SULT1A1 rs9282861 polymorphism-a potential modifier of efficacy of the systemic adjuvant therapy in breast cancer?

<p>Abstract</p> <p>Background</p> <p>Sulfotransferase 1A1 (SULT1A1) participates in the elimination of 4-hydroxy-tamoxifen (4-OH-TAM), which is one of the major active metabolites of tamoxifen (TAM). Homozygous <it>SULT1A1 </it>variant allele genotype has been associated with lower catalytic activity and thermostability of the enzyme. Previous clinical studies suggest that the <it>SULT1A1 </it>rs9282861 polymorphism may influence the survival of breast cancer patients treated with TAM in the adjuvant setting. We investigated the effect of rs9282861 genotypes on the survival of Finnish breast cancer patients treated with adjuvant chemotherapy or TAM.</p> <p>Methods</p> <p>The rs9282861 genotypes of 412 Finnish breast cancer patients with early breast cancer were identified by using PCR-RFLP method. Seventy six patients were treated with adjuvant cyclophosphamide based chemotherapy only, 65 patients received adjuvant TAM, and four patients were treated with both adjuvant chemotherapy and TAM. Overall long-term survival (OS), breast cancer specific survival (BCSS), and relapse-free survival (RFS) by rs9282861 genotypes were evaluated by the Kaplan-Meier method and Cox regression analysis.</p> <p>Results</p> <p>The multivariate analysis of 145 patients receiving either adjuvant TAM or chemotherapy showed a statistically significantly improved OS in patients with the rs9282861 homozygous variant AA genotype (hazard ratio [HR] = 0.50, 95% confidence interval [CI] = 0.29-0.88, <it>P </it>= 0.015). In the separate analyses of patients receiving only chemotherapy or adjuvant TAM, there were no statistically significant differences in survival.</p> <p>Conclusions</p> <p>In this prospective study, we observed a previously unreported association between the <it>SULT1A1 </it>rs9282861 genotype and OS of breast cancer patients treated with adjuvant chemotherapy or TAM. This novel finding suggests that the rs9282861 polymorphism modifies the long-term clinical outcome of patients receiving adjuvant TAM or chemotherapy.</p

Expression, activity and pharmacokinetic impact of ocular transporters

The eye is protected by several tissues that limit the permeability and entry of potentially harmful substances, but also hamper the delivery of drugs in the treatment of ocular diseases. Active transport across the ocular barriers may affect drug distribution, but the impact of drug transporters on ocular drug delivery is not well known. We have collected and critically reviewed the literature for ocular expression and activity of known drug transporters. The review concentrates on drug transporters that have been functionally characterized in ocular tissues or primary cells and on transporters for which there is available expression data at the protein level. Species differences are highlighted, since these may explain observed inconsistencies in the influence of specific transporters on drug disposition. There is variable evidence about the pharmacokinetic role of transporters in ocular tissues. The strongest evidence for the role of active transport is available for the blood-retinal barrier. We explored the role of active transport in the cornea and blood retinal barrier with pharmacokinetic simulations. The simulations show that the active transport is important only in the case of specific parameter combinations. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

An assessment of prevalence of Type 1 CFI rare variants in European AMD, and why lack of broader genetic data hinders development of new treatments and healthcare access

PurposeAdvanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.MethodsCollective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.ResultsType 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.ConclusionsThe relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.Peer reviewe

FANCM mutation c.5791C > T is a risk factor for triple-negative breast cancer in the Finnish population

The FANCM c.5101C > T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C > T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. We genotyped the FANCM c.5791C > T mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C > T and c.5791C > T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C > T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. The frequency of the FANCM c.5791C > T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87-4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65-16.0, P = 0.005). The combined analysis for c.5101C > T and c.5791C > T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32-2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77-5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.Peer reviewe

Two truncating variants in FANCC and breast cancer risk

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44�1.33, p=0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are diferences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants

Case-control analysis of truncating mutations in DNA damage response genes connects TEX15 and FANCD2 with hereditary breast cancer susceptibility

Several known breast cancer susceptibility genes encode proteins involved in DNA damage response (DDR) and are characterized by rare loss-of-function mutations. However, these explain less than half of the familial cases. To identify novel susceptibility factors, 39 rare truncating mutations, identified in 189 Northern Finnish hereditary breast cancer patients in parallel sequencing of 796 DDR genes, were studied for disease association. Mutation screening was performed for Northern Finnish breast cancer cases (n = 578-1565) and controls (n = 337-1228). Mutations showing potential cancer association were analyzed in additional Finnish cohorts.c.7253dupT in TEX15, encoding a DDR factor important in meiosis, associated with hereditary breast cancer (p = 0.018) and likely represents a Northern Finnish founder mutation. A deleterious c.2715 + 1G > A mutation in the Fanconi anemia gene, FANCD2, was over two times more common in the combined Finnish hereditary cohort compared to controls. A deletion (c.640_644del5) in RNF168, causative for recessive RIDDLE syndrome, had high prevalence in majority of the analyzed cohorts, but did not associate with breast cancer. In conclusion, truncating variants in TEX15 and FANCD2 are potential breast cancer risk factors, warranting further investigations in other populations. Furthermore, high frequency of RNF168 c.640_644del5 indicates the need for its testing in Finnish patients with RIDDLE syndrome symptoms.Peer reviewe

FANCM c.5101C > T mutation associates with breast cancer survival and treatment outcome

Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C> T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple-negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C> T mutation carriers and 3,832 non-carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C>T mutation associated with poor 10-year breast cancer-specific survival (hazard ratio (HR) 51.66, 95% confidence interval (CI) 1.09-2.52, p=0.018), with a more pronounced survival effect among familial cases (HR=2.93, 95% CI 1.5-5.76, p=1.80 x 10 23). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR=1.8, 95% CI 1.09-2.98, p=0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR=3.43, 95% CI 1.6-7.34, p=1.50x10(-3)) but not among radiotherapy treated patients (HR=1.35, 95% CI 0.82-2.23, p=0.237). Significant interaction was found between the mutation and radiotherapy (p=0.040). Immunohistochemical analyses show that c.5101C> T carriers have reduced PAR-activity. Our results suggest that FANCM c.5101C>T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.Peer reviewe