Amy French - Academia.edu (original) (raw)

Papers by Amy French

Research paper thumbnail of Supplementary Figure Legends 1-2 from Frequent Truncating Mutation of <i>TFAM</i> Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer

Relative mtDNA copy number was determined by the quantitative real-time PCR as described in Mater... more Relative mtDNA copy number was determined by the quantitative real-time PCR as described in Materials and Methods. The efficiency of the real-time PCR amplification was established from 20 ng to 5 pg (4-fold repeated dilutions) of cellular DNA from CRL-1807 normal colon epithelial cells, which were allowed to react with primers specific to mtDNA (ND1 gene) and nDNA (β-actin gene), respectively. The correlation coefficient R2 was 0.9993 for nDNA and 0.9994 for mtDNA, respectively. Supplementary Figure 2. Verification of Wt-or Mut-TFAM expression in RKO cells following Lentiviral transduction. (A) The recombinant pCDH-CMV-MCS-EF1-copGFP-Wt-or Mut-TFAM lentivirus (with GFP-IRES) were packaged and applied to RKO cells as described in Materials and Methods. The infection efficiency was above 95% with GFP as infection efficiency marker. (B) The expression of Wt-(*) or Mut-TFAM (**) in infected RKO cells were verified using immunoblotting method with anti-TFAM antibody (left) and anti-Myc antibody (right). The lentiviral vector was used as control.

Research paper thumbnail of Supplementary Tables S1 - S5, Figures S1 - S5 from A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supple... more Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supplementary Table S2. Genome-wide significant SNPs found in our cohort. Supplementary Table S3. Cis-eQTL expression of rs4646284. Supplementary Table S4. Results at the 105 loci previously found to be associated with prostate cancer. Supplementary Table S5. Risk score of and variance explained by the 105 previously reported hits. Supplementary Figure S1. Manhattan and Q-Q plots of each race/ethnicity and meta-analysis. Supplementary Figure S2. Local plots of novel replicated rs4646284 and suggestive rs2659124. Supplementary Figure S3. Cis-eQTL of SLC22A1 and SLC22A3. Supplementary Figure S4. Comparison of ORs of KP to previous reports by race/ethnicity. Supplementary Figure S5. KP AUC estimates.

Research paper thumbnail of Additional file 3: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU ID and taxonomy. (TXT 654 kb)

Research paper thumbnail of Additional file 2: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU read counts by sample. (TSV 5546 kb)

Research paper thumbnail of Additional file 4: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU ID and sequences. (FASTA 2042 kb)

Research paper thumbnail of Tea and Chocolate Consumption and Colorectal Cancer Risk by Molecularly Defined Subtypes in a Prospective Cohort Study of Older Women: Presidential Poster

American Journal of Gastroenterology, 2013

Research paper thumbnail of Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors

Cancer Research, 2017

The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the C... more The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding region...

Research paper thumbnail of A large multi-ethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences

Cancer discovery, 2015

A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,78... more A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously-identified locus 6q25.3 that replicated in PEGASUS (N=7,539) and MEC (N=4,679) (p=1.0x10(-19), OR=1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (p=1.3x10(-23)) and SLC22A3 (p=3.2x10(-52)). At the known 19q13.33 locus rs2659124 (p=1.3x10(-13), OR=1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (p<1.0x10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic Whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained ~7.6% of disease heritability. The entire GWAS array explained ~33.4...

Research paper thumbnail of Abstract 1676: Associations between hormone therapy with incident colorectal cancer by p53 protein expression in a population-based cohort of older women

Cancer Research, 2012

Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53... more Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, > 40) and cum...

Research paper thumbnail of Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases

Annals of Oncology, 2003

Background: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and ha... more Background: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 215) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. Patients and methods: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MSI+ tumour tissues, respectively. Results: The MSI+ phenotype was detected in 75 (24%) patients, with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial [18/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria; (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. Conclusions: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis.

Research paper thumbnail of Body mass index and molecular subtypes of colorectal cancer

JNCI: Journal of the National Cancer Institute

Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence fo... more Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG i...

Research paper thumbnail of A microRNA Transcriptome-wide Association Study of Prostate Cancer Risk

Frontiers in Genetics, 2022

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms... more Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analys...

Research paper thumbnail of High-throughput screening of prostate cancer risk loci by single nucleotide polymorphisms sequencing

Nature communications, May 22, 2018

Functional characterization of disease-causing variants at risk loci has been a significant chall... more Functional characterization of disease-causing variants at risk loci has been a significant challenge. Here we report a high-throughput single-nucleotide polymorphisms sequencing (SNPs-seq) technology to simultaneously screen hundreds to thousands of SNPs for their allele-dependent protein-binding differences. This technology takes advantage of higher retention rate of protein-bound DNA oligos in protein purification column to quantitatively sequence these SNP-containing oligos. We apply this technology to test prostate cancer-risk loci and observe differential allelic protein binding in a significant number of selected SNPs. We also test a unique application of self-transcribing active regulatory region sequencing (STARR-seq) in characterizing allele-dependent transcriptional regulation and provide detailed functional analysis at two risk loci (RGS17 and ASCL2). Together, we introduce a powerful high-throughput pipeline for large-scale screening of functional SNPs at disease risk l...

Research paper thumbnail of FIRE: functional inference of genetic variants that regulate gene expression

Bioinformatics, 2017

Motivation Interpreting genetic variation in noncoding regions of the genome is an important chal... more Motivation Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies. Results We developed FIRE (Functional Inference of Regulators of Expression), a tool to score both noncoding and coding SNVs based on their potential to regulate the expression levels of nearby genes. FIRE consists of 23 random forests trained to recognize SNVs in cis-expression quantitative trait loci (cis-eQTLs) using a set of 92 genomic annotations as predictive features. FIRE scores discriminate cis-eQTL SNVs from non-eQTL SNVs in the training set with a cross-validated area under the receiver operating character...

Research paper thumbnail of Comprehensively Evaluating cis -Regulatory Variation in the Human Prostate Transcriptome by Using Gene-Level Allele-Specific Expression

The American Journal of Human Genetics, 2015

Research paper thumbnail of BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair

Cancer research, 2003

Frequent BRAF mutations were reported recently in a variety of human malignancies, including colo... more Frequent BRAF mutations were reported recently in a variety of human malignancies, including colorectal cancer. In this study, we screened 293 colorectal cancers for mutations in exons 11 and 15, two regions containing hotspots for BRAF mutation. Of the 293 cancers, 170 had normal mismatch repair, and 123 had defective mismatch repair (originating from both somatic as well as germ-line mutations in several of the mismatch repair genes). A total of 63 exonic mutations (22%) were detected, 60 of which were V599E, and one each of D593G, G468E, and D586A. Of the tumors with defective mismatch repair, 34% (42 of 123) had a mutation in BRAF, whereas only 12% (21 of 170) of tumors with proficient mismatch repair demonstrated a mutation (P < 0.0001). Interestingly, BRAF mutations were found most often in cases with an hMHL1 abnormality (35 of 60) and rarely in cases with an hMSH2 abnormality (1 of 39; P < 0.0001). More interestingly, of the 31 hMLH1 cases with a BRAF mutation, 30 occu...

Research paper thumbnail of Analysis of hMLH1 and hMSH2 Gene Dosage Alterations in Hereditary Nonpolyposis Colorectal Cancer Patients by Novel Methods

The Journal of Molecular Diagnostics, 2005

Research paper thumbnail of Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

New England Journal of Medicine, 2003

Colon cancers with high-frequency microsatellite instability have clinical and pathological featu... more Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. methods Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. results Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellitestable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability. conclusions Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.

Research paper thumbnail of Allelic Imbalance and Microsatellite Instability in Resected Dukeʼs D Colorectal Cancer

Diagnostic Molecular Pathology, 1997

Research paper thumbnail of Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women

Cancer Epidemiology, Biomarkers & Prevention, 2013

Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influenc... more Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistoche...

Research paper thumbnail of Supplementary Figure Legends 1-2 from Frequent Truncating Mutation of <i>TFAM</i> Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer

Relative mtDNA copy number was determined by the quantitative real-time PCR as described in Mater... more Relative mtDNA copy number was determined by the quantitative real-time PCR as described in Materials and Methods. The efficiency of the real-time PCR amplification was established from 20 ng to 5 pg (4-fold repeated dilutions) of cellular DNA from CRL-1807 normal colon epithelial cells, which were allowed to react with primers specific to mtDNA (ND1 gene) and nDNA (β-actin gene), respectively. The correlation coefficient R2 was 0.9993 for nDNA and 0.9994 for mtDNA, respectively. Supplementary Figure 2. Verification of Wt-or Mut-TFAM expression in RKO cells following Lentiviral transduction. (A) The recombinant pCDH-CMV-MCS-EF1-copGFP-Wt-or Mut-TFAM lentivirus (with GFP-IRES) were packaged and applied to RKO cells as described in Materials and Methods. The infection efficiency was above 95% with GFP as infection efficiency marker. (B) The expression of Wt-(*) or Mut-TFAM (**) in infected RKO cells were verified using immunoblotting method with anti-TFAM antibody (left) and anti-Myc antibody (right). The lentiviral vector was used as control.

Research paper thumbnail of Supplementary Tables S1 - S5, Figures S1 - S5 from A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences

Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supple... more Supplementary Table S1. Descriptive factors for KP study population, broken down by study. Supplementary Table S2. Genome-wide significant SNPs found in our cohort. Supplementary Table S3. Cis-eQTL expression of rs4646284. Supplementary Table S4. Results at the 105 loci previously found to be associated with prostate cancer. Supplementary Table S5. Risk score of and variance explained by the 105 previously reported hits. Supplementary Figure S1. Manhattan and Q-Q plots of each race/ethnicity and meta-analysis. Supplementary Figure S2. Local plots of novel replicated rs4646284 and suggestive rs2659124. Supplementary Figure S3. Cis-eQTL of SLC22A1 and SLC22A3. Supplementary Figure S4. Comparison of ORs of KP to previous reports by race/ethnicity. Supplementary Figure S5. KP AUC estimates.

Research paper thumbnail of Additional file 3: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU ID and taxonomy. (TXT 654 kb)

Research paper thumbnail of Additional file 2: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU read counts by sample. (TSV 5546 kb)

Research paper thumbnail of Additional file 4: of Distinct microbes, metabolites, and ecologies define the microbiome in deficient and proficient mismatch repair colorectal cancers

sOTU ID and sequences. (FASTA 2042 kb)

Research paper thumbnail of Tea and Chocolate Consumption and Colorectal Cancer Risk by Molecularly Defined Subtypes in a Prospective Cohort Study of Older Women: Presidential Poster

American Journal of Gastroenterology, 2013

Research paper thumbnail of Abstract 1286: Targeted deep sequencing of colorectal tumor tissues to study associations of tumor subtypes with germline genetic, lifestyle, and environmental risk factors

Cancer Research, 2017

The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the C... more The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) in collaboration with the Colorectal Cancer Family Registry (CCFR) aims to identify genetic variants and environmental risk factors that impact colorectal cancer (CRC). Over 30 studies from North America, Europe, and Australia participate in GECCO. These studies have collected clinical, epidemiological, and survival data, as well as blood and tumor biospecimens, for over 80,000 CRC cases and controls. The current study aims to conduct targeted deep sequencing of tumors and matching normal DNA to identify recurrent and novel somatic and germline variants in 4,200 CRC cases. To achieve this goal, an AmpliSeq targeted sequencing panel of 1.12 Mbp was constructed to sequence the coding regions of 190 significantly mutated genes identified from whole exome sequencing datasets generated by the Nurses’ Health Study and Health Professional’s Follow-up Study, and The Cancer Genome Atlas. The panel also covers coding region...

Research paper thumbnail of A large multi-ethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences

Cancer discovery, 2015

A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,78... more A genome-wide association study of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously-identified locus 6q25.3 that replicated in PEGASUS (N=7,539) and MEC (N=4,679) (p=1.0x10(-19), OR=1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (p=1.3x10(-23)) and SLC22A3 (p=3.2x10(-52)). At the known 19q13.33 locus rs2659124 (p=1.3x10(-13), OR=1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (p<1.0x10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic Whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained ~7.6% of disease heritability. The entire GWAS array explained ~33.4...

Research paper thumbnail of Abstract 1676: Associations between hormone therapy with incident colorectal cancer by p53 protein expression in a population-based cohort of older women

Cancer Research, 2012

Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53... more Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, > 40) and cum...

Research paper thumbnail of Microsatellite instability and mutation analysis among southern Italian patients with colorectal carcinoma: detection of different alterations accounting for MLH1 and MSH2 inactivation in familial cases

Annals of Oncology, 2003

Background: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and ha... more Background: Microsatellite instability (MSI) is due to defective DNA mismatch repair (MMR) and has been detected at various rates in colorectal carcinoma (CRC). The role of MSI in colorectal tumorigenesis was assessed further in this study by both microsatellite analysis of two CRC subsets [unselected patients (n = 215) and patients <50 years of age (n = 95)], and mutation screening of the two major MMR genes MLH1 and MSH2 among familial CRC cases. Patients and methods: PCR-based microsatellite analysis was performed on paraffin-embedded tissues. In CRC families, MLH1/MSH2 mutation analysis and MLH1/MSH2 immunostaining were performed on germline DNA and MSI+ tumour tissues, respectively. Results: The MSI+ phenotype was detected in 75 (24%) patients, with higher incidence in early-onset or proximally located tumours. Among 220 patients investigated for family cancer history, MSI frequency was markedly higher in familial [18/27 (67%)] than in sporadic [32/193 (17%)] cases. Three MLH1 and six MSH2 germline mutations were identified in 14 out of 36 (39%) CRC families. Prevalence of MLH1/MSH2 mutations in CRC families was significantly increased by the presence of: (i) fulfilled Amsterdam criteria; (ii) four or more CRCs; or (iii) one or more endometrial cancer. While MSH2 was found mostly mutated, almost all [8/9 (89%)] familial MSI+ cases with loss of the MLH1 protein were negative for MLH1 germline mutations. Conclusions: Both genetic (for MSH2) and gene-silencing (for MLH1) alterations seem to be involved in CRC pathogenesis.

Research paper thumbnail of Body mass index and molecular subtypes of colorectal cancer

JNCI: Journal of the National Cancer Institute

Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence fo... more Background Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease. Methods We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables. Results Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG i...

Research paper thumbnail of A microRNA Transcriptome-wide Association Study of Prostate Cancer Risk

Frontiers in Genetics, 2022

Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms... more Large genome-wide association studies have identified hundreds of single-nucleotide polymorphisms associated with increased risk of prostate cancer (PrCa), and many of these risk loci is presumed to confer regulatory effects on gene expression. While eQTL studies of long RNAs has yielded many potential risk genes, the relationship between PrCa risk genetics and microRNA expression dysregulation is understudied. We performed an microRNA transcriptome-wide association study of PrCa risk using small RNA sequencing and genome-wide genotyping data from N = 441 normal prostate epithelium tissue samples along with N = 411 prostate adenocarcinoma tumor samples from the Cancer Genome Atlas (TCGA). Genetically regulated expression prediction models were trained for all expressed microRNAs using the FUSION TWAS software. TWAS for PrCa risk was performed with both sets of models using single-SNP summary statistics from the recent PRACTICAL consortium PrCa case-control OncoArray GWAS meta-analys...

Research paper thumbnail of High-throughput screening of prostate cancer risk loci by single nucleotide polymorphisms sequencing

Nature communications, May 22, 2018

Functional characterization of disease-causing variants at risk loci has been a significant chall... more Functional characterization of disease-causing variants at risk loci has been a significant challenge. Here we report a high-throughput single-nucleotide polymorphisms sequencing (SNPs-seq) technology to simultaneously screen hundreds to thousands of SNPs for their allele-dependent protein-binding differences. This technology takes advantage of higher retention rate of protein-bound DNA oligos in protein purification column to quantitatively sequence these SNP-containing oligos. We apply this technology to test prostate cancer-risk loci and observe differential allelic protein binding in a significant number of selected SNPs. We also test a unique application of self-transcribing active regulatory region sequencing (STARR-seq) in characterizing allele-dependent transcriptional regulation and provide detailed functional analysis at two risk loci (RGS17 and ASCL2). Together, we introduce a powerful high-throughput pipeline for large-scale screening of functional SNPs at disease risk l...

Research paper thumbnail of FIRE: functional inference of genetic variants that regulate gene expression

Bioinformatics, 2017

Motivation Interpreting genetic variation in noncoding regions of the genome is an important chal... more Motivation Interpreting genetic variation in noncoding regions of the genome is an important challenge for personal genome analysis. One mechanism by which noncoding single nucleotide variants (SNVs) influence downstream phenotypes is through the regulation of gene expression. Methods to predict whether or not individual SNVs are likely to regulate gene expression would aid interpretation of variants of unknown significance identified in whole-genome sequencing studies. Results We developed FIRE (Functional Inference of Regulators of Expression), a tool to score both noncoding and coding SNVs based on their potential to regulate the expression levels of nearby genes. FIRE consists of 23 random forests trained to recognize SNVs in cis-expression quantitative trait loci (cis-eQTLs) using a set of 92 genomic annotations as predictive features. FIRE scores discriminate cis-eQTL SNVs from non-eQTL SNVs in the training set with a cross-validated area under the receiver operating character...

Research paper thumbnail of Comprehensively Evaluating cis -Regulatory Variation in the Human Prostate Transcriptome by Using Gene-Level Allele-Specific Expression

The American Journal of Human Genetics, 2015

Research paper thumbnail of BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair

Cancer research, 2003

Frequent BRAF mutations were reported recently in a variety of human malignancies, including colo... more Frequent BRAF mutations were reported recently in a variety of human malignancies, including colorectal cancer. In this study, we screened 293 colorectal cancers for mutations in exons 11 and 15, two regions containing hotspots for BRAF mutation. Of the 293 cancers, 170 had normal mismatch repair, and 123 had defective mismatch repair (originating from both somatic as well as germ-line mutations in several of the mismatch repair genes). A total of 63 exonic mutations (22%) were detected, 60 of which were V599E, and one each of D593G, G468E, and D586A. Of the tumors with defective mismatch repair, 34% (42 of 123) had a mutation in BRAF, whereas only 12% (21 of 170) of tumors with proficient mismatch repair demonstrated a mutation (P < 0.0001). Interestingly, BRAF mutations were found most often in cases with an hMHL1 abnormality (35 of 60) and rarely in cases with an hMSH2 abnormality (1 of 39; P < 0.0001). More interestingly, of the 31 hMLH1 cases with a BRAF mutation, 30 occu...

Research paper thumbnail of Analysis of hMLH1 and hMSH2 Gene Dosage Alterations in Hereditary Nonpolyposis Colorectal Cancer Patients by Novel Methods

The Journal of Molecular Diagnostics, 2005

Research paper thumbnail of Tumor Microsatellite-Instability Status as a Predictor of Benefit from Fluorouracil-Based Adjuvant Chemotherapy for Colon Cancer

New England Journal of Medicine, 2003

Colon cancers with high-frequency microsatellite instability have clinical and pathological featu... more Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. methods Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. results Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confidence interval, 0.14 to 0.72]; P=0.004). Among patients who received adjuvant chemotherapy, high-frequency microsatellite instability was not correlated with increased overall survival (hazard ratio for death, 1.07 [95 percent confidence interval, 0.62 to 1.86]; P=0.80). The benefit of treatment differed significantly according to the microsatellite-instability status (P=0.01). Adjuvant chemotherapy improved overall survival among patients with microsatellitestable tumors or tumors exhibiting low-frequency microsatellite instability, according to a multivariate analysis adjusted for stage and grade (hazard ratio for death, 0.72 [95 percent confidence interval, 0.53 to 0.99]; P=0.04). By contrast, there was no benefit of adjuvant chemotherapy in the group with high-frequency microsatellite instability. conclusions Fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency microsatellite instability but not those with tumors exhibiting high-frequency microsatellite instability.

Research paper thumbnail of Allelic Imbalance and Microsatellite Instability in Resected Dukeʼs D Colorectal Cancer

Diagnostic Molecular Pathology, 1997

Research paper thumbnail of Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women

Cancer Epidemiology, Biomarkers & Prevention, 2013

Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influenc... more Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistoche...