ABSTRACT
Microsatellite instability (MSI) is detected in approximately 15% of colorectal cancers (CRCs). WD40 and tetratricopeptide repeats 1 (WDTC1) is frequently mutated in MSI CRC, indicating that it may contribute to CRC development. However, the functional evidence of the role of WDTC1 in CRC development remains unknown. Herein, we conducted in vitro assays to examine the function of WDTC1 using knockdown experiments in three CRC cell lines, SW480, CACO2, and LoVo. We provided strong evidence that silencing WDTC1 significantly suppressed cell proliferation, migration, and invasion consistently in all three CRC cell lines. To evaluate the potential role of WDTC1 in regulating CRC-related genes, we conducted RNA sequencing after 24 and 48 h in SW480 cells after treating WDTC1-siRNA and its vehicle control cells. Differential gene expression analysis identified 44 (42 downregulated and 2 upregulated) and 16 (all downregulated) genes, at time points of 24 and 48 h, respectively, whereas 15 downregulated genes were commonly detected at both time points. The ingenuity pathways analysis suggested that the most significant enrichments associated with cancer function and upstream regulator ATM/ATR were observed for these commonly observed genes. We further verified differential gene expression of eight cancer-related genes, ARHGEF12, GSTP1, FNDC3A, TMTC3, RTN4, RRM2, UHMK1, and PTPRF, using RT-PCR in all three cell lines. Our findings provided additional insight into the oncogenic role of WDTC1 in CRC development.
Subject(s)
Colorectal Neoplasms , Humans , Caco-2 Cells , Carcinogenesis/genetics , Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Fibronectins/genetics , Membrane Proteins/genetics , Microsatellite Instability , Oncogenes/geneticsABSTRACT
PURPOSE: Studies conducted primarily among European ancestry women reported 12 breast cancer predisposition genes. However, etiologic roles of these genes in breast cancer among African ancestry women have been less well-investigated. METHODS: We conducted a case-control study in African American women, which included 1117 breast cancer cases and 2169 cancer-free controls, and a pooled analysis, which included 7096 cases and 8040 controls of African descent. Odds ratios of associations with breast cancer risk were estimated. RESULTS: Using sequence data, we identified 61 pathogenic variants in 12 breast cancer predisposition genes, including 11 pathogenic variants not yet reported in previous studies. Pooled analysis showed statistically significant associations of breast cancer risk with pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, TP53, NF1, RAD51C, and RAD51D (all P < .05). The associations with BRCA1, PALB2, and RAD51D were stronger for estrogen receptor (ER)-negative than for ER-positive breast cancer (P heterogeneity < .05), whereas the association with CHEK2 was stronger for ER-positive than for ER-negative breast cancer. CONCLUSION: Our study confirmed previously identified associations of breast cancer risk with BRCA1, BRCA2, PALB2, ATM, TP53, NF1, and CHEK2 and provided new evidence to extend the associations of breast cancer risk with RAD51C and RAD51D, which was identified previously in European ancestry populations, to African ancestry women.
Subject(s)
Breast Neoplasms , Breast Neoplasms/genetics , Case-Control Studies , Female , Genes, BRCA2 , Genetic Predisposition to Disease , Germ-Line Mutation , HumansABSTRACT
Maternal lineages of West Eurasian and North African origin account for 11.5% of total mitochondrial ancestry in Puerto Rico. Historical sources suggest that this ancestry arrived mostly from European migrations that took place during the four centuries of the Spanish colonization of Puerto Rico. This study analyzed 101 mitochondrial control region sequences and diagnostic coding region variants from a sample set randomly and systematically selected using a census-based sampling frame to be representative of the Puerto Rican population, with the goal of defining West Eurasian-North African maternal clades and estimating their possible geographical origin. Median-joining haplotype networks were constructed using hypervariable regions 1 and 2 sequences from various reference populations in search of shared haplotypes. A posterior probability analysis was performed to estimate the percentage of possible origins across wide geographic regions for the entire sample set and for the most common haplogroups on the island. Principal component analyses were conducted to place the Puerto Rican mtDNA set within the variation present among all reference populations. Our study shows that up to 38% of West Eurasian and North African mitochondrial ancestry in Puerto Rico most likely migrated from the Canary Islands. However, most of those haplotypes had previously migrated to the Canary Islands from elsewhere, and there are substantial contributions from various populations across the circum-Mediterranean region and from West African populations related to the modern Wolof and Serer peoples from Senegal and the nomad Fulani who extend up to Cameroon. In conclusion, the West Eurasian mitochondrial ancestry in Puerto Ricans is geographically diverse. However, haplotype diversity seems to be low, and frequencies have been shaped by population bottlenecks, migration waves, and random genetic drift. Consequently, approximately 47% of mtDNAs of West Eurasian and North African ancestry in Puerto Rico probably arrived early in its colonial history.
Subject(s)
Black People/genetics , DNA, Mitochondrial/genetics , Racial Groups/genetics , White People/genetics , Africa, Western/ethnology , Black People/history , Female , Geography/methods , Haplotypes/genetics , History, 19th Century , Human Migration/trends , Humans , Male , Polymerase Chain Reaction/methods , Puerto Rico/ethnology , Racial Groups/history , Sequence Analysis, DNA/methods , Spain/ethnology , White People/historyABSTRACT
Hereditary cancer predisposition gene testing allows the identification of individuals at high risk of cancer that may benefit from increased surveillance, chemoprevention, and prophylactic surgery. In order to implement clinical genetic strategies adapted to each population's needs and intrinsic genetic characteristic, this review aims to present the current status of knowledge about the spectrum of BRCA pathogenic variants in Latin American populations. We have conducted a comprehensive review of 33 studies published between 1994 and 2015 reporting the prevalence and/or spectrum of BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) variants. The combined sample size for these studies consisted of 4835 individuals from 13 countries in Latin America and the Caribbean, as well as in Hispanics in the United States. A total of 167 unique pathogenic variants have been reported in the existing literature. In unselected breast cancer cases, the prevalence ranged from 1.2 to 27.1%. Some countries presented a few recurrent pathogenic variants, while others were characterized by diverse, non-recurrent variants. The proportion of BRCA pathogenic variants shared between Hispanics in the United States and Latin American populations was estimated at 10.4%. Within Latin America and the Caribbean, 8.2% of the BRCA variants reported were present in more than one country. Countries with high prevalence of BRCA pathogenic variants may benefit from more aggressive testing strategies, while testing of recurrent variant panels might present a cost-effective solution for improving genetic testing in some, but not all, countries.
Subject(s)
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Genetic Testing , Breast Neoplasms/genetics , Caribbean Region , Female , Gene Frequency , Genetic Predisposition to Disease , Genetics, Population , Hispanic or Latino , Humans , Latin America , Mutation , Ovarian Neoplasms/genetics , United StatesABSTRACT
BACKGROUND: Lung cancer risk attributable to smoking is dose dependent, yet few studies examining a polygenic risk score (PRS) by smoking interaction have included comprehensive lifetime pack-years smoked. METHODS: We analyzed data from participants of European ancestry in the Framingham Heart Study Original (n = 454) and Offspring (n = 2,470) cohorts enrolled in 1954 and 1971, respectively, and followed through 2018. We built a PRS for lung cancer using participant genotyping data and genome-wide association study summary statistics from a recent study in the OncoArray Consortium. We used Cox proportional hazards regression models to assess risk and the interaction between pack-years smoked and genetic risk for lung cancer adjusting for European ancestry, age, sex, and education. RESULTS: We observed a significant submultiplicative interaction between pack-years and PRS on lung cancer risk (P = 0.09). Thus, the relative risk associated with each additional 10 pack-years smoked decreased with increasing genetic risk (HR = 1.56 at one SD below mean PRS, HR = 1.48 at mean PRS, and HR = 1.40 at one SD above mean PRS). Similarly, lung cancer risk per SD increase in the PRS was highest among those who had never smoked (HR = 1.55) and decreased with heavier smoking (HR = 1.32 at 30 pack-years). CONCLUSIONS: These results suggest the presence of a submultiplicative interaction between pack-years and genetics on lung cancer risk, consistent with recent findings. Both smoking and genetics were significantly associated with lung cancer risk. IMPACT: These results underscore the contributions of genetics and smoking on lung cancer risk and highlight the negative impact of continued smoking regardless of genetic risk.
Subject(s)
Lung Neoplasms , Humans , Lung Neoplasms/etiology , Lung Neoplasms/genetics , Smoke , Genetic Risk Score , Prospective Studies , Genome-Wide Association Study , Risk Factors , Longitudinal StudiesABSTRACT
PURPOSE: Despite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or "cascade" of genomic risk information. METHODS: Using a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size. RESULTS: The time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations. CONCLUSION: Peridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.
Subject(s)
Early Detection of Cancer/methods , Genetic Predisposition to Disease/genetics , Germ-Line Mutation , Mass Screening/methods , Neoplasms/genetics , Adult , Female , Humans , Linear Models , Male , Middle Aged , Neoplasms/diagnosis , Neoplasms/prevention & control , Reproducibility of Results , Sensitivity and Specificity , United StatesABSTRACT
Breast cancer is the most common cause of cancer diagnosis in women and is responsible for considerable mortality among the women of Puerto Rico. However, there are few studies in Puerto Rico on the genetic factors influencing risk. To determine the contribution of pathogenic mutations in BRCA1 and BRCA2, we sequenced these genes in 302 cases from two separate medical centers, who were not selected for age of onset or family history. We identified nine cases that are carriers of pathogenic germline mutation. This represents 2.9% of unselected cases and 5.6% of women meeting National Comprehensive Cancer Network (NCCN) criteria for BRCA testing. All of the identified pathogenic mutations were in the BRCA2 gene and the most common mutation is the p.Glu1308Ter (E1308X) mutation in BRCA2 found in eight out of nine cases, representing 89% of the pathogenic carriers. The E1308X mutation has been identified in breast and ovarian cancer families in Spain, and analysis of flanking DNA polymorphisms shows that all E1308X carriers occur on the same haplotype. This is consistent with BRCA2 E1308X being a founder mutation for the Puerto Rican population. These results will contribute to better inform genetic screening and counseling of breast and ovarian cancer cases in Puerto Rico and Puerto Rican populations in mainland United States.