CDKN2A Germline Rare Coding Variants and Risk of Pancreatic Cancer in Minority Populations

Abstract

Background:

Pathogenic germline mutations in the CDKN2A tumor suppressor gene are rare and associated with highly-penetrant familial melanoma and pancreatic cancer (PC) in non-Hispanic Whites (NHWs). To date, the prevalence and impact of CDKN2A rare coding variants (RCV) in racial minority groups remain poorly characterized. We examined the role of CDKN2A RCVs on risk of PC among minority subjects.

Methods:

We sequenced CDKN2A in 220 African American (AA) PC cases, 900 non-cancer AA controls, and 183 Nigerian controls. RCV frequencies were determined for each group and compared with that of 1,537 NHW PC patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for both a case-case comparison of RCV frequencies in AAs versus NHWs, and case-control comparison between AA cases versus non-cancer AA controls plus Nigerian controls. Smaller sets of Hispanic and Native American cases and controls also were sequenced.

Results:

One novel missense RCV and one novel frameshift RCV were found among AA patients: 400G>A and 258_278del. RCV carrier status was associated with increased risk of PC among AA cases (11/220; OR=3.3, 95%CI: 1.5–7.1;p=0.004) compared with AA and Nigerian controls (17/1083). Further, AA cases had higher frequency of RCVs, 5.0% (OR=13.4, 95%CI 4.9–36.7;p<0.001) compared to NHW cases(0.4%).

Conclusions:

CDKN2A RCVs are more common in AA than in NHW PC patients, and associated with moderately increased PC risk among AAs.

Impact:

RCVs in CDKN2A are frequent in AAs and are associated with risk for PC.

Introduction

Pancreatic cancer (PC), especially pancreatic ductal adenocarcinoma, is a highly lethal cancer with 1-year and 5-year survival rates of 26% and 8%, respectively [1]. Long-term survival with PC is generally dependent on resection of an early stage tumor. However, early detection of PC is uncommon, with only 20% of all patients found to have localized disease at the time of diagnosis [1]. African Americans (AAs) consistently have a higher incidence of PC and poorer survival after diagnosis compared with non-Hispanic Whites (NHWs)[1]. AAs tend also to present with more advanced-staged cancer at diagnosis [2]. Reasons for the higher incidence of PC among AAs are not completely clear. Known epidemiologic risk factors, such as obesity and tobacco smoking, do not fully explain the excess risk of PC among AAs [3]. It is therefore plausible that the higher incidence of PC among AAs may be due in part to inherited predisposition.

It is well-established that risks for PC and melanoma are increased in families of the cyclin dependent kinase inhibitor 2A gene (CDKN2A) germline mutation carriers [4–8]. In general, melanoma occurs primarily in NHWs, with an annual incidence rate of 32.3 per 100,000 men and 20.0 per 100,000 women in the United States, which is far in excess of that observed among AAs (1.0 per 100,000 in males and females), Hispanics (4.8 per 100,000 males, and 4.6 per 100,000 females), or Native Americans (4.1 per 100,000 males and 4.0 per 100,000 females)[9]. The prevalence of CDKN2A RCVs among NHWs with melanoma is approximately 20–57% in melanoma-prone families [10], but the prevalence is only about 1–2% among unselected patients with a single melanoma diagnosis in their families [11]. The penetrance estimates for melanoma among NHW CDKN2A mutation carriers is 28% by age 80 years [12], and for PC approximately 58% by age 80 [13]. Somatic mutations and loss of p16 expression are commonly found in cutaneous malignant melanoma (17, 18). Similarly, somatic alterations (including mutations, loss of heterozygosity, hypermethylation, etc.) in CDKN2A have been reported in up to 95% of pancreatic tumors, underscoring the importance of this gene in pancreatic tumorigenesis [14].

Thus, our objective was to elucidate the role of pathogenic germline rare coding variants (RCVs) of CDKN2A in relation to PC risk in minority groups. There are major challenges to the study of germline CDKN2A RCVs in PC because of (a) the requirement for rapid case ascertainment to obtain biospecimens suitable for genetic analysis due to the poor prognosis of PC [15], (b) the anticipated low frequency of deleterious RCVs [13], (c) the lower absolute numbers of AA, Hispanic, and Native American PC patients [16], and (d) the perennially low participation rates of minority groups in clinical research [17–19]. To overcome these challenges, we performed a pooled analysis of individual-level data from 12 centers to investigate the role of pathogenic CDKN2A RCVs in incident PC.

Materials and Methods

Patient recruitment

This study was reviewed and approved by the Mayo Clinic Institutional Review Board (IRB), as well as IRBs of all collaborating centers. Risk factor questionnaires or medical record surveys were used by each site to solicit self-reported information on participants’ race and ethnicity. Lymphocyte DNA or DNA from buccal cells obtained from patients with histologically or clinically documented pancreatic ductal adenocarcinoma were provided by investigators from the following research registries: Mayo Clinic Biospecimen Resource for Pancreas Research [20, 21] at all three Mayo Clinic campuses (Minnesota, Arizona, Florida); MD Anderson Cancer Center [22]; the H. Lee Moffitt Cancer Center, and the Vanderbilt-Ingram Cancer Center [23, 24]. Germline DNA was extracted from surgically resected normal tissue of PC patients from Columbia University. Control subjects were identified from: 1) de-identified healthy AAs who underwent clinical testing for cystic fibrosis in Rochester, MN [25], 2) a convenience sample of AAs recruited through a church-based study in Jacksonville, FL [26], 3) the Mayo Clinic Biobank in Rochester, MN [27], 4) a large breast cancer control group including Chicago-area AAs [28], 5) Native Nigerians [29], 6) the MD Anderson Cancer Center [22], 7) the H. Lee Moffitt Cancer Center, and 8) the Southern Community Cohort Study (SCCS) at the Vanderbilt-Ingram Cancer Center [23, 24]. All cases and controls were recruited prospectively except the Columbia patients and the samples from Mayo Clinic Laboratory Medicine, which were retrospective. The study sample comprised of PC cases and non-cancer controls of NHW, AA, Nigerian, Hispanic, and Native American races/ethnicities.

Sequencing

All DNA samples were shipped to the Mayo Clinic Genome Analysis Core for analyses. Sanger sequencing was performed as previously described in detail [13, 30]. Resequencing of the four exons of the CDKN2A gene, including three exons of CDKN2A isoform 1 (NM_000077) and exon 1 of CDKN2A isoform 4 (NM_058195), was performed. Primer sets for polymerase chain reactions (PCR) were designed using the web-based design tool Primer 3 software (version 0.4.0). Intronic primers covering sequences of interest were designed at least 30bp away from the intron-exon boundaries of the gene. PCRs were carried out using AmpliTaq Gold® DNA Polymerase (Applied Biosystems™, Waltham, MA) following manufacturer’s protocol. After PCR reactions, the amplicons were treated with the ExoSAP-IT (USB Corp, Cleveland, OH) to degrade unincorporated PCR primers and deoxynucleotide triphosphates. The cleaned products were mixed with 5 picomoles of the forward or reverse PCR primers for sequencing. DNA sequence variants were identified using PolyPhred [31].

Variant calling and in silico analysis

Each potential coding variant identified was investigated and classified as polymorphic (non-pathogenic) or high impact (deleterious or probably damaging), affecting protein coding of p16 or p14ARF, excluding known polymorphisms (e.g., A148T). We used available online databases for determination of variant frequency in populations, along with identification of prior reports of variants, including Exome Sequencing Project (ESP)[32], the catalogue of somatic mutations in cancer (COSMIC) [33], the University of Vermont CDKN2A gene database (UVM Biodesktop) [34], dbSNP[35], the gnomAD database [36], the genoMEL paper [10], the CDKN2A LOVD database (August 31 2016 version) [37], and ClinVar[38]. Using the cDNA position and amino acid change, a thorough literature search was performed to determine whether variants had previously been reported in cancer kindreds, in melanoma or PC patients, or in functional studies of CDKN2A [10, 39–48]. In silico descriptive analyses were performed with SIFT [49] and PolyPhen2 [50] for the variants identified (insertions/deletions assumed deleterious by those tools are not annotated) when available but were not used for final determination of variant status due to their imperfect specificity [51].

Statistical Analysis

The PC patients and non-cancer controls were classified based on whether they carried at least one non-synonymous or frame-shift rare coding variant (RCV) in CDKN2A. Race/ethnicity was determined by self-report. Variants previously determined to be polymorphic (>= 1%) in the above-cited publicly available databases were excluded from the analysis. Differences in demographic characteristics were compared among the racial/ethnic groups using Kruskal Wallis test for continuous variables and Fisher’s exact test for categorical variables. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated by comparing the proportion of RCV carriers among the PC cases with the proportion of carriers among the non-cancer controls in each minority group (i.e., AAs only, AAs plus Nigerians, Hispanics, and Native Americans). We also performed case-case comparison by comparing proportion of carriers among NHW cases (referent groups) [13] versus proportion of carriers among cases in each of the minority groups. All statistical tests were two-sided and were considered significant at the α=0.05 level. Analyses were performed in SAS version 9.4 (SAS Institute, Cary, NC). Population attributable risk (PAR) was estimated by the difference in incidence rates between the AAs and NHWs divided by incidence in the AAs. Approximations from previously published studies of prevalence and SEER incidence rates were used.

Results

Biospecimens and epidemiological and sequencing data used in the present study originated from 12 hospital-based and population-based studies. Table 1 presents the design, source population, and participant characteristics, including age, sex, and race or ethnicity, for each of the participating centers. In total, the study included 220 AA PC cases and 900 healthy AA controls, 183 healthy Nigerian controls, 119 Hispanic cases and 58 healthy Hispanic controls, 11 Native American cases and 20 healthy Native American controls, and 1,537 NHW PC cases.

Table 1.

Sources of case and control subjects in study, race and ethnicity, median age, and sex

Center	Type of study; case status	Origin	No. of Subjects	Median Age (range)	Sex (% Male)
African/African American
Columbia University Medical Center	Case series	Hospital – U.S.	7	69 (36–86)	29
Lee Moffitt Cancer Center	Case-control; cases	Hospital – U.S.	15	59 (38–82)	40
Mayo Clinic Pancreas Biospecimen Resource	Case-Control; cases	Clinic –U.S.	48	62.5 (38–89)	42
MD Anderson Cancer Center	Case-Control; cases	Hospital – U.S.	52	61.5 (37–80)	48
Vanderbilt University	Cohort; cases	Population-based– Southern U.S.	98	58 (40–79)	48
Lee Moffitt Cancer Center	Case-control; controls	Hospital – U.S.	15	60 (37–79)	40
Mayo Clinic Laboratory Medicine	Clinical biorepository; controls	Referral lab	191	--	--
Mayo Clinic BioBank	Cohort; controls	Olmsted County, MN	80	48 (21–82)	44
Mayo Clinic MGUS Study	Cohort; controls	Jacksonville, FL	118	57.5 (37–91)	28
MD Anderson Cancer Center	Case-Control; controls	Hospital – U.S.	25	55 (36–82)	48
University of Chicago	Case-Control; controls	Chicago, IL	185	56 (27–95)	8
University of Chicago	Case-Control; controls	Nigeria	183	59 (37–100)	0
Vanderbilt University	Cohort; controls	Population-based – Southern U.S.	286	58 (40–79)	49
Hispanic
Columbia University Medical Center	Case series	Hospital – U.S.	20	62 (53–83)	45
H. Lee Moffitt Cancer Center	Case-control; cases	Hospital-U.S.	6	53 (39–65)	50
Mayo Clinic Pancreas Biospecimen Resource	Case-Control; cases	Clinic –U.S.	31	60 (20–88)	58
MD Anderson Cancer Center	Case-Control; cases	Hospital – U.S.	62	61 (40–79)	53
H. Lee Moffitt Cancer Center	Case-control; controls	Hospital – U.S.	6	53.5 (39–64)	50
MD Anderson Cancer Center	Case-Control; controls	Hospital – U.S.	49	53 (38–78)	61
Mayo Clinic MGUS Study	Cohort; controls	Jacksonville, FL	3	50 (46–56)	100
Native American
Mayo Clinic Pancreas Biospecimen Resource	Case-Control; cases	Clinic –U.S.	9	53 (44–69)	56
MD Anderson Cancer Center	Case-Control; cases	Hospital – U.S.	2	62.5 (62–63)	50
Mayo Clinic BioBank	Cohort; controls	Olmsted County, MN	20	57.5 (25–85)	40
Non-Hispanic White
Mayo Clinic Pancreas Biospecimen Resource	Case-Control; cases	Clinic-U.S.	1,537	65.5 (28–91)	56

Note: 2 AA cases and 2 AA controls each carried two variants

Supplementary Table 1 summarizes the RCVs found in each race or ethnic group. Some variants are not reported, if they appeared to be polymorphisms, defined a priori as presence in more than 1% in publicly available databases. The RCVs were classified as deleterious, probably damaging, or possibly damaging/tolerated based on SIFT and Polyphen designation. We found five novel RCVs: 3 missense variants Exon 1B:c.116A>G, Exon 2: c.192G>C, Exon 2:c.400G>A, and two frameshift variants on Exon 2:(c.258_278del) and Exon 2:c.280dupC. Two of these RCVs were unique to our 220 AA PC patients only: c258_278del and c.400G>A, two were RCVs found in our 900 AA controls only: 116A>G and 280dupC. One other novel RCV was found in the 1537 NHW PC cases. Among the PC cases, RCV frequencies were highest among Native Americans (1/11; 9.1%), followed by AAs (11/220; 5.0%) and Hispanics (4/119; 3.4%), and lowest among NHWs (6/1537; 0.4%) (Table 2). Among the healthy controls, RCV frequencies were highest in AAs (16/900; 1.8%) followed by Nigerians (1/183; 0.5%). No RCV was found among healthy controls of Hispanic and Native American ancestry (Table 2). Two AA cases and two AA controls carried multiple RCVs. Phase was not determined.

Table 2:

Frequency of CDKN2A Rare Coding Variant (RCV) carriers among population samples of pancreatic cancer cases and controls by race and ethnicity, and RCV frequencies. Odds ratios (OR), 95% confidence intervals (CIs), and p-values are reported for (A) case-case comparison between NHW cases versus cases in the racial minority groups, and (B) comparisons between pancreatic cancer cases versus controls by in each race or ethnic group.

A	Pancreatic Cancer Cases		Healthy Controls		Cases vs Controls
Group	N carriers/ N tested	%	N carriers/ N tested	%	OR (95% CI)	p-value
African American and African Nigeria Controls (Combined)	11/220	5.0	17/1083	1.6	3.3 (1.5–7.1)	0.004
• African American	11/220	5.0	16/900	1.8	2.9 (1.3–6.4)	0.005
• African - Nigeria a	-	-	1/183	0.5	-	-
Hispanic	4/119	3.4	0/58	0	4.6 (0.2–86.1)	0.30
Native American	1/11	9.1	0/20	0	5.9 (0.2–156.6)	0.35

B	Pancreatic Cancer Cases		Minority Cases vs NHW Cases
Group	N carriers/ N tested	%	OR (95% CI)	p-value
Non-Hispanic White (NHW)	6/1537	0.4	Reference	--
African American	11/220	5.0	13.4 (4.9–36.7)	<0.001
Hispanic	4/119	3.4	8.9 (2.5–31.9)	0.004
Native American	1/11	9.1	25.5 (2.8–231.8)	0.048

^aData were not available for Nigerian pancreatic cancer cases

We performed case-control analyses within each race/ethnicity and found higher RCV prevalence among AA PC cases compared with AA controls (OR 2.9, 95% CI: 1.3–6.4, p=0.005). The RCV prevalence estimate among the AA cases increased slightly when the Nigerian controls were combined with AA controls and used as the comparison group (OR=3.3, 95% CI: 1.5–7.1, p=0.004) (Table 2A). After exclusion of variants predicted by SIFT or PolyPhen to be benign/tolerated, the association remained significant (10/220 AA cases vs 15/1083 AA controls; OR=3.4, 95% CI 1.5–7.6, p=0.005). Adjustment for age, smoking status (ever/never), and diabetes (yes/no) further increased the observed association (OR=4.3, 95% CI: 1.5–12.2, p=0.006). ORs for comparison of RCV prevalence between Hispanic cases and controls (OR=4.6, 95% CI: 0.2–86.1, p=0.30) and between Native American cases and controls (OR=5.9, 95% CI: 0.2–156.6, p=0.35) did not differ significantly, likely due to the small numbers of cases and controls in these groups.

We further performed a case-case comparison of RCV frequencies among PC cases in the NHW sample (referent group) with RCV frequencies among AA cases, Hispanic cases, and Native American cases. Compared to NHW PC cases, AA PC cases had higher RCV prevalence (OR=13.4, 95% CI: 4.9–36.7, p<0.001), as did Hispanic cases (OR=8.9, 95% CI: 2.5–31.9, p=0.004), and Native American cases (OR=25.5, 95% CI 2.8–231.8, p = 0.048) (Table 2B). Because of the known potential contributions of splice-site and upstream variants to disease risk, we also performed an ancillary analysis comparing frequency of these RCVs among NHW PC patients (0.9%) with that of PC patients in the minority groups. We found higher RCV prevalence among the AA (5.9%, OR=6.8, 95% CI: 3.2–14.7, p<0.001), Hispanic (6.7%, OR=7.8, 95% CI: 3.2–19.1, p<0.001), and Native American (9.1%, OR=10.9, 95% CI: 1.3–90.8, p=0.006) PC patients, although no statistically significant differences were observed in comparisons by minority group (Supplementary Table 2).

By assuming 1) a 1.8% prevalence of CDKN2A RCVs in AAs; 2) a 0.1% prevalence of CDKN2A RCVs in NHWs (assuming a lower prevalence than the 0.4% reported in NHW cases); 3) a PC incidence rate about 5–7% higher in AAs than NHWs; and 4) the current SEER PC rates for AAs (15.5/100,000) and NHWs (12.7/100,000) or 22% higher for AAs, we estimate that the CDKN2A RCVs may account for approximately one-fourth of the excess risk of PC in AAs.

We had previously reported that 4 of 9 (44%) and 2 of 9 (22%) of NHW carriers had a family history of PC and malignant melanoma, respectively [13]. Among 11 AA PC cases who carried a RCV in CDKN2A, 7 had family history information available. One carrier (14.3%) reported PC diagnosis in a first-degree relative compared to 6.3% of 111 AA cases without a RCV detected who had family history data available (p=0.40). No family history of melanoma was reported among the 7 AA RCV carriers, and one family history of melanoma was reported among the 88 non-carriers. Mean age at diagnosis of PC was similar among AA CDKN2A RCV carriers and non-carriers (58.5 years vs 60.6, p=0.66), and these ages are similar to those reported for NHW [13]. We also found in our Hispanic PC cases that none of the 4 carriers and 3 of 112 non-carriers had a positive family history of PC and no cases reported a family history of melanoma. Among our Native American cases no family history of either PC or melanoma were reported.

Discussion

We report the first collaborative study of germline CDKN2A variation among samples of subjects who are non-White. We discovered that high-impact CDKN2A RCVs are more common in persons of African descent and are associated with increased risk for PC. The frequencies of RCVs are in striking contrast to that of NHW PC patients, among whom we had previously identified only 0.4% as mutation carriers [13]. The ORs of 2.9 to 3.3 seen in AA subjects are much less than the relative risk of 46.6 (95% CI 24.7–76.4) of PC reported for the highly penetrant Leiden CDKN2A founder mutation [52], but more similar in magnitude to the moderate 2–4 fold risk for breast cancer in NHW conferred by mutations in CHEK2, ATM, PALB2, and NBS1, all with allele frequencies in the general population of ~1% [53].

The aggregate high frequency of RCVs identified in AA PC cases and controls may potentially be explained by evolutionary/population genetic considerations. First, CDKN2A is thought primarily to function as a melanoma tumor suppressor gene. It is well-established that individuals with darker skin (due to higher melanin concentration), including African Americans, have lower risk of developing skin cancer and melanoma in the presence of ultraviolet radiation [54, 55]. It stands to reason that any selection against variation would be minimized in populations with low incidence of melanoma, (i.e., relaxed selection in African populations versus Whites). In contrast, any potential selection pressure through PC is unlikely to affect reproductive success, given its median age of onset above 70 years. Secondly, African populations are evolutionarily the most ancestral among humans [56, 57]; therefore, one might postulate that the existence of any given gene variation may be expected to be higher in this population than others. However, an exome sequencing study of 1,351 persons of European ancestry and 1,088 persons of African ancestry suggested that most RCVs are evolutionarily recent. Further, among likely functional SNVs, the proportions of rare and intermediate frequency variants per individual are higher among African ancestry individuals compared to those of European ancestry [58].

In our study, five identified RCVs of CDKN2A are novel, which may reflect the understudied nature of this gene in non-White populations. Interestingly, the higher frequencies seen in AAs are comparable to a recent report of high RCV frequencies identified in 225 Italian PC families (31%) and sporadic (5.7%) patients [59]. Similarly, in a study among Greek melanoma patients, germline RCVs were identified in 3.3% of 304 sporadic melanoma patients and 22% of familial melanoma kindreds [60]. We observed a relatively high frequency of RCVs in Native Americans and Hispanics with PC, but not among corresponding controls. We acknowledge this may be an artifact because of smaller sample sizes, but they are suggestive of high CDKN2A RCV frequencies in these groups and require validation in larger samples.

Our results permit a limited estimate of the impact of the CDKN2A gene on risk of PC among AAs. Given our observed 1.8% prevalence of CDKN2A RCVs in the general population of AAs, and inferring a prevalence of 0.1% in the general population of NHWs (prevalence of 0.4% was found among NHW PC cases in this study), and a 3 to 4-fold increase in PC risk associated with CDKN2A RCVs, AAs would be expected have a PC incidence rate about 5% to 7% higher than NHWs due to variation in the CDKN2A gene. Furthermore, with the current SEER PC incidence rates of 15.5 per 100,000 for AAs and 12.7 per 100,000 for NHWs (i.e., 22% higher for AAs)[61], CDKN2A may account for about one-fourth of the excess PC risk in AAs.

CDKN2A is a cell cycle gene that encodes two different proteins, p16 and p14ARF [62–64]. P16 (exons 1B, 2, and 3) regulates progression through the G1 cell cycle checkpoint by inhibiting CDK4/6 and subsequently preventing downstream phosphorylation of the retinoblastoma protein (pRb), which affects downstream inhibition of E2F, a transcription factor [62]. P14ARF (exons 1A and 2) inhibits mdm2, which stabilizes p53 [63], exerts a downstream regulatory effect on transcription of genes involved in the G1/S checkpoint [64]. Both p16 and p14 appear to suppress tumorigenesis [62, 63].

This is the largest study of CDKN2A gene RCVs and PC risk conducted to date among minority groups, an important strength of a multicenter consortium effort. However, our study has some limitations, including the potential heterogeneity of sample sets from diverse centers. Given the relative rarity of minority patients, ascertainment was limited to convenience samples, including controls. Because not all centers contributed data and biospecimens on both cases and controls, we were unable to adjust for other established risk factors such as smoking, family history, diabetes, and obesity in the logistic regression analyses; this should be considered in the interpretation of findings. Genetically, there is always a difficulty with determining the functional role of missense variants such as those identified in this study. We excluded all known polymorphic variants, but the challenges of in silico analysis of RCVs are well known [51]. Our findings merit further study concerning quantifying the absolute risk for cancer among single and compound RCV carriers, not only for PC, but also other malignancies such as melanoma, head/neck cancer, and bladder cancer. The clinical application of CDKN2A RCV status will require more comprehensive studies of risk and outcomes. The underlying biologic implications of relaxed or even positive selection for CDKN2A germline variants and the role of environmental factors, such as sun exposure, vitamin D receptor status and deficiency, will be vital to further our understanding of any disease role of CDKN2A among different populations. Moreover, CDKN2A RCVs may have therapeutic implications. Commonly mutated in somatic pancreatic tumors [14], CDKN2A’s transcript p16 inhibits CDK4, a key function of cell cycle regulation in PC [65] and CDK4/6 inhibitors have demonstrated strong activity in breast cancer [66], with recent FDA approvals of palbociclib and ribociclib, and some early evidence of activity of CDK4/6 inhibition in PC is emerging [67]. Whether this or other screening or treatment strategies emerge related to CDKN2A RCVs, biological differences among diverse populations may have a great impact on precision medicine.

Conclusions

RCVs in CDKN2A are substantially more common among AAs than among NHW. RCVs among persons of African descent are of moderate penetrance, conferring a 3.3 fold increased risk for PC and may partially account for some excess risk of PC among AAs.

Abbreviations

AA

African American

CDKN2A

Cyclin dependent kinase inhibitor 2A gene

CI

Confidence interval

COSMIC

Catalogue of somatic mutations in cancer

ESP

Exome Sequencing Project

IRB

Institutional Review Board

NHW

Non-Hispanic Whites

OR

Odds ratio

PC

Pancreatic cancer

PCR

Polymerase chain reaction

PolyPhen

Polymorphism phenotyping

pRb

Retinoblastoma protein

RCV

Rare coding variant

SEER

Surveillance Epidemiology and End Results Program

SIFT

Sorting intolerant from tolerant genetic variants

SNV

Single nucleotide variant

UVM Biodesktop

University of Vermont CDKN2A gene database