Abstract
Mitotic regulator genes have been associated with several cancers, however little is known about their possible association with pancreatic cancer. Smoking and family history are the strongest risk factors for this highly fatal disease. The main purpose of this study was to determine if polymorphisms of mitotic regulator genes are associated with pancreatic cancer and whether they modify the association between cigarette smoking and pancreatic cancer risk. A population-based case-control study was conducted in Ontario with 455 pathology-confirmed pancreatic cancer cases and 893 controls. Cigarette smoking history was collected using questionnaires and DNA obtained from blood samples. Genotypes were determined by mass-spectrometry. Odds ratio estimates were obtained using multivariate logistic regression. Interactions between genetic variant and smoking were assessed using stratified analyses and the likelihood ratio statistic (significance P < 0.05). Variants of MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1 were not independently associated with pancreatic cancer risk. A significant interaction was observed between pack-years and MCPH1-2550-C > T (P = 0.02). Compared to never smokers, individuals with 10–27 pack-years and MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR = 2.49, 95% confidence interval [95% CI]: 1.55, 4.00) as were those with >27 pack-years and MCPH1-2550-TC genotype (MVOR = 2.42, 95% CI: 1.45, 4.05). A significant interaction was observed between smoking status and TopBP1-3257-A > G (P = 0.04) using a dominant model. Current smokers with the TopBP1-3257 A allele were at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67). MCPH1-2550-C > T and TopBP1-3257-A > G modify the association between smoking and pancreatic cancer. These findings provide insights into the potential molecular mechanisms behind smoking-associated pancreatic cancer.
Keywords: pancreatic neoplasms, smoking, polymorphism, single nucleotide, mitosis, case-control studies
INTRODUCTION
Mitotic regulators operate at various points in the cell cycle to maintain genomic integrity and cell division control. Given the uncontrolled, proliferative nature of cancer, it is not surprising that mutations in these regulatory genes may be associated with cancer [1,2].
Genetic variants of mitotic regulators have previously been investigated in cancer. Polymorphisms of adenomatous polyposis coli (APC) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1) have been associated with increased colorectal cancer risk [3] and poorer colorectal cancer survival [4], respectively. Polymorphisms of tyrosine protein kinase Fyn (FYN) have been associated with breast cancer risk with odds ratios ranging from 1.38 to 1.45 [5]. A higher frequency of the topoisomerase 2-binding protein 1 (TopBP1)-1010-C > T polymorphism was reported among familial breast and/or ovarian cancer cases compared to controls [6]. Individuals with the TC genotype of protein kinase C alpha (PRKCA) (rs734287) have been found to have a 30% risk reduction for breast cancer compared to wildtypes [7].
A recent study [8] suggests an association between polymorphisms of mitotic regulator genes, cigarette smoking, and pancreatic cancer risk with smokers carrying polymorphisms of TopBP1, polo-like kinase 2 (PLK2), and microcephalin (MCPH1) at significantly increased pancreatic cancer risk, while those with polymorphisms in FYN, ninein (NIN), SNW domain-containing protein 1 (SNW1), and PRKCA showed decreased risk.
To further explore and validate these pancreatic cancer findings, we investigated the potential interactions between variants of mitotic regulator genes MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1, cigarette smoking and pancreatic cancer risk.
MATERIALS AND METHODS
Study Design
A population-based case–control study was conducted with cases obtained through the Ontario Pancreas Cancer Study (OPCS), one of six study sites of the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium [9]. Control subjects were obtained from the accompanying Ontario Familial Colorectal Cancer Registry (OFCCR), one of six sites of the Colon Cancer Family Registry (C-CFR) [10]. Detailed methodologies of the OPCS, the OFCCR and the current study design have previously been described [11–14]. Key methodological details pertinent to the present study are included below.
Participants
Cases are Ontario residents with a primary pathology-confirmed adenocarcinoma of the pancreas or metastasis diagnosed between April 2003 and July 2009. Cases completed three self-administered questionnaires (Family History Questionnaire [FHQ], Personal History [epidemiology] Questionnaire [PHQ], and Clinical Patient Questionnaire [CPQ]), and provided consent for blood samples, medical records, and tumor specimens. 455 cases were included in this study with a median age of diagnosis of 65 yr (range: 20–89 yr), and 54% of them being male. 8/455 cases (1.76%) had a proxy respondent (e. g., spouse) complete the questionnaires on their behalf.
Population-based controls in the study were originally recruited as controls for the OFCCR. All controls in this study do not have a personal history of colorectal or pancreatic cancer. Controls were recruited by random-digit dialing and the Ministry of Finance Property Assessment Database. They also completed self-administered questionnaires. Cases and controls are frequency-matched by age and sex. In total, 893 controls were included with the median age of questionnaire completion (recruitment) being 64 yr (range: 29–79 yr), and 53% of them being male.
Data Collection
Three cigarette smoking variables were derived from data collected using the PHQ: (1) Smoking status (classified as never smoker, former smoker for those who regularly smoked cigarettes >2 yr prior to pancreatic cancer diagnosis for cases and >2 yr prior to questionnaire completion for controls, and current smoker for those who reported regularly smoking cigarettes ≤2 yr prior to pancreatic cancer diagnosis for cases and ≤2 yr prior to questionnaire completion for controls); (2) pack-years defined as the number of packs of cigarettes smoked per day multiplied by the number of smoking years reported at questionnaire completion. Categories were based on tertiles of controls who were ever-smokers; and (3) years smoked defined as the number of years participants reported of smoking cigarettes at questionnaire completion. Categories were based on tertiles of controls who were ever-smokers.
DNA Collection and Genotyping
Sequence variants in genes regulating the mitotic process were identified through literature searches and the National Center for Biotechnology Information dbSNP database [15]. Variants with a published minor allele frequency >5% were selected for analysis. After reviewing the findings reported by Couch et al. [8] we further selected SNPs of genes that Couch et al. [8] reported to be significant in their study. Given the limited sample size and consequent power of the present study, all possible mitotic regulator gene polymorphisms could not be investigated. Genetic variants that were tested in the present study are listed in Table 1.
Table 1.
List of Genes and National Center for Biotechnology Information (NCBI) Single Nucleotide Polymorphisms Database Number (dbSNP) Tested in Cases and Controls
| Gene | NCBI dbSNP no. | Minor allele frequency | Allele change | Amino acid change |
|---|---|---|---|---|
| MCPH1 | rs1057091 | 0.22 | C > T | p.Pro 828 Ser |
| FYN | rs1465061 | 0.37 | A > G | N/A |
| APC | rs2431238 | 0.26 | C > T | N/A |
| PRKCA | rs7342847 | 0.45 | C > T | N/A |
| NIN | rs10145182 | 0.23 | A > T | N/A |
| TopBP1 | rs10935070 | 0.18 | A > G | p.Asn1042Ser |
| RIPK1 | rs12209182 | 0.33 | C > T | N/A |
| SNW1 | rs1477261 | 0.19 | A > T | N/A |
NCBI db SNP, National Center for Biotechnology Information Single Nucleotide Polymorphisms Database Number; minor allele frequency, Global minor allele frequency from NCBI db SNP; MCPH1, microcephalin; FYN, tyrosine protein kinase Fyn; N/A, not available; APC, adenomatous polyposis coli; PRKCA, protein kinase C alpha; NIN, ninein; TopBP1, topoisomerase 2-binding protein; RIPK1, receptor-interacting serine/threonine-protein kinase 1; SNW1, SNW domain-containing protein.
Genotyping of variants was performed using the SequenomiPLEX genotyping assay and MassARRAY-MALDI-TOF Mass Spectrometry system (Sequenom, San Diego, CA). Primers for amplification of each variant were designed using the MassARRAY Workstation 3.0 (Sequenom) software into three multiplex PCR reactions. Samples were then randomly ali-quoted onto 384-well plates and blinded by disease status. All plates included positive and negative controls for each variant as well as a 10% repeat samples for quality control. The concordant rate of 10% repeat samples for quality control was >99% in agreement. Genotypes were analyzed using the MassARRAY Workstation 3.0 software and confirmed by visual assessment of the data.
Statistical Analysis
Multivariate unconditional logistic regression analysis was conducted to obtain age-, sex-adjusted odds ratio (ASOR) and multivariate-adjusted odds ratio (MVOR) estimates. Pancreatic cancer risk factors (ethnicity, body mass index, alcohol consumption, personal history of diabetes mellitus diagnosis, aspirin use, non-steroidal anti-inflammatory drug use, and family history of pancreatic cancer) were evaluated as potential confounders in the associations between pancreatic cancer and all three types of cigarette smoking variables. To build the most parsimonious multivariate models, only potential confounding variables that changed the ASOR by >10% [16] were deemed to be confounding variables, and were subsequently adjusted for in multivariate models. As ethnicity was the only confounding variable that changed the ASOR >10%, it was the only additional variable (plus age and sex) that was adjusted for in multivariate models. Caucasians were heavily represented in both our cases and controls at 85% and 96%, respectively.
Main genetic effects were investigated with multivariate unconditional logistic regression investigating the effect of each genetic genotype on pancreatic cancer risk as well as a dominant model for genes if such a trend was suggested when analyzed by genotype.
Stratified analyses and the likelihood ratio statistic (LRS) comparing models with and without the interaction term at a statistically significant result set at P < 0.05 were used to investigate effect modification between each genetic variant and smoking.
All statistical analyses were conducted using SAS (SAS Institute, Cary, NC).
Deviation from Hardy–Weinberg equilibrium (HWE) was tested for each polymorphism on a subset of control participants only using HWE.test in the genetics package [17] of R [18] with the statistically significance level set at P = 0.05.
Ethics Approval
This project was approved by the research ethics boards of University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada.
RESULTS
A previous report using the same cases and controls as in the present study has described this study sample’s distribution of risk factors and smoking variables in detail [14].
Testing of HWE was completed for all polymorphisms showed in Table 1. APC (rs2431238; P = 0.003), and NIN (rs10145182; P = 0.049) deviated from HWE. All other genetic variants described in this study were within HWE (P > 0.05). P values of HWE. test [17,18] for MCPH1 (rs1057091), FYN (rs1465061), PRKCA (rs7342847), TOPBP1 (rs10935070), RIPK1 (rs12209182), and SNW1 (rs1477261) were 0.34, 0.43, 0.57, 0.82, 0.84, and 0.07, respectively.
Table 2 illustrates genotype frequencies for cases and controls, and ASOR estimates for the association between each genotype and pancreatic cancer risk. None of the genetic variants investigated were significantly associated with pancreatic cancer risk.
Table 2.
Distribution of Pancreatic Cancer Cases, Controls, and Age-, Sex-Adjusted Odds Ratio (ASOR) Estimates for Selected Genetic Polymorphisms
| Genetic polymorphism | Cases (n = 455)
|
Controls (n = 893)
|
ASOR | 95% CI | ||
|---|---|---|---|---|---|---|
| No. | % | No. | % | |||
| MCPH1 (rs1057091) | ||||||
| CC | 215 | 48 | 419 | 47 | 1.00 (referent) | |
| TC | 201 | 45 | 389 | 44 | 1.00 | 0.78, 1.27 |
| TT | 31 | 7 | 77 | 9 | 0.80 | 0.51, 1.26 |
| FYN (rs1465061) | ||||||
| GG | 158 | 35 | 341 | 39 | 1.00 (referent) | |
| AG | 224 | 50 | 424 | 48 | 1.17 | 0.91, 1.51 |
| AA | 68 | 15 | 116 | 13 | 1.28 | 0.89, 1.83 |
| FYN (rs1465061) | ||||||
| AG +þ AA | 292 | 65 | 540 | 61 | 1.00 (referent) | |
| GG | 158 | 35 | 341 | 39 | 0.84 | 0.66, 1.07 |
| APC (rs2431238) | ||||||
| CC | 207 | 47 | 403 | 46 | 1.00 (referent) | |
| CT | 184 | 41 | 353 | 40 | 0.98 | 0.76, 1.26 |
| TT | 53 | 12 | 120 | 14 | 0.89 | 0.62, 1.29 |
| PRKCA (rs7342847) | ||||||
| CC | 181 | 40 | 349 | 40 | 1.00 (referent) | |
| CT | 208 | 46 | 406 | 46 | 1.00 | 0.78, 1.29 |
| TT | 62 | 14 | 128 | 15 | 0.96 | 0.67, 1.38 |
| NIN (rs10145182) | ||||||
| TT | 161 | 36 | 336 | 38 | 1.00 (referent) | |
| TA | 224 | 50 | 394 | 45 | 1.18 | 0.92, 1.53 |
| AA | 66 | 15 | 152 | 17 | 0.83 | 0.58, 1.19 |
| TopBP1 (rs10935070) | ||||||
| AA | 213 | 47 | 407 | 46 | 1.00 (referent) | |
| GA | 193 | 43 | 381 | 43 | 0.95 | 0.74, 1.21 |
| GG | 45 | 10 | 93 | 11 | 0.95 | 0.64, 1.41 |
| RIPK1 (rs12209182) | ||||||
| TT | 157 | 35 | 292 | 33 | 1.00 (referent) | |
| CT | 205 | 46 | 437 | 49 | 0.88 | 0.68, 1.14 |
| CC | 87 | 19 | 158 | 18 | 1.02 | 0.73, 1.42 |
| SNW1 (rs1477261) | ||||||
| TT | 284 | 71 | 593 | 68 | 1.00 (referent) | |
| AT | 107 | 27 | 263 | 30 | 0.85 | 0.65, 1.11 |
| AA | 11 | 3 | 18 | 2 | 1.31 | 0.61, 2.83 |
No., numbers may not add to total due to missing values; ASOR, age, sex-adjusted odds ratio; 95% CI, 95% confidence interval; MCPH1, microcephalin; FYN, tyrosine protein kinase fyn; APC, adenomatous polyposis coli; PRKCA, protein kinase C alpha; NIN, ninein; TopBP1, topoisomerase 2-binding protein; RIPK1, receptor-interacting serine/threonine-protein kinase 1; SNW1, SNW domain-containing protein.
Potential interactions between smoking and genetic variants listed in Table 1 were investigated, and only the statistically significant and marginally significant results are presented in Table 3. A significant interaction was observed between pack-years and MCPH1-2550-C > T (rs1057091; P = 0.02). Compared to never smokers, individuals with 10–27 pack-years and the MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR = 2.49, 95% confidence interval [95% CI]: 1.55, 4.00) =as were those with >27 pack-years and the MCPH1-2550-TC genotype (MVOR = 2.42, 95% CI: 1.45, 4.05). A marginally significant interaction was observed between smoking status and TopBP1-3257-A > G (P = 0.07), with the trend of MVORs suggesting an interaction; our study may have been underpowered to detect a statistically significant interaction. However, when those with the A allele of TopBP1-3257 were grouped together, again current smokers were at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67), and a statistically significant interaction was observed (P = 0.04).
Table 3.
Multivariate-Adjusted Odds Ratio (MVOR) Estimates and 95% Confidence Interval (95% CI) for Smoking Status Stratified by Genotypes Selected Based on Significance
| Genetic variant
|
||||||||
|---|---|---|---|---|---|---|---|---|
| MVOR
|
95% CI
|
MVOR
|
95% CI
|
MVOR
|
95% CI
|
|||
|
MCPH1 2550 C > T (rs1057091)
| ||||||||
|
|
CC (n = 634)
|
TC (n = 590)
|
TT (n = 108)
|
df
|
Pinteraction
|
|||
| Smoking pack-years | ||||||||
| Never smoker | 1.00 (referent) | 1.00 (referent) | 1.00 (referent) | |||||
| ≤9 | 1.00 | 0.58, 1.73 | 1.26 | 0.76, 2.07 | 0.99 | 0.23, 4.29 | ||
| 10–27 | 2.49 | 1.55, 4.00 | 1.00 | 0.59, 1.70 | 1.09 | 0.31, 3.81 | ||
| >27 | 1.40 | 0.87, 2.26 | 2.42 | 1.45, 4.05 | 1.75 | 0.54, 5.74 | 6 | 0.02 |
| Genetic variant
|
||||||||
|---|---|---|---|---|---|---|---|---|
| MVOR
|
95% CI
|
MVOR
|
95% CI
|
MVOR
|
95% CI
|
|||
|
TopBP1 3257 A > G (rs10935070)
| ||||||||
|
|
AA (n = 620)
|
GA (n = 574)
|
GG (n = 138)
|
df
|
Pinteraction
|
|||
| Smoking status | ||||||||
| Never | 1.00 (referent) | 1.00 (referent) | 1.00 (referent) | |||||
| Former | 1.38 | 0.91, 2.11 | 0.82 | 0.53, 1.25 | 0.94 | 0.40, 2.20 | ||
| Current | 2.79 | 1.66, 4.70 | 2.32 | 1.39, 3.88 | 0.55 | 0.13, 2.34 | 4 | 0.07 |
| Genetic variant
|
||||||||
|---|---|---|---|---|---|---|---|---|
| MVOR
|
95% CI
|
MVOR
|
95% CI
|
MVOR
|
95% CI
|
|||
|
TopBP1 3257 A > G (rs10935070)
| ||||||||
|
|
AA + GA (n = 1194)
|
GG (n = 138)
|
|
|
df
|
Pinteraction
|
||
| Smoking status | ||||||||
| Never | 1.00 (referent) | 1.00 (referent) | ||||||
| Former | 1.05 | 0.78, 1.42 | 0.94 | |||||
| Current | 2.55 | 1.77, 3.67 | 0.55 | 0.13, 2.34 | 2 | 0.04 | ||
MVOR, multivariate-adjusted odds ratio; adjusted for age, sex, ethnicity; 95% CI, 95% confidence interval; df, degrees of freedom; Pinteraction, P-value for interaction; MCPH1, microcephalin; TopBP1, topoisomerase 2-binding protein.
DISCUSSION
Couch et al. [8] conducted the only previous study that evaluated the potential interaction between smoking, polymorphisms of mitotic regulator genes, and pancreatic cancer risk. In contrast to this earlier study that reported an increased risk associated with APC (rs2431238) [8], we did not find such association with APC. However, it is important to consider this finding with consideration that in our study, APC (rs2431238) deviated from HWE, while this polymorphism was in HWE in the previous report [8]. Consistent with the previous study [8], we found that NIN AA genotype was associated with a non-significant reduced risk for pancreatic cancer (ASOR = 0.83, 95% CI: 0.58, 1.19). No significant associations were found between pancreatic cancer and MCPH1, FYN, PRKCA, TopBP1, RIPK1, and SNW1. Congruent with previous finding [8] of TopBP1 (rs10935070) being significantly associated with increased pancreatic cancer risk among current smokers, we report current smokers with the TopBP1-3257-AA and TopBP1-3257-GA genotypes are at increased risks with MVOR estimates of ~2.50. Furthermore under a dominant model, current smokers with the TopBP1-3257 AA and GA genotypes are at increased risk for pancreatic cancer (MVOR = 2.55, 95% CI: 1.77, 3.67), and a statistically significant interaction was observed between smoking and TopBP1-3257 using a dominant model (P = 0.04). A significant interaction between MCPH1 and pack-years (P = 0.02) was observed, with individuals with 10–27 pack-years and the MCPH1-2250-CC genotype and those with MCPH1-2250-TC and >27 pack-years being at a particularly high risk for pancreatic cancer with MVORs of ~2.50. It is unclear why significantly increased risk for pancreatic cancer was only observed among MCPH1-2250-CC carriers with 10–27 pack-years, but not among those with >27 pack-years, and similarly why only smokers with >27 pack-years and the MCPH1-2250-TC genotype were at increased risk. It is possible that we were underpowered to detect a statistically significant effect for those with >27 pack-years and the MCPH1-2250-CC genotype and/or there is a dose-dependent effect where individuals with one copy of the C allele require higher exposure to cigarette smoking to have a statistically significant increased risk. Similarly Couch et al. [8] reported that MCPH1 (rs2433149) is associated with increased pancreatic cancer risk among ever and former smokers. It is important to note that MCPH1 (rs1057091) in our study, and MCPH1 (rs2433149) in the previous study [8] are in high linkage disequilibrium.
The MCPH1 protein has been shown to regulate the expression of CHK1 and BRCA1 [19] and mitotic checkpoints [20]. Specifically in relation to cancer, it has been demonstrated that cytoplasmic MCPH1 is only found in cultures of high-grade epithelial ovarian cancer cells [21]. Meanwhile, in vitro studies have demonstrated that TopBP1 plays a role in cell cycle regulation and responding to DNA damage [22,23]. Mutations of TopBP1 [24] have been observed in tumor cells and in relation to p53 [25]. Epidemiologically, previous studies report TopBP1 variants being associated with breast cancer [6]. In summary, there is growing biological evidence that MCPH1 and TopBP1 may be contributors to carcinogenesis, supporting our hypothesis that the combination of cigarette smoking and polymorphisms of mitotic regulators can increase pancreatic cancer risk.
Limitations of the present study are that despite a relatively large sample size for a pancreatic cancer study, we were still limited in statistical power for certain calculations, particularly interactions. Specifically compared to Couch et al.’s [8] study ours was relatively underpowered with a total sample size of 1348 compared to Couch et al.’s [8] 2240. Similar to other retrospective pancreatic cancer studies, our study is susceptible to survival bias given the poor prognosis of pancreatic cancer. Given the modest response rates of our cases and controls at ~30% [11] and ~61% [13], respectively, response bias is possible. Data on smoking and potential confounding variables were collected using self-administered questionnaires, hence recall bias cannot be excluded. HWE testing for genetic variants demonstrated that two variants deviated from HWE (APC [rs2431238], NIN [rs10145182]) and, genotyping errors in these variants cannot be excluded.
Strengths of the study are that as a population-based study, our findings are not limited by biased sampling frames (e.g., hospital-based). As the OPCS and OFCCR collect extensive epidemiological data, we were able to adjust for pancreatic cancer risk factors, reducing the possibility of our findings being biased by uncontrolled confounding.
This is the first study to investigate mitotic regulator gene variants and pancreatic cancer risk in a Canadian population. While we did not find significant independent associations between the variants that we investigated and pancreatic cancer risk, we report that the MCPH1-2550-C > T variant significantly modifies the association between smoking and pancreatic cancer. These results validate earlier findings [8] indicating a potentially significant role of MCPH1 in modifying the risk of pancreatic cancer associated with cigarette smoking. As few results are replicated in genetic epidemiology, these findings are particularly noteworthy. While the modification of TopBP1 on cigarette smoking and pancreatic cancer failed to reach statistical significance initially, a statistically significant interaction was observed using a dominant model of grouping individuals with the A allele versus without.
Future studies are necessary to elucidate the mechanism by which MCPH1 and TopBP1 influence the pathogenesis of pancreatic cancer, and replications of our findings are needed to validate our report.
Acknowledgments
The authors thank Cheryl Crozier and Xiangdong Liu at the Analytical Genetics Technology Centre for their assistance with the genotyping experiments, Darshana Daftary and Teresa Selander at the OFCCR for their assistance with data collection and sample extraction, and Laura Anderson for her assistance in data management and interpretation. This work was supported by funding from the Grant Miller Cancer Research Award, Faculty of Medicine, University of Toronto, the National Institutes of Health [R01 CA97075, as part of the PACGENE consortium], and the National Cancer Institute, National Institutes of Health under RFA number CA-95-011, the Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783], and through cooperative agreements with members of the Colon Cancer Family Registry (CFRs) and Principle Investigators, and the National Cancer Institute of Canada [grant number 13304]. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR.
Abbreviations
- APC
adenomatous polyposis coli
- RIPK1
receptor-interacting serine/threonine-protein kinase 1
- FYN
tyrosine protein kinase Fyn
- TopBP1
topoisomerase 2-binding protein 1
- PRKCA
protein kinase C alpha
- MCPH1
microcephalin
- NIN
ninein
- SNW1
SNW domain-containing protein 1
- PACGENE
pancreatic cancer genetic epidemiology
- OFCCR
Ontario Familial Colorectal Cancer Registry
- OPCS
Ontario Pancreas Cancer Study
- CPQ
Clinical Patient Questionnaire
- ASOR
age-, sex-adjusted odds ratio
- MVOR
multivariate-adjusted odds ratio
- HWE
Hardy–Weinberg equilibrium
- 95% CI
95% confidence interval
- C-CFR
Colon Cancer Family Registry
- FHQ
Family History Questionnaire
- LRS
Likelihood ratio statistic
- OR
odds ratio
- PHQ
Personal Health Questionnaire
- PLK2
Polo-like kinase 2
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