A coding IRAK2 protein variant compromises Toll-like receptor (TLR) signaling and is associated with colorectal cancer survival.

Within innate immune signaling pathways, interleukin-1 receptor-associated kinases (IRAKs) fulfill key roles downstream of multiple Toll-like receptors and the interleukin-1 receptor. Although human IRAK4 deficiency was shown to lead to severe immunodeficiency in response to pyogenic bacterial infection during childhood, little is known about the role of human IRAK2. We here identified a non-synonymous IRAK2 variant, rs35060588 (coding R214G), as hypofunctional in terms of NF-κB signaling and Toll-like receptor-mediated cytokine induction. This was due to reduced ubiquitination of TRAF6, a key step in signal transduction. IRAK2 rs35060588 occurs in 3-9% of individuals in different ethnic groups, and our studies suggested a genetic association of rs35060588 with colorectal cancer survival. This for the first time implicates human IRAK2 in a human disease and highlights the R214G IRAK2 variant as a potential novel and broadly applicable biomarker for disease or as a therapeutic intervention point.

Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors.

PURPOSE: The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations. METHODS: After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive Allele-Specific PCR™ genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases). RESULTS: In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively). CONCLUSION: Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.

Functional TLR5 genetic variants affect human colorectal cancer survival.

Toll-like receptors (TLR) are overexpressed on many types of cancer cells, including colorectal cancer cells, but little is known about the functional relevance of these immune regulatory molecules in malignant settings. Here, we report frequent single-nucleotide polymorphisms (SNP) in the flagellin receptor TLR5 and the TLR downstream effector molecules MyD88 and TIRAP that are associated with altered survival in a large cohort of Caucasian patients with colorectal cancer (n = 613). MYD88 rs4988453, a SNP that maps to a promoter region shared with the acetyl coenzyme-A acyl-transferase-1 (ACAA1), was associated with decreased survival of patients with colorectal cancer and altered transcriptional activity of the proximal genes. In the TLR5 gene, rs5744174/F616L was associated with increased survival, whereas rs2072493/N592S was associated with decreased survival. Both rs2072493/N592S and rs5744174/F616L modulated TLR5 signaling in response to flagellin or to different commensal and pathogenic intestinal bacteria. Notably, we observed a reduction in flagellin-induced p38 phosphorylation, CD62L shedding, and elevated expression of interleukin (IL)-6 and IL-1ß mRNA in human primary immune cells from TLR5 616LL homozygote carriers, as compared with 616FF carriers. This finding suggested that the well-documented effect of cytokines like IL-6 on colorectal cancer progression might be mediated by TLR5 genotype-dependent flagellin sensing. Our results establish an important link between TLR signaling and human colorectal cancer with relevance for biomarker and therapy development.

Genetic variants in C-type lectin genes are associated with colorectal cancer susceptibility and clinical outcome.

Inflammatory responses play a vital role at different stages of colorectal carcinogenesis. C-type lectins mediate inflammatory/immune responses and participate in immune escape of pathogens and tumors. Our study aimed to evaluate the correlation between polymorphisms in three C-type lectin genes, CD209, MBL2 and REG4, and colorectal cancer (CRC) risk and clinical outcome. We genotyped 15 potentially functional single nucleotide polymorphisms (SNPs) and assessed their associations with CRC risk in a case-control study of 1353 CRC cases and 767 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall and event-free survival in 414 patients. Two CD209 SNPs were associated with CRC risk after adjustment for multiple comparison. Minor allele carriers of the promoter SNP rs2287886 had an increased risk of CRC (OR 1.30, 95% CI 1.08-1.56), while minor allele carriers of the 3'UTR SNP, rs7248637, had a decreased risk (OR 0.74, 95% CI 0.60-0.91). Multivariate survival analyses, including age, gender, TNM stage and grade, showed that patients without distant metastasis at the time of diagnosis and carrying the rs2994809 T allele had a decreased overall and event-free survival (HR 2.11, 95% CI 1.20-3.72 and HR 2.00, 95% CI 1.18-3.39, respectively). We show that SNPs in CD209 may affect CRC risk, while a SNP in REG4 may be a useful marker for CRC progression.

Genetic polymorphisms in host innate immune sensor genes and the risk of nasopharyngeal carcinoma in North Africa.

Nasopharyngeal carcinoma (NPC) is a rare malignancy in most parts of the world. It is an Epstein-Barr virus-associated malignancy with an unusual racial and geographical distribution. The host innate immune sensor genes play an important role in infection recognition and immune response against viruses. Therefore, we examined the association between polymorphisms in genes within a group of pattern recognition receptors (including families of Toll-like receptors, C-type lectin receptors, and retinoic acid-inducible gene I-like receptors) and NPC susceptibility. Twenty-six single-nucleotide polymorphisms (SNPs) in five pattern-recognition genes were genotyped in 492 North African NPC cases and 373 frequency-matched controls. TLR3_rs3775291 was the most significantly associated SNP (odds ratio [OR] 1.49; 95% confidence interval [95% CI] 1.11-2.00; P = 0.008; dominant model). The analysis showed also that CD209_rs7248637 (OR 0.69; 95% CI 0.52-0.93; P = 0.02; dominant model) and DDX58_rs56309110 (OR 0.70; 95% CI 0.51-0.98; P = 0.04) were associated with the risk of NPC. An 18% increased risk per allele was observed for the five most significantly associated SNPs, TLR3_rs3775291, CD209_rs7248637, DDX58_rs56309110, CD209_rs4804800, and MBL2_rs10824792, (ptrend = 8.2 × 10(-4)). Our results suggest that genetic variation in pattern-recognition genes is associated with the risk of NPC. These preliminary findings require replication in larger studies.

Association study identifying polymorphisms in CD47 and other extracellular matrix pathway genes as putative prognostic markers for colorectal cancer.

PURPOSE: We identified recently the extracellular matrix (ECM) receptor interaction pathway as a consistently overrepresented category among gene expression profiling studies on colorectal cancer (CRC) prognosis. METHODS: Putative regulatory single nucleotide polymorphisms (SNPs) in genes from the ECM pathway were genotyped in 613 CRC patients from Northern Germany (PopGen cohort) and tested for association with disease progression and survival. RESULTS: The eSNP (SNP associated with expression) rs12695175 in CD47 associated with CRC specific survival (HR = 2.18, 95 % CI 1.10-4.33, CC versus AA) and with overall survival (HR = 1.99, 95 % CI 1.04-3.81, CC versus AA). This association remained significant after adjustment for age at diagnosis, tumour stage (T) and lymph node status (N). Three polymorphisms in CD47 were associated with distant metastasis in a dominant model: rs9879947 and rs3206652 in the 3'-UTR (OR = 1.64, 95 % CI 1.01-2.64 and OR = 1.88, 95 % CI 1.27-2.80, respectively) and the eSNP rs3804639 (OR = 1.73, 95 % CI 1.17-2.57). CONCLUSIONS: The novel associations of eSNPs in CD47 with worse survival and distant metastasis should be confirmed by additional studies, since increased expression of this gene has recently been shown to be an indicator of poor prognosis in cancer patients.

Influence of genetic variants in type I interferon genes on melanoma survival and therapy.

Melanoma is an immunogenic tumor; however, the efficacy of immune-therapy shows large inter-individual variation with possible influence of background genetic variation. In this study we report the influence of genetic polymorphisms in the type I interferon gene cluster on chromosome 9p22 on melanoma survival. We genotyped 625 melanoma patients recruited in an oncology center in Germany for 44 polymorphisms located on chromosome 9p22 that were informative for 299 polymorphisms and spanned 15 type I interferon genes. Our results showed associations between time to metastasis/survival and two linked (r(2) = 0.76) polymorphisms, rs10964859 (C>G) and rs10964862 (C>A). The rs10964859 polymorphism was located at 3'UTR and rs10964862 was 9.40 Kb towards 5'UTR of IFNW1 gene. The carriers of the variant alleles of the rs10964859 and rs10964862 polymorphisms were associated with a reduced disease-free survival. The validation of data in an independent group of 710 patients from Spain showed that the direction of the effect was similar. Stratification based on therapy showed that the adverse effect on metastasis development was statistically significant in the patients from Spain who did not receive any treatment and were homozygous for variant allele of rs10964862 (HR = 2.52, 95% CI 1.07-5.90; P = 0.03). Patients homozygous for rs10964859 (HR = 2.01, 95% CI 1.17-3.44; P = 0.01) and rs10964862 (HR 1.84, 95%CI 1.03-3.27, P = 0.04) were associated to increased risk of death following metastasis. GTCGACAA haplotype, found in 8.8% of the patients, was associated with an increased risk of death (HR 1.94, 95%CI 1.16-3.26, P = 0.01). In conclusion, our results identified genetic variants in interferon genes that influence melanoma progression and survival with modulation of effect due to treatment status.

Shared ancestral susceptibility to colorectal cancer and other nutrition related diseases.

BACKGROUND: The majority of non-syndromic colorectal cancers (CRCs) can be described as a complex disease. A two-stage case-control study on CRC susceptibility was conducted to assess the influence of the ancestral alleles in the polymorphisms previously associated with nutrition-related complex diseases. METHODS: In stage I, 28 single nucleotide polymorphisms (SNPs) were genotyped in a hospital-based Czech population (1025 CRC cases, 787 controls) using an allele-specific PCR-based genotyping system (KASPar(®)). In stage II, replication was carried out for the five SNPs with the lowest p values. The replication set consisted of 1798 CRC cases and 1810 controls from a population-based German study (DACHS). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between genotypes and CRC risk were estimated using logistic regression. To identify signatures of selection, Fay-Wu's H and Integrated Haplotype Score (iHS) were estimated. RESULTS: In the Czech population, carriers of the ancestral alleles of AGT rs699 and CYP3A7 rs10211 showed an increased risk of CRC (OR 1.26 and 1.38, respectively; two-sided p≤0.05), whereas carriers of the ancestral allele of ENPP1 rs1044498 had a decreased risk (OR 0.79; p≤0.05). For rs1044498, the strongest association was detected in the Czech male subpopulation (OR 0.61; p=0.0015). The associations were not replicated in the German population. Signatures of selection were found for all three analyzed genes. CONCLUSIONS: Our study showed evidence of association for the ancestral alleles of polymorphisms in AGT and CYP3A7 and for the derived allele of a polymorphism in ENPP1 with an increased risk of CRC in Czechs, but not in Germans. The ancestral alleles of these SNPs have previously been associated with nutrition-related diseases hypertension (AGT and CYP3A7) and insulin resistance (ENPP1). Future studies may shed light on the complex genetic and environmental interactions between different types of nutrition-related diseases.

Polymorphisms in the mitochondrial oxidative phosphorylation chain genes as prognostic markers for colorectal cancer.

BACKGROUND: Currently, the TNM classification of malignant tumours based on clinicopathological staging remains the standard for colorectal cancer (CRC) prognostication. Recently, we identified the mitochondrial oxidative phosphorylation chain as a consistently overrepresented category in the published gene expression profiling (GEP) studies on CRC prognosis. METHODS: We evaluated associations of putative regulatory single nucleotide polymorphisms (SNPs) in genes from the oxidative phosphorylation chain with survival and disease prognosis in 613 CRC patients from Northern Germany (PopGen cohort). RESULTS: Two SNPs in the 3' untranslated region of UQCRB (complex III), rs7836698 and rs10504961, were associated with overall survival (HR = 0.52, 95% CI 0.32-0.85 and HR = 0.64, 95% CI 0.42-0.99, for TT carriers). These associations were restricted to the group of patients with cancer located in the colon (HR = 0.42, 95% CI 0.22-0.82 and HR = 0.46, 95% CI 0.25-0.83). Multivariate analysis indicated that both markers might act as independent prognostic markers. Additionally, the TT carriers were ~2 times more likely to develop tumours in the colon than in the rectum. Two SNPs in COX6B1 (complex IV) were associated with lymph node metastasis in a dominant model (rs6510502, OR = 1.75, 95% CI 1.20-2.57; rs10420252, OR = 1.68, 95% CI 1.11-2.53); rs6510502 was associated also with distant metastasis (OR = 1.67, 95% CI 1.09-2.56 in a dominant model). CONCLUSIONS: This is the first report suggesting that markers in genes from the mitochondrial oxidative chain might be prognostic factors for CRC. Additional studies replicating the presented findings are needed.

Incidence of cancer of unknown primary in Sweden: analysis by location of metastasis.

Increasing incidences of cancer of unknown primary (CUP) have been observed in Sweden previously. However, it is not known how the incidence trends for specific locations of metastasis vary. Site-specific data are available on the basis of the ninth international classification of diseases. CUP patients were identified between 1987 and 2008 from the Swedish Family-Cancer Database. Malignant neoplasms of ill-defined sites were diagnosed in 4042 patients, 1976 developed metastasis in lymph nodes, 9615 had metastasis in specified organs, and in 8052 patients, the malignant neoplasm was diagnosed without further specification. Age-standardized incidence rates for 23 685 patients were analyzed using a direct method of standardization. Overall, the incidence of CUP decreased from 6.98 to 6.00 per 100 000 from 1987 to 2008. The number of patients diagnosed with metastasis in specified organs decreased, whereas the number of patients diagnosed with CUP without further specification increased from 2.65 to 3.02 per 100 000. With improvements in diagnostic methods and imaging techniques for identification of cancer, the incidences of CUP have been decreasing because primary tumors can be specified more often. Computed tomography is typically sensitive in detecting lung, kidney, and colorectal cancers, which are known to have a genetic link with CUP. Prostate-specific antigen testing is used to detect prostate cancer, for which bone is a common metastatic site. Liver metastases are common if the primary tumor is located in the colorectum. If the primary tumor is found, this cancer site replaces the diagnosis of CUP within the Cancer Register and therefore CUP incidence is decreased.

Prognostic impact of polymorphisms in the MYBL2 interacting genes in breast cancer.

MYBL2 is a transcription factor, which regulates the expression of genes involved in cancer progression. In this study, we investigated whether putative functional variants in genes regulating MYBL2 (E2F1, E2F3 and E2F4) or in genes, which are regulated by MYBL2 (BCL2, BIRC5, COL1A1, COL1A2, COL5A2, ERBB2, CLU, LIN9 and TOP2A) affect breast cancer (BC) susceptibility and clinical outcome. Twenty-eight SNPs were genotyped in a population-based series of 782 Swedish BC cases and 1,559 matched controls. BC-specific survival analysis of BIRC5 suggested that carriers of the minor allele of rs8073069 and rs1042489 have a worse survival compared with the major homozygotes (HR 2.46, 95% CI 1.39-4.36 and HR 1.81, 95% CI 1.01-3.25, respectively). The poor survival was observed especially in women with aggressive tumours. Multivariate analysis supported the role of rs8073069 as an independent prognostic marker. For BCL2, minor allele carriers of rs1564483 were more likely to have hormone receptor-positive tumours than the major homozygotes. Another SNP in BCL2, rs4987852, was associated with tumour stages II-IV and histologic grade 3. In CLU, the minor allele carriers of rs9331888 were more likely to have tumours with regional lymph node metastasis and stages II-IV than the major homozygotes. In conclusion, our study suggests a role of genetic variation in BIRC5, BCL2 and CLU as progression and prognostic markers for BC, supporting previous studies based on the expression of the genes.

Genetic variation in ALCAM and other chromosomal instability genes in breast cancer survival.

Chromosomal instability is a hallmark of many cancers and it has a potential to predict clinical outcome of a cancer patient. We hypothesized that genes whose expression status differs between chromosomal stable and unstable breast tumors represent target genes for the identification of genetic variants predicting breast cancer (BC) risk, disease progression, and survival. We used a published list of 38 genes associated with chromosomal instability as a basis for searching potentially functional and informative tagging single nucleotide polymorphisms (SNPs). As a result, 33 SNPs in 16 genes were genotyped in a population-based series of 783 Swedish BC cases. Two SNPs in the ALCAM gene associated with BC-specific survival. For rs1044243, the HR was 4.35 (95% CI 1.34-14.18), and for rs1157, the HR was 3.42 (95% CI 1.32-8.83) for the homozygous carriers of the minor alleles. For the minor allele carriers of CCL18 SNP rs14304, we observed a significant association with aggressive tumor characteristics: large tumor size (OR 1.53, 95% CI 1.10-2.14), positive lymph node metastasis (OR 1.75, 95% CI 1.02-3.00), and high stage (OR 1.37, 95% CI 1.02-1.85). In a Polish population consisting of 506 familial/early onset BC cases, no association with event-free survival for the ALCAM SNPs nor any association with tumor characteristics for the CCL18 SNP were observed, suggesting either a chance finding in the Swedish population or population-based or etiological differences between sporadic and familial/early onset BC.

Risk of breast cancer in families of multiple affected women and men.

Family history of first and second-degree relatives is known to increase the risk for breast cancer. Less data are available on the risks between defined multiple affected close and distant relatives for which the reliability of data may be an issue. Data on affected males are sparse. These questions and the probable genetic models were addressed in this study by means of a nationwide Swedish Family-Cancer Database. We estimated the effect of family history of breast cancer by Poisson regression for women of at least 30 years of age after adjusting for age, period, region, socioeconomic status, number of children, and age at first birth. The results of the study showed that relative risk (RR) for breast cancer was associated with a first degree as well as second-degree family history. Having at least two female affected first-degree relatives increased the RR at least to 2.8, favoring an additive interaction. The risk was increased around ten times in women with both parents affected. When either a father or a mother was affected, the RRs were nearly identical (RR = 1.73 and 1.74, respectively). The RR for a woman increased more when a brother was affected (RR = 2.48) compared to when a sister was affected (RR = 1.87). Having an affected grandmother showed lower familial excess risks than having an affected half sister (RR = 1.27, and 1.26; and RR = 1.39, and 1.50; respectively, for maternal and paternal relatives). We concluded that when both parents were diagnosed with breast cancer, the risk for the daughter was increased tenfold. Having an affected brother showed a somewhat higher risk than having an affected sister. The data suggest that male breast cancer has a higher genetic basis than female breast cancer, which invites further search of the underlying mechanisms.

Single nucleotide polymorphisms in the 20q13 amplicon genes in relation to breast cancer risk and clinical outcome.

The 20q13 region is frequently amplified/overexpressed in breast tumours. However, the nature of this amplification/overexpression is unknown. Here, we investigated genetic variation in five 20q13 amplicon genes (MYBL2, AURKA, ZNF217, STK4 and PTPN1) and its impact on breast cancer (BC) susceptibility and clinical outcome. As a novel finding, four polymorphisms in STK4 (rs6017452, rs7271519) and AURKA (rs2273535, rs8173) associated with steroid hormone receptor status both in a Swedish population-based cohort of 783 BC cases and in a Polish familial/early onset cohort of 506 BC cases. In the joint analysis, the minor allele carriers of rs6017452 had more often hormone receptor positive tumours (OR 0.57, 95% CI 0.40-0.81), while homozygotes for the minor allele of rs7271519, rs2273535 and rs8173 had more often hormone receptor negative tumours (2.26, 1.30-3.39; 2.39, 1.14-5.01; 2.39, 1.19-4.80, respectively) than homozygotes for the common allele. BC-specific survival analysis of AURKA suggested that the Swedish carriers of the minor allele of rs16979877, rs2273535 and rs8173 might have a worse survival compared with the major homozygotes. The survival probabilities associated with the AURKA genotypes depended on the tumour phenotype. In the Swedish case-control study, associations with BC susceptibility were observed in a dominant model for three MYBL2 promoter polymorphisms (rs619289, P = 0.02; rs826943, P = 0.03 and rs826944, P = 0.02), two AURKA promoter polymorphisms (rs6064389, P = 0.04 and rs16979877, P = 0.02) and one 3'UTR polymorphism in ZNF217 (rs1056948, P = 0.01). In conclusion, our data confirmed the impact of the previously identified susceptibility locus and provided preliminary evidence for novel susceptibility variants in BC. We provided evidence for the first time that genetic variants at 20q13 may affect hormone receptor status in breast tumours and influence tumour aggressiveness and survival of the patients. Future studies are needed to confirm the prognostic value of our findings in the clinic.

Influence of family size and birth order on risk of cancer: a population-based study.

BACKGROUND: Family size and birth order are known to influence the risk of some cancers. However, it is still unknown whether these effects change from early to later adulthood. We used the data of the Swedish Family-Cancer Database to further analyze these effects. METHODS: We selected over 5.7 million offspring with identified parents but no parental cancer. We estimated the effect of birth order and family size by Poisson regression adjusted for age, sex, period, region and socioeconomic status. We divided the age at diagnosis in two groups, below and over 50 years, to identify the effect of family size and birth order for different age periods. RESULTS: Negative associations for increasing birth order were found for endometrial, testicular, skin, thyroid and connective tissue cancers and melanoma. In contrast, we observed positive association between birth order and lung, male and female genital cancers. Family size was associated with decreasing risk for endometrial and testicular cancers, melanoma and squamous cell carcinoma; risk was increased for leukemia and nervous system cancer. The effect of birth order decreased for lung and endometrial cancer from age at diagnosis below to over 50 years. Combined effects for birth order and family size were marginally significant for thyroid gland tumors. Especially, the relative risk for follicular thyroid gland tumors was significantly decreased for increasing birth order. CONCLUSION: Our findings suggest that the effect of birth order decreases from early to late adulthood for lung and endometrial cancer.

Polymorphisms in CTNNBL1 in relation to colorectal cancer with evolutionary implications.

Colorectal cancer (CRC) is a complex disease related to environmental and genetic risk factors. Several studies have shown that susceptibility to complex diseases can be mediated by ancestral alleles. Using RNAi screening, CTNNBL1 was identified as a putative regulator of the Wnt signaling pathway, which plays a key role in colorectal carcinogenesis. Recently, single nucleotide polymorphisms (SNPs) in CTNNBL1 have been associated with obesity, a known risk factor for CRC. We investigated whether genetic variation in CTNNBL1 affects susceptibility to CRC and tested for signals of recent selection. We applied a tagging SNP approach that cover all known common variation in CTNNBL1 (allele frequency >5%; r(2)>0.8). A case-control study was carried out using two well-characterized study populations: a hospital-based Czech population composed of 751 sporadic cases and 755 controls and a family/early onset-based German population (697 cases and 644 controls). Genotyping was performed using allele specific PCR based TaqMan® assays (Applied Biosystems, Weiterstadt, Germany). In the Czech cohort, containing sporadic cases, the ancestral alleles of three SNPs showed evidence of association with CRC: rs2344481 (OR 1.44, 95%CI 1.06-1.95, dominant model), rs2281148 (OR 0.59, 95%CI 0.36-0.96, dominant model) and rs2235460 (OR 1.38, 95%CI 1.01-1.89, AA vs. GG). The associations were less prominent in the family/early onset-based German cohort. Data derived from several databases and statistical tests consistently pointed to a likely shaping of CTNNBL1 by positive selection. Further studies are needed to identify the actual function of CTNNBL1 and to validate the association results in other populations.

Genetic variation in genes encoding for polymerase ζ subunits associates with breast cancer risk, tumour characteristics and survival.

Chromosomal instability is a known hallmark of many cancers. DNA polymerases represent a group of enzymes that are involved in the mechanism of chromosomal instability as they have a central function in DNA metabolism. We hypothesized that genetic variation in the polymerase genes may affect gene expression or protein configuration and by that cancer risk and clinical outcome. We selected four genes encoding for the catalytic subunits of the polymerases ß, δ, θ and ζ (POLB, POLD1, POLQ and REV3L, respectively) and two associated proteins (MAD2L2 and REV1) because of their previously reported association with chromosomal instability and/or tumorigenesis. We selected potentially functional and most informative tagging single nucleotide polymorphisms (SNPs) for genotyping in a population-based series of 783 Swedish breast cancer (BC) cases and 1562 controls. SNPs that showed a significant association in the Swedish population were additionally genotyped in a Polish population consisting of 506 familial/early onset BC cases and 568 controls. SNPs in all three polymerase ζ subunit genes associated either with BC risk or prognosis. Two SNPs in REV3L and one SNP in MAD2L2 associated with BC risk: rs462779 (multiplicative model: OR 0.79, 95% CI 0.68-0.92), rs3204953 (dominant model: OR 1.28, 95% CI 1.05-1.56) and rs2233004 (recessive model: OR 0.49, 95% CI 0.28-0.86). Homozygous carriers of the minor allele C of the third SNP in REV3L, rs11153292, had significantly worse survival compared to the TT genotype carriers (HR 2.93, 95% CI 1.34-6.44). Minor allele carriers of two REV1 SNPs (rs6761391 and rs3792142) had significantly more often large tumours and tumours with high histological grade and stage. No association was observed for SNPs in POLB, POLQ and POLD1. Altogether, our data suggest a significant role of genetic variation in the polymerase ζ subunit genes regarding the development and progression of BC.

Does the time interval between first and last birth influence the risk of endometrial and ovarian cancer?

BACKGROUND: Age at first and last birth and the number of children are known to influence the risk of endometrial and ovarian cancers. However, it remains unknown whether the difference in years between first and last childbirth plays a role. The Swedish Family-Cancer Database allowed us to carry out the largest study ever on reproductive factors in these cancers. MATERIAL AND METHODS: We selected over 5.7 million women from the database. We estimated the effect of number of children, age at birth and difference between age at first and last birth by Poisson regression adjusted for age, period, region and socioeconomic status. RESULTS: The risk for endometrial cancer is negatively associated with increasing number of children and increasing age at first as well as age at last birth. Weaker associations are found for ovarian cancer. Age at last birth is the factor that shows highest influence. A large difference in first and last childbirth shows a protective effect on the risk of endometrial cancer. CONCLUSION: Our findings suggest that the risk of endometrial cancer is significantly decreased for women having at least a difference of 10 years between their first and last birth. Ovarian cancer does not seem to be influenced by the time interval between first and last birth.