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

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

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

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.</p

E-cadherin breast tumor expression, risk factors and survival : Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium

E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, > 2 cm, and HER2-negative. Loss of E-cadherin expression (score <100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.Peer reviewe

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

Expression profiles of small non-coding RNAs in breast cancer tumors characterize clinicopathological features and show prognostic and predictive potential

Abstract Precision medicine approaches are required for more effective therapies for cancer. As small non-coding RNAs (sncRNAs) have recently been suggested as intriguing candidates for cancer biomarkers and have shown potential also as novel therapeutic targets, we aimed at profiling the non-miRNA sncRNAs in a large sample set to evaluate their role in invasive breast cancer (BC). We used small RNA sequencing and 195 fresh-frozen invasive BC and 22 benign breast tissue samples to identify significant associations of small nucleolar RNAs, small nuclear RNAs, and miscellaneous RNAs with the clinicopathological features and patient outcome of BC. Ninety-six and five sncRNAs significantly distinguished (Padj < 0.01) invasive local BC from benign breast tissue and metastasized BC from invasive local BC, respectively. Furthermore, 69 sncRNAs significantly associated (Padj < 0.01) with the tumor grade, hormone receptor status, subtype, and/or tumor histology. Additionally, 42 sncRNAs were observed as candidates for prognostic markers and 29 for predictive markers for radiotherapy and/or tamoxifen response (P < 0.05). We discovered the clinical relevance of sncRNAs from each studied RNA type. By introducing new sncRNA biomarker candidates for invasive BC and validating the potential of previously described ones, we have guided the way for further research that is warranted for providing novel insights into BC biology

Circulating Cell-Free DNA Reflects the Clonal Evolution of Breast Cancer Tumors

Liquid biopsy of cell-free DNA (cfDNA) is proposed as a potential method for the early detection of breast cancer (BC) metastases and following the clonal evolution of BC. Though the use of liquid biopsy is a widely discussed topic in the field, only a few studies have demonstrated such usage so far. We sequenced the DNA of matched primary tumor and metastatic sites together with the matched cfDNA samples from 18 Eastern Finnish BC patients and investigated how well cfDNA reflected the clonal evolution of BC interpreted from tumor DNA. On average, liquid biopsy detected 56.2 &plusmn; 7.2% of the somatic variants that were present either in the matched primary tumor or metastatic sites. Despite the high discordance observed between matched samples, liquid biopsy was found to reflect the clonal evolution of BC and identify novel driver variants and therapeutic targets absent from the tumor DNA. Tumor-specific somatic variants were detected in cfDNA at the time of diagnosis and 8.4 &plusmn; 2.4 months prior to detection of locoregional recurrence or distant metastases. Our results demonstrate that the sequencing of cfDNA may be used for the early detection of locoregional and distant BC metastases. Observed discordance between tumor DNA sequencing and liquid biopsy supports the parallel sequencing of cfDNA and tumor DNA to yield the most comprehensive overview for the genetic landscape of BC