse association was seen for non-carriers (HR=0.71; 95% CI: 0.51–0.97; P=0.03).Conclusions:Among BRCA2 carriers, ER-positive status is an adverse prognostic factor. BRCA2 carrier status should be known at the time when treatment decisions are made.

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.

[Epidemiology of the two types of gastric adenocarcinoma in Iceland according to the Laurén histological classification 1990-2009].

BACKGROUND In the mid twentieth century gastric cancer was the most common type of cancer in Iceland. In recent decades, however, the incidence rate of gastric cancer has decreased markedly and currently only represents 2-3% of cancer cases. The Laurén classification system classifies adenocarcinoma into two types, intestinal and diffuse. The main purpose of our study was to describe the epidemiology of the two types of gastric adenocarcinoma in Iceland between the years 1990-2009. METHODS This is a retrospective cohort study. Information on patients diagnosed with gastric cancer in Iceland between 1990 and 2009 was collected from the population based Cancer Registry. Histological descriptions were reviewed and classified according to the Laurén classification system. The records of patients diagnosed with either having intestinal or diffuse adenocarcinomas were reviewed and epidemiological information gathered. RESULTS Between 1990 and 2009, 730 patients were diagnosed with gastric adenocarcinoma in Iceland, 447 had intestinal adenocarcinoma and 168 diffuse adenocarcinoma. Patients diagnosed with diffuse adenocarcinoma were significantly younger at diagnosis than those diagnosed with intestinal adenocarcinoma. The sex ratio for intestinal adenocarcinoma was 2.3:1 (M:F) and 1.1:1 (M:F) for diffuse adenocarcinoma. The incidence of intestinal adenocarcinoma decreased more rapidly than that of diffuse adenocarcinoma during this period (0.92/100,000 vs. 0.12/100,000). Median survival rates of intestinal and diffuse adenocarcinomas were 23.7 and 20.6 months, respectively. The difference in survival was found to be statistically significant. The hazard ratio between the two groups was 1.31 (CI 1.03-1.67), corrected for age, sex, stage, year of diagnosis and surgical outcome (radical, non-radical or no operation). CONCLUSION The overall incidence rate of gastric cancer has decreased dramatically in the past 20 years. However, the reduction is largely limited to the intestinal adenocarcinoma sub-group. We conclude that the Laurén classification predicts prognosis in gastric adenocarcinoma with diffuse adenocarcinoma having worse prognosis. KEY WORDS gastric cancer, Laurén classification, survival, incidence. Correspondence: Halla Sif Olafsdottir, hsolafsdottir@gmail.com.

A Genetic Polymorphism in CTLA-4 Is Associated with Overall Survival in Sunitinib-Treated Patients with Clear Cell Metastatic Renal Cell Carcinoma

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI. Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis. Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72–0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54–0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72–0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found. Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350–6. ©2018 AACR.