Heritable genomic diversity in breast cancer driver genes and associations with risk in a Chilean population.

BACKGROUND: Driver mutations are the genetic components responsible for tumor initiation and progression. These variants, which may be inherited, influence cancer risk and therefore underlie many familial cancers. The present study examines the potential association between SNPs in driver genes SF3B1 (rs4685), TBX3 (rs12366395, rs8853, and rs1061651) and MAP3K1 (rs72758040) and BC in BRCA1/2-negative Chilean families. METHODS: The SNPs were genotyped in 486 BC cases and 1258 controls by TaqMan Assay. RESULTS: Our data do not support an association between rs4685:C > T, rs8853:T > C, or rs1061651:T > C and BC risk. However, the rs12366395-G allele (A/G + G/G) was associated with risk in families with a strong history of BC (OR = 1.2 [95% CI 1.0-1.6] p = 0.02 and OR = 1.5 [95% CI 1.0-2.2] p = 0.02, respectively). Moreover, rs72758040-C was associated with increased risk in cases with a moderate-to-strong family history of BC (OR = 1.3 [95% CI 1.0-1.7] p = 0.02 and OR = 1.3 [95% CI 1.0-1.8] p = 0.03 respectively). Finally, risk was significantly higher in homozygous C/C cases from families with a moderate-to-strong BC history (OR = 1.8 [95% CI 1.0-3.1] p = 0.03 and OR = 1.9 [95% CI 1.1-3.4] p = 0.01, respectively). We also evaluated the combined impact of rs12366395-G and rs72758040-C. Familial BC risk increased in a dose-dependent manner with risk allele count, reflecting an additive effect (p-trend = 0.0002). CONCLUSIONS: Our study suggests that germline variants in driver genes TBX3 (rs12366395) and MAP3K1 (rs72758040) may influence BC risk in BRCA1/2-negative Chilean families. Moreover, the presence of rs12366395-G and rs72758040-C could increase BC risk in a Chilean population.

Association of single nucleotide polymorphisms in Pre-miR-27a, Pre-miR-196a2, Pre-miR-423, miR-608 and Pre-miR-618 with breast cancer susceptibility in a South American population.

BACKGROUND: MicroRNAs (miRNAs) are a novel class of endogenous, non-coding, single-stranded RNAs capable of regulating gene expression by suppressing translation or degrading mRNAs. Single nucleotide polymorphisms (SNP) can alter miRNA expression, resulting in diverse functional consequences. Previous studies have examined the association of miRNA SNPs with breast cancer (BC) susceptibility. The contribution of miRNA gene variants to BC susceptibility in South American women had been unexplored. Our study evaluated the association of the SNPs rs895819 in pre-miR27a, rs11614913 in pre-miR-196a2, rs6505162 in pre-miR-423, rs4919510 in miR-608, and rs2682818 in pre-mir-618 with familial BC and early-onset non-familial BC in non-carriers of BRCA1/2 mutations from a South American population. RESULTS: We evaluated the association of five SNPs with BC risk in 440 cases and 807 controls. Our data do not support an association of rs11614913:C > T and rs4919510:C > G with BC risk. The rs6505162:C > A was significantly associated with increased risk of familial BC in persons with a strong family history of BC (OR = 1.7 [95 % CI 1.0-2.0] p = 0.05). The rs2682818:C > A genotype C/A is associated with an increased BC risk in non-familial early-onset BC. For the rs895819:A > G polymorphism, the genotype G/G is significantly associated with reduced BC risk in families with a moderate history of BC (OR = 0.3 [95 % CI 0.1-0.8] p = 0.01). CONCLUSIONS: The contribution of variant miRNA genes to BC in South American women had been unexplored. Our findings support the following conclusions: a) rs6505162:C > A in pre-miR-423 increases risk of familial BC in families with a strong history of BC; b) the C/A genotype at rs2682818:C > A (pre-miR-618) increases BC risk in non-familial early-onset BC; and c) the G/G genotype at rs895819:A > G (miR-27a) reduces BC risk in families with a moderate history of BC.

[Pre and intraoperative scintigraphic detection of sentinel nodes in breast cancer]. / Linfonodo centinela en cáncer de mama: correlación entre detección isotópica y quirúrgica.

BACKGROUND: Sentinel node detection localizes the first node that drains a malignant lesion aiming to detect tumor dissemination. AIM: To assess the yield of sentinel node detection in breast cancer, using pre or intraoperative scintigraphy. MATERIAL AND METHODS: Review of medical records of patients with breast cancer who had a scintigraphic detection of sentinel nodes. Lymph node scintigraphy and surgery were performed in the same day. RESULTS: We studied 174 women aged 53 ± 13 years, operated with a diagnosis of breast cancer, including six highly suspicious lesions in the contralateral breast (totaling 180 studied breasts). Preoperative scintigraphy showed a sentinel node in 174 of 180 breasts (97%). Intraoperative gamma probe confirmed the presence of the sentinel node in the same 174 breasts and detected an additional one reaching a detection yield of 97%. Four patients in whom a sentinel node was not detected in the preoperative scintigraphy, had macrometastases. Frozen section biopsies were available in 177 of 180 breasts. Metastases were informed in 45 patients who underwent axillary lymph node dissection, plus one additional patient with a suspicious lesion. CONCLUSIONS: A high rate of sentinel node detection in the preoperative scintigraphy was observed. Most sentinel nodes not detected with nuclear medicine had macrometastases. In 71% of patients, the detection of sentinel node avoided axillary lymph node dissection.

Association of PALB2 sequence variants with the risk of familial and early-onset breast cancer in a South-American population.

BACKGROUND: Germline mutations in PALB2 have been identified in approximately 1% of familial breast cancer (BC) in several populations. Nevertheless its contribution in the South-American population is unknown. The goal of this study was to determine the prevalence of PALB2 mutations in the Chilean population. METHODS: 100 Chilean BRCA1/2-negatives familial BC cases were included for the PALB2 mutation analysis. We use conformational sensitive gel electrophoresis and direct sequencing. Using a case-control design, we studied the identified variants in 436 BC cases and 809 controls to evaluate their possible association with BC risk. RESULTS: No pathogenic mutations were detected. We identified three variants, the variant c.1861C > A not previously described was found in one of the 436 cases and none of the 809 controls. The bioinformatic analyses indicate that this variant probably is not pathogenic. PALB2 c.1676A > G (rs152451A/G) and c.2993C > T (rs45551636C/T) variants were significantly associated with increased BC risk only in cases with a strong family history of BC (OR = 1.9 [CI 95% 1.3-2.8] p < 0.01 and OR = 3.3 [CI 95% 1.4-7.3] p < 0.01, respectively). The rs152451A/G-rs45551636C/T composite genotype produce increase of the BC risk in cases with a strong family history of BC (OR = 3.6 [CI 95% 1.7-8.0] p = 0.003). The rs152451-G/rs45551636-C and rs152451-G/rs45551636-T haplotypes were associated with an increased BC risk only in cases with a strong family history of BC (OR = 1.6 [CI 95% 1.0-2.5] p = 0.05 and OR = 3.7 [CI 95% 1.8-7.5] p < 0.001, respectively). CONCLUSION: Our results suggest that PALB2 c.1676A > G and c.2993C > T play roles in BC risk in women with a strong family history of BC.

Association of genetic variants at TOX3, 2q35 and 8q24 with the risk of familial and early-onset breast cancer in a South-American population.

Recent Genome-Wide Association Studies have identified several single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) among women of Asian, European, and African-American ancestry. Nevertheless, the contribution of these variants in the South American population is unknown. Furthermore, there is little information about the effect of these risk alleles in women with early BC diagnosis. In the present study, we evaluated the association between rs3803662 (TOX3, also known as TNRC9), rs13387042 (2q35), and rs13281615 (8q24) with BC risk in 344 Chilean BRCA1/2-negative BC cases and in 801 controls. Two SNPs, rs3803662 and rs13387042, were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC. The risk of BC increased in a dose-dependent manner with the number of risk alleles (P-trend < 0.0001 and 0.0091, respectively). The odds ratios for BC in familial BC and in early-onset non-familial BC were 3.76 (95%CI 1.02-13.84, P = 0.046) and 8.0 (95%CI 2.20-29.04, P = 0.002), respectively, for the maximum versus minimum number of risk alleles. These results indicate an additive effect of the TOX3 rs3803662 and 2q35 rs13387042 alleles for BC risk. We also evaluated the interaction between rs3803662 and rs13387042 SNPs. We observed an additive interaction only in non-familial early-onset BC cases (AP = 0.72 (0.28-1.16), P = 0.001). No significant association was observed for rs13281615 (8q24) with BC risk in women from the Chilean population. The strongly increased risk associated with the combination of low-penetrance risk alleles supports the polygenic inheritance model of BC.

Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population.

Genome-Wide Association Studies have identified several loci associated with breast cancer (BC) in populations of different ethnic origins. One of the strongest associations was found in the FGFR2 gene, and MAP3K1 has been proposed as a low-penetrance BC risk factor. In this study, we evaluated the associations among FGFR2 SNPs rs2981582, rs2420946, and rs1219648; and MAP3K1 rs889312, with BC risk in 351 BRCA1/2-negative Chilean BC cases and 802 controls. All the SNPs studied were significantly associated with increased BC risk in familial BC and in non-familial early-onset BC, in a dose-dependent manner. Subjects with 3 risk alleles were at a significantly increased risk of BC compared with subjects with 0-2 risk alleles, in both familial BC and early-onset non-familial BC (OR = 1.47, 95 % CI 1.04-2.07, P = 0.026 and OR = 2.04 95 % CI 1.32-3.24, P < 0.001, respectively). In the haplotype analysis, the FGFR2 rs2981582 T / rs2420946 T / rs1219648 G haplotype (ht2) was associated with a significantly increased BC risk compared with the rs2981582 C / rs2420946 C / rs1219648 A haplotype in familial BC and in non-familial early-onset BC (OR = 1.32, 95 % CI 1.06-1.65, P = 0.012; OR = 1.46, 95 % CI 1.11-1.91, P = 0.004, respectively). When the FGFR2 ht2 and MAP3K1 rs889312 were evaluated as risk alleles, the risk of BC increased in a dose-dependent manner as the number of risk alleles increased (P trend <0.0001), indicating an additive effect. Nevertheless, there is no evidence of an interaction between FGFR2 ht2 and the MAP3K1 rs889312 C allele. These findings suggest that genetic variants in the FGFR2 and MAP3K1 genes may contribute to genetic susceptibility to BC.

Regional differences in gallbladder cancer pathogenesis: insights from a comparison of cell cycle-regulatory, PI3K, and pro-angiogenic protein expression.

BACKGROUND: The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents. METHODS: Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center. RESULTS: Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06). CONCLUSIONS: Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.

The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population.

Since the discovery of the BRCA1 and BRCA2 genes, much work has been carried out to identify further breast cancer (BC) susceptibility genes. BARD1 (BRCA1-associated ring domain) was originally identified as a BRCA1-interacting protein but has also been described in tumor-suppressive functions independent of BRCA1. Some association studies have suggested that the BARD1 Cys557Ser variant might be associated with increased risk of BC, but others have failed to confirm this finding. To date, this variant has not been analyzed in Spanish or South-American populations. In this study, using a case-control design, we analyzed the C-terminal Cys557Ser change in 322 Chilean BC cases with no mutations in BRCA1 or BRCA2 and in 570 controls in order to evaluate its possible association with BC susceptibility. BARD1 Cys557Ser was associated with an increased BC risk (P = 0.04, OR = 3.4 [95 % CI 1.2-10.2]) among cases belonging to families with a strong family history of BC. No difference between single cases affected with age <50 years at diagnosis (n = 117) and controls was observed for carriers of Cys/Ser genotype. It is likely that this variant is not involved in BC risk in this group of women. We also analyzed a possible interaction between BARD1 557Ser/XRCC3 241Met variants considering the role of both genes in the maintenance of genome integrity. The combined genotype Cys/Ser-carrier with the XRCC3 241Met allele was associated with an increased BC risk (P = 0.02, OR = 5.01 [95 % CI 1.36-18.5]) among women belonging to families with at least three BC and/or ovarian cancer cases. Our results suggest that BARD1 557Ser and XRCC3 241Met may play roles in BC risk in women with a strong family history of BC. Nevertheless there is no evidence of an interaction between the two SNPs. These findings should be confirmed by other studies and in other populations.

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families.

The distribution of BRCA1/2 germline mutations in breast/ovarian cancer (BC/OC) families varies among different populations. In the Chilean population, there are only two reports of mutation analysis of BRCA1/2, and these included a low number of BC and/or OC patients. Moreover, the prevalence of BRCA1/2 genomic rearrangements in Chilean and in other South American populations is unknown. In this article, we present the mutation-detection data corresponding to a set of 326 high-risk families analyzed by conformation-sensitive gel electrophoresis and heteroduplex analysis. To determine the contribution of BRCA1/2 LGRs in Chilean BC patients, we analyzed 56 high-risk subjects with no pathogenic BRCA1/2 point mutations. Germline BRCA1/2 point mutations were found in 23 (7.1%) of the 326 Chilean families. Families which had at least three BC and/or OC cases showed the highest frequency of mutations (15.9%). We identified 14 point pathogenic mutations. Three recurrent mutations in BRCA1 (c.187_188delAG, c.2605_2606delTT, and c.3450_3453delCAAG) and three in BRCA2 (c.4969_4970insTG, c.5374_5377delTATG, and c.6503_6504delTT) contributed to 63.6 and 66.7% of all the deleterious mutations of each gene, which may reflect the presence of region-specific founder effects. Taken together BRCA1/2 recurrent point mutations account for 65.2% (15/23) of the BRCA1/2 (+) families. No large deletions or duplications involving BRCA1/2 were identified in a subgroup of 56 index cases negative for BRCA1/2 point mutations. Our study, which is the largest conducted to date in a South American population, provides a comprehensive analysis on the type and distribution of BRCA1/2 mutations and allelic variants.

Combined total gastrectomy, total esophagectomy, and D2 lymph node dissection with transverse colonic interposition for adenocarcinoma of the gastroesophageal junction.

The surgical treatment of adenocarcinoma of the gastroesophageal junction (GEJ) is complex. A large tumor involving a substantial portion of both the esophagus and stomach requires complete resection with negative proximal and distal margins as well as D2 lymph node dissection. Some investigators have found that patients who do not undergo radical resection have a worse prognosis; however, more aggressive surgical treatments are associated with increased morbidity and mortality. We describe our operative technique designed for complete resection of tumors of the GEJ. We used this technique to operate on nine patients, none of whom suffered anastomotic leakage or necrosis of the colonic interposition graft.

Variants in DNA double-strand break repair genes and risk of familial breast cancer in a South American population.

The double-strand break (DSB) DNA repair pathway has been implicated in breast cancer (BC). RAD51 and its paralogs XRCC3 and RAD51D play an important role in the repair of DSB through homologous recombination (HR). Some polymorphisms including XRCC3-Thr241Met, RAD51-135G>C, and RAD51D-E233G have been found to confer increased BC susceptibility. In order to detect novel mutations that may contribute to BC susceptibility, 150 patients belonging to 150 Chilean BRCA1/2-negative families were screened for mutations in XRCC3. No mutations were detected in the XRCC3 gene. In addition, using a case-control design we studied the XRCC3-Thr241Met, and RAD51D-E233G polymorphisms in 267 BC cases and 500 controls to evaluate their possible association with BC susceptibility. The XRCC3 Met/Met genotype was associated with an increased BC risk (P = 0.003, OR = 2.44 [95%CI 1.34-4.43]). We did not find an association between E233G polymorphism and BC risk. We also analyzed the effect of combined genotypes among RAD51-135G>C, Thr241Met, and E233G polymorphisms on BC risk. No interaction was observed between Thr241Met and 135G>C. The combined genotype Thr/Met-E/G was associated with an increased BC risk among women who (a) have a family history of BC, (b) are BRCA1/2-negative, and (c) were <50 years at onset (n = 195) (P = 0.037, OR = 10.5 [95%CI 1.16-94.5]). Our results suggested that the variability of the DNA HR repair genes XRCC3 and RAD51D may play a role in BC risk, but this role may be underlined by a mutual interaction between these genes. These findings should be confirmed in other populations.

Incidental gallbladder cancer: analysis of surgical findings and survival.

BACKGROUND AND OBJECTIVES: Incidental gallbladder cancer (IGBCA) has risen worldwide and its prognosis depends on complete radical cholecystectomy (CRC). This study evaluated surgical findings during re-operation and survival of patients with IGBCA. METHODS: Demographics, surgical treatment, staging, and survival data for all IGBCA patients who underwent surgery at Instituto Oncológico Fundación Arturo López Pérez (FALP) between 2000 and 2008 were analyzed. Differences between groups were analyzed by Student's t-test, Mann-Whitney, chi-square, or Fisher log-rank tests. RESULTS: Forty-nine patients were studied (38 women/11 men, median age = 58 years). Pathology reports from cholecystectomy showed that 32 patients had a T2 tumor and 12 had positive resection margin. Thirty-six patients underwent surgical re-exploration and 20 underwent CRC; 10 with (+) residual disease and 10 with (-). For patients with at least T1b tumor, median survival was 28 months and 5-year disease-specific survival (DSS) was 29%. The 3-year DSS was 64% for CRC (-), 30% for CRC (+), and 8% for non-resected cases (P < 0.007). The 3-year DSS was better for patients with stage Ib than those with stages II and IV (P < 0.007). CONCLUSIONS: Patients with IGBCA have a high chance of intra-abdominal metastases or local residual disease. In CRC patients, intra-abdominal metastases were associated with a worse prognosis.

[Complications and mortality of extended gastrectomy for gastric cancer]. / Gastrectomía extendida en cáncer gástrico. Evaluación de la morbilidad y mortalidad postoperatoria.

BACKGROUND: Extended gastrectomy allows a complete tumor excision in patients with advanced gastric cancer. AIM: To compare the surgical results of extended (ER) and non-extended gastrectomy (NER) among patients with gastric cancer, and determine factors associated with complications and mortality. MATERIAL AND METHODS: Review of medical records of patients with gastric cancer who underwent complete resection between 2002 and 2008 in an oncological hospital. Demographics, patient-related and therapeutic features were compared between groups, and independent factors were established with multivariate analysis. RESULTS: Seventy four patients, (44 men, median age 62 years) underwent an ER and 103 patients, (56 men, median age 61 years) a NER. Specifically, ER included splenectomy alone in 27 patients, splenectomy associated with other procedure in 24, partial esophagectomy in 18, distal pancreatectomy in 13, hemicolectomy in 8, total esophagectomy in 7, partial hepatectomy in 4, and adrenalectomy in 1. Postoperative complications were observed in 19 patients treated with an ER (26%) and in 11 patients treated with a NER (11%), p < 0.05. Serious complications were higher in patients who underwent an ER compared with NER (6 patients (8%) vs. 4 (4%), respectively) p < 0.05. In the same way, mortality was higher in patients treated with ER when it was compared with NER (4 patients (5%) vs two (2%), respectively), p < 0.05. ER and serum albumin levels were independent factors associated to a higher risk of mortality and rate of complications. CONCLUSIONS: ER was associated with a higher rate of general and severe complications, and mortality.

Germline Variants in Driver Genes of Breast Cancer and Their Association with Familial and Early-Onset Breast Cancer Risk in a Chilean Population.

The genetic variations responsible for tumorigenesis are called driver mutations. In breast cancer (BC), two studies have demonstrated that germline mutations in driver genes linked to sporadic tumors may also influence BC risk. The present study evaluates the association between SNPs and SNP-SNP interaction in driver genes TTN (rs10497520), TBX3 (rs2242442), KMT2D (rs11168827), and MAP3K1 (rs702688 and rs702689) with BC risk in BRCA1/2-negative Chilean families. The SNPs were genotyped in 489 BC cases and 1078 controls by TaqMan Assay. Our data do not support an association between rs702688: A>G or rs702689: G>A and BC risk. The rs10497520-T allele was associated with a decreased risk in patients with family history of BC or early-onset BC (OR = 0.6, p < 0.0001 and OR = 0.7, p = 0.05, respectively). rs2242442-G was associated with a protective effect and rs11168827-C was associated with increased BC risk in families with a strong history of BC (OR = 0.6, p = 0.02 and OR = 1.4, p = 0.05, respectively). As rs10497520-T and rs2242442-G seemed to protect against BC risk, we then evaluated their combined effect. Familial BC risk decreased in a dose-dependent manner with the protective allele count, reflecting an additive effect (p-trend < 10-4). To our knowledge, this is the first association study of BC driver gene germline variations in a Chilean population.

The role of PET-CT in patients with incidental gallbladder cancer.

INTRODUCTION: After a cholecystectomy, incidental gallbladder cancer (IGC) requires accurate imaging studies to determine the actual extent of the disease to properly tailor subsequent treatment. The aim of this study was to evaluate the utility of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) to provide optimal pre-treatment staging in patients with IGC. MATERIAL AND METHODS: Between January 2006 and August 2008, all patients with IGC and at least muscular layer invasion were studied with (18)FDG PET-CT. The examination was considered positive when the standardized uptake values (SUV) were >/=2.5. In all instances patients were offered to undergo definitive exploration and possible radical resection. RESULTS: The series included 32 patients, 26 women and 6 men, with a median age of 57 years (range 30-81 years). The examination was performed at a median time of 6 weeks after cholecystectomy (range 2-52 weeks). (18)FDG PET-CT was negative in 13 patients and positive in 19 patients: 9 with localized potentially resectable disease (PRD) and in 10 with disseminated disease. Of the 13 patients with negative PET-CT, 9 refused surgery and 4 underwent formal exploration: 3 patients were resected with no disease identified in the final pathology report (FPR) and 1 was not resected as a result of peritoneal carcinomatosis. Of the 9 with PRD, 4 patients refused reoperation and 5 underwent exploration: 3 were resected with residual disease noted in the FPR and 2 did not undergo resection because of dissemination. Two patients with disseminated disease were reoperated and in both instances disseminated disease was confirmed. The median survival for the entire group was 20.3 months (range 1.6-32.9 months). The median survival for those patients with negative PET-CT was 13.5 months (range 5.6-32.9 months), 6.2 months (range 1.6-18.7 months) for localized potentially resectable disease and 4.9 months (range 2-14.1 months) for disseminated disease (P < 0.003). CONCLUSIONS: For patients presenting with stage T1b or greater IGC, the use of (18)FDG PET-CT will help reduce the number of patients undergoing non-therapeutic re-exploration and may help to determine the likely prognosis. (18)FDG PET-CT might be a useful tool for the selection of patients for potentially curative treatment.

Association of common ATM variants with familial breast cancer in a South American population.

BACKGROUND: The ATM gene has been frequently involved in hereditary breast cancer as a low-penetrance susceptibility gene but evidence regarding the role of ATM as a breast cancer susceptibility gene has been contradictory. METHODS: In this study, a full mutation analysis of the ATM gene was carried out in patients from 137 Chilean breast cancer families, of which 126 were BRCA1/2 negatives and 11 BRCA1/2 positives. We further perform a case-control study between the subgroup of 126 cases BRCA1/2 negatives and 200 controls for the 5557G>A missense variant and the IVS38-8T>C and the IVS24-9delT polymorphisms. RESULTS: In the full mutation analysis we detected two missense variants and eight intronic polymorphisms. Carriers of the variant IVS24-9delT, or IVS38-8T>C, or 5557G>A showed an increase in breast cancer risk. The higher significance was observed in the carriers of IVS38-8T>C (OR = 3.09 [95%CI 1.11-8.59], p = 0.024). The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype confered a 3.19 fold increase in breast cancer risk (OR = 3.19 [95%CI 1.16-8.89], p = 0.021). The haplotype estimation suggested a strong linkage disequilibrium between the three markers (D' = 1). We detected only three haplotypes in the cases and control samples, some of these may be founder haplotypes in the Chilean population. CONCLUSION: The IVS24-9 T/(-T), IVS38-8 T/C, 5557 G/A composite genotype alone or in combination with certain genetic background and/or environmental factors, could modify the cancer risk by increasing genetic instability or by altering the effect of the normal DNA damage response.

Genetic Variants in pre-miR-146a, pre-miR-499, pre-miR-125a, pre-miR-605, and pri-miR-182 Are Associated with Breast Cancer Susceptibility in a South American Population.

Breast cancer (BC) is one of the most frequent tumors affecting women worldwide. microRNAs (miRNAs) single-nucleotide polymorphisms (SNPs) likely contribute to BC susceptibility. We evaluated the association of five SNPs with BC risk in non-carriers of the BRCA1/2-mutation from a South American population. The SNPs were genotyped in 440 Chilean BRCA1/2-negative BC cases and 1048 controls. Our data do not support an association between rs2910164:G>C or rs3746444:A>G and BC risk. The rs12975333:G>T is monomorphic in the Chilean population. The pre-miR-605 rs2043556-C allele was associated with a decreased risk of BC, both in patients with a strong family history of BC and in early-onset non-familial BC (Odds ratio (OR) = 0.5 [95% confidence interval (CI) 0.4⁻0.9] p = 0.006 and OR = 0.6 [95% CI 0.5⁻0.9] p = 0.02, respectively). The rs4541843-T allele is associated with increased risk of familial BC. This is the first association study on rs4541843 and BC risk. Previously, we showed that the TOX3-rs3803662:C>T was significantly associated with increased risk of familial BC. Given that TOX3 mRNA is a target of miR-182, and that both the TOX3 rs3803662-T and pri-miR-182 rs4541843-T alleles are associated with increased BC risk, we evaluated their combined effect. Risk of familial BC increased in a dose-dependent manner with the number of risk alleles (p-trend = 0.0005), indicating an additive effect.

RAD51 135G>C polymorphism and risk of familial breast cancer in a South American population.

Several studies have reported that mutations in genes involved in maintenance of genome integrity may be responsible for increased cancer risk. Human RAD51, known to function in DNA repair, interacts with a number of proteins implicated in breast cancer (BC), including BRCA1 and BRCA2. Few studies have investigated the role of RAD51 gene variations in familial BC. To detect potential novel gene defects that may contribute to hereditary BC susceptibility, 143 patients belonging to 143 Chilean families tested for BRCA1 and BRCA2 mutations were screened for mutations in RAD51, using conformational sensitive gel electrophoresis (CSGE) and DNA sequencing. No mutations were detected in the exon or splice-boundary regions of the RAD51 gene in these families. The RAD51 135G>C polymorphism (c.-98G>C, rs1801320) was studied in a case-control design, to evaluate its possible association with BC susceptibility. The frequency of the RAD51 135C allele was established in 143 cases and 247 controls, using restriction fragment length polymorphism-polymerase chain reaction. RAD51 135C genotypes (G/C and C/C) were associated with an increased BC risk only among women with (a) a family history of BC, (b) BRCA1/2 negative (n = 131), and (c) age at onset <50 years (P = 0.020; OR = 2.17, 95% CI = 1.11-4.24). Thus, we propose that RAD51 135G>C polymorphism presents an increased risk of familial BC in women with age < 50 years at diagnosis, and this polymorphism may be a BC risk variant. This finding should be confirmed in other populations.

Heritable genomic diversity in breast cancer driver genes and associations with risk in a Chilean population

BACKGROUND: Driver mutations are the genetic components responsible for tumor initiation and progression. These variants, which may be inherited, influence cancer risk and therefore underlie many familial cancers. The present study examines the potential association between SNPs in driver genes SF3B1 (rs4685), TBX3 (rs12366395, rs8853, and rs1061651) and MAP3K1 (rs72758040) and BC in BRCA1/2-negative Chilean families. METHODS: The SNPs were genotyped in 486 BC cases and 1258 controls by TaqMan Assay. RESULTS: Our data do not support an association between rs4685:C > T, rs8853:T > C, or rs1061651:T > C and BC risk. However, the rs12366395-G allele (A/G + G/G) was associated with risk in families with a strong history of BC (OR = 1.2 [95% CI 1.0-1.6] p = 0.02 and OR = 1.5 [95% CI 1.0-2.2] p = 0.02, respectively). Moreover, rs72758040-C was associated with increased risk in cases with a moderate-to-strong family history of BC (OR = 1.3 [95% CI 1.0-1.7] p = 0.02 and OR = 1.3 [95% CI 1.0-1.8] p = 0.03 respectively). Finally, risk was significantly higher in homozygous C/C cases from families with a moderate-to-strong BC history (OR = 1.8 [95% CI 1.0-3.1] p = 0.03 and OR = 1.9 [95% CI 1.1-3.4] p = 0.01, respectively). We also evaluated the combined impact of rs12366395-G and rs72758040-C. Familial BC risk increased in a dose-dependent manner with risk allele count, reflecting an additive effect (p-trend = 0.0002). CONCLUSIONS: Our study suggests that germline variants in driver genes TBX3 (rs12366395) and MAP3K1 (rs72758040) may influence BC risk in BRCA1/2-negative Chilean families. Moreover, the presence of rs12366395-G and rs72758040-C could increase BC risk in a Chilean population.

Linfonodo centinela en cáncer de mama: correlación entre detección isotópica y quirúrgica / Pre and intraoperative scintigraphic detection of sentinel nodes in breast cancer

Background: Sentinel node detection localizes the first node that drains a malignant lesion aiming to detect tumor dissemination. Aim: To assess the yield of sentinel node detection in breast cancer, using pre or intraoperative scintigraphy. Material and Methods: Review of medical records of patients with breast cancer who had a scintigraphic detection of sentinel nodes. Lymph node scintigraphy and surgery were performed in the same day. Results: We studied 174 women aged 53 ± 13 years, operated with a diagnosis of breast cancer, including six highly suspicious lesions in the contralateral breast (totaling 180 studied breasts). Preoperative scintigraphy showed a sentinel node in 174 of 180 breasts (97%). Intraoperative gamma probe confirmed the presence of the sentinel node in the same 174 breasts and detected an additional one reaching a detection yield of 97%. Four patients in whom a sentinel node was not detected in the preoperative scintigraphy, had macrometastases. Frozen section biopsies were available in 177 of 180 breasts. Metastases were informed in 45 patients who underwent axillary lymph node dissection, plus one additional patient with a suspicious lesion. Conclusions: A high rate of sentinel node detection in the preoperative scintigraphy was observed. Most sentinel nodes not detected with nuclear medicine had macrometastases. In 71% of patients, the detection of sentinel node avoided axillary lymph node dissection.