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RESEARCH 

Relationship between the TP53 SNP 

rs1800371 and Lung Cancer in African 

Americans 
Noah Nichols1, Khadijah Mitchell1, Adriana Zingone1, Claire Meaney1, Elise D. Bowman1, Bríd M. Ryan1 

1Laboratory of Human Carcinogenesis, Centre for Cancer Research, NCI, Building 37, Room 3060C, 

Bethesda, MD, 20892,  

*Corresponding author e-mail: Brid.Ryan@nih.gov 

 

ABSTRACT 
Germline and somatic mutations in TP53 have been investigated and intensely catalogued. One of these 

germline mutations, TP53 P47S SNP is only found in populations with African ancestry. The S47 variant 

was associated with an impaired ability to induce cell death following cisplatin treatment, and with a 

high rate of spontaneous cancer formation in mice engineered to carry S47. Lung cancer incidence is 

higher among men of African descent. We therefore tested the hypothesis that P47S was associated 

with increased risk of lung cancer. We included 926 controls and 425 cases, all of whom were African 

Americans. We genotyped rs1800371 using a predesigned Taqman assay. No serine/serine genotypes 

were detected in the population. The proline/serine genotype was detected in 42 individuals (32/891 

controls (3.5%) and 10/434 cases (2.3%). The serine allele was not associated with risk of lung cancer 

(OR: 0.65, 95% C.I. 0.28-1.48). rs1800371 is not associated with risk of lung cancer among African 

Americans. 

 

KEYWORDS: TP53, SNP, health disparities 

 

Citation: Nicholas N et al (2019) Relationship between the TP53 SNP rs1800371 and Lung Cancer in African 

Americans. Cancer Health Disparities 3: e1-e9. doi:10.9777/chd.2019.1005.



 
 
 
 
 

 

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INTRODUCTION 

Lung cancer is the leading cause of cancer-related 

death in the United States and the second most 

common form of cancer in both men and women 

(Siegel et al., 2017). Several studies have 

demonstrated an increased lung cancer burden in 

African Americans (AA) (Siegel et al., 2016). Smoking 

is the major etiological cause of lung cancer (Doll 

and Peto, 1976; Peto, 2001); however, a combination 

of environmental and genetic factors could 

predispose an individual to lung cancer. 

The p53 tumor suppressor (TP53) is widely studied 

and its importance in tumorigenesis is 

underpinned by the fact that it is the most 

frequently mutated gene in human cancers (Olivier 

et al., 2010). Somatic mutations in TP53 have been 

investigated and intensely catalogued. 

Additionally, individuals with Li-Fraumeni 

syndrome, who carry germline mutations in TP53, 

have an increased risk of developing cancer 

(Malkin, 1993). Acting as a transcription factor, p53 

binds regulatory elements in DNA and facilitates 

the transcription of genes that protect against 

tumor growth. Pathways activated by p53 include 

cell cycle arrest, apoptosis, and angiogenesis 

inhibition (Whibley et al., 2009). 

Harris and colleagues first identified the TP53 P47S 

SNP (rs1800371) in 1992 (Felley-Bosco et al., 1993; 

Gerwin et al., 1992). This polymorphism, 

characterized by a C>T transition at position 1 of 

codon 47 (CCG-TCG), causes a non-synonymous 

amino acid change from proline to serine. Felley-

Bosco et al., noted that the individuals in that 

study, who identified as Caucasian American, were 

homozygous for the proline allele. However, the 

CT genotype was observed in 3/37 African 

Americans. In a functional analysis of this 

polymorphism, the authors concluded that, in their 

model, the S47 allele functioned similar to wild-

type p53. 

Phosphorylation of the N-terminal domain of p53 

facilitates its transactivation activity of pro-

apoptotic genes (Kurihara et al., 2007). For 

example, p38 MAPK and HIPK2 transactivation by 

p53 occurs through proline-directed 

phosphorylation of codon 46 at the N-terminal 

domain. Therefore, it was hypothesized that loss of 

the adjacent proline residue at position 47 could 

impair apoptotic activation. Indeed, Li et al. 

demonstrated that the S47 variant is an inferior 

substrate for p38 MAPK and exhibited a decreased 

ability to induce apoptosis in vivo compared with 

wild-type p53 (Li et al., 2005). The S47 variant was 

also associated with an impaired ability to induce 

cell death following cisplatin treatment (Jennis et 

al., 2016). Furthermore, the serine variant was 

associated with decreased transcription of a subset 

of target genes involved in metabolism and pro-

apoptotic signaling (Jennis et al., 2016). Mice 

engineered to carry S47 had a high rate of 

spontaneous cancer formation, as 80% of S47 

homozygous mice developed hepatocellular 

carcinoma, B-cell lymphoma, and other tumor 

types (Jennis et al., 2016). 

Previous work has established the increased 

frequency of the S47 allele in African Americans 

and other populations with West African ancestry. 

Despite convincing evidence from mouse models 

and cell culture experiments suggesting that the 

S47 variant is functionally significant and 

mechanistically differs from the proline variant, 

several studies have failed to show an association 

with cancer risk or survival (Alawadi et al., 2011; 

Almeida et al., 2009; Jaiswal et al., 2011; Kaur et al., 

2014; Mostaid et al., 2014; Sameer et al., 2010; 



 
 
 
 
 

 

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Santos et al., 2011; Singamsetty et al., 2014), 

though many of these studies included small 

sample sizes. Herein, we genotyped 425 lung 

cancer cases and 926 controls. The objective of 

this study is to determine whether rs1800371 is 

associated with lung cancer risk and survival in 

African Americans and admixed European 

Americans. 

METHODS AND MATERIALS 

Patient Population 

Participants were selected from the ongoing 

National Cancer Institute-Maryland Case-Control 

Study. We included 926 controls and 425 cases for 

whom DNA was available (all African American). 

The NCI-Maryland Lung Cancer Case-Control 

study is an ongoing study that started in 1998 and 

includes participants recruited from the greater 

Baltimore and Eastern Shore regions of Maryland 

(Mechanic et al., 2007).. Cases, recruited from 

seven hospitals in the greater Baltimore 

metropolitan area, were diagnosed with 

histologically confirmed NSCLC (of any stage). 

Population controls, frequency matched to cases 

on age, race, and sex, were recruited from 

Maryland Department of Motor Vehicles records. 

General inclusion criteria included having been 

born in the United States, an ability to speak 

English well enough to be interviewed, being in 

good health and not residing in an institution. 

Trained interviewers administered a standardized 

questionnaire to capture information regarding 

demographics, socioeconomic characteristics, 

tobacco smoking history (current, former [those 

who reported to have quit smoking one year prior 

to the interview], or never [those who smoked less 

than 100 cigarettes over their lifetime]), as well as 

pack-years of smoked cigarettes, alcohol history, 

medical history, family cancer history, reproductive 

history, and occupational history. Body mass index 

(BMI) was determined using reported measures of 

height and weight by the participant. 

  

Table 1. Demographic characteristics of the cases and controls. 

 African Americans  

 Controls 

N=926 

Cases 

N=445 
P-value 

Age (mean, sd) 64.6 (8.8) 63.6 (9.9) 0.06 

Gender (N, %)   <0.0001 

Males 615 (66.4) 231 (51.9)  

Females 311 (33.6) 214 (48.1)  

Smoking (N, %)   <0.0001 

Never 321 (34.7) 31 (7.0)  

Former 397 (42.8) 156 (35.1)  

Current 185 (20.0) 193 (43.4)  

Former smoker: Quit within 1 year of interview 23 (2.5) 65 (14.6)  

Pack-years of smoking (Median, IQR) 7.4 (0-25.0) 29.7 (15.0-45.5) <0.0001 

Family History of Lung Cancer (N, %)   0.003 



 
 
 
 
 

 

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No 628 (67.8) 260 (58.4)  

Yes  177 (19.1) 112 (25.2)  

Missing  121 73  

Histology (N, %)    

Adenocarcinoma  198 (44.5)  

Squamous Cell Carcinoma  123 (27.6)  

NSCLC*  67 (15.1)  

Other   32 (7.2)  

Missing  25  
 

Genotyping 

Genomic DNA was isolated from cheek cells or 

buffy coat samples containing white blood cells 

from patients in the case–control study using 

Flexigene DNA Kit (Qiagen), according to the 

manufacturer's instructions. Case, control, and 

duplicate samples (10%) were randomized and 

blinded for processing. Genotypes were 

obtained using a standard TaqMan SNP 

Genotyping Assay for rs1800391 and followed 

the manufacturer’s protocol. Genotyping failed 

for 4 individuals. Cases and controls were 

randomized across all the plates. Duplicate 

concordance was 100%. We also genotyped a 

series of European Americans (n=1349). All 

were homozygous wild-type for the SNP (CC). 

Global Genetic Ancestry 

Global genetic ancestry analysis was performed as 

previously described (Al-Alem et al., 2014). Briefly, 

DNA from blood was genotyped for 100 ancestry 

informative markers (AIMs) using the Sequenom 

MassARRAY iPLEX platform. The AIMs panel 

consisted of carefully selected autosomal markers 

that were previously identified and validated for 

estimating continental ancestry information in 

admixed populations (Kosoy et al., 2009; Nassir et 

al., 2009). Individual SNP genotype calls were 

generated using Sequenom TYPER software. A 

genotype concordance rate of 99.5% was 

observed for all markers. Genotyping call rates 

exceeded 97% for all individuals included in the 

analyses. Individual admixture estimates for each 

study participant were calculated using a model-

based clustering method as implemented in the 

program STRUCTURE v2.3 (Falush et al., 2003). 

STRUCTURE 2.3 was run using parental population 

genotypes from West Africans, Europeans, and 

Native Americans (Kosoy et al., 2009) under the 

admixture model using the Bayesian Markov chain 

Monte Carlo method (K = 3, assuming three 

founding populations) and a burn-in length of 

30,000 for 70,000 repetitions. 

Statistical Analysis 

Chi-square tests were used to compare categorical 

variables between cases and controls. A logistic 

regression model was used to estimate odds ratios 

and 95% confidence interval (CI), before and after 

adjustment for known and potential confounders, 

including age, gender, smoking status, pack-years 

of smoking and BMI. Cox proportional hazard 

models were used to estimate hazard ratios (HR) 

and 95% CI for disease-free survival after 

adjustment for age, gender, smoking status, pack-

years, tumor stage and histological subtype. 

Survival was calculated using the difference in time 



 
 
 
 
 

 

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between the date of surgery or diagnosis and the 

date of last known follow-up or death from lung 

cancer. All statistical tests were two-sided, and a p-

value of 0.05 was used to assess significance. We 

used Stata version 14 to perform all analyses. 

 

 

 

RESULTS 

Frequency of rs1800371 genotypes 

The Proline/Serine genotype was detected in 42 

individuals (3.1%), giving an allele frequency of 

1.5%. Of these, 32 (3.5%) were controls and 10 

(2.3%) were cases (Table 2). No Serine/Serine 

genotypes were reported. Also, the Proline/Serine 

genotype was only detected in African Americans, 

which is consistent with the ancestral origin of the 

serine allele. 
 

Table 2. Frequency of rs1800371 in cases and controls. 

 European American African American 

rs1800371 Control Case Control Case 

Proline/Proline 717 (100%) 632 (100%) 891 (96.5%) 434 (97.8%) 

Proline/Serine   32 (3.5%) 10 (2.3%) 

Serine/Serine     

 

Relationship between rs1900371 with lung cancer 

risk 

As the serine allele was only detected in African 

Americans, we restricted our analysis to this 

subgroup of the population. We observed a non-

significant association between the SNP and lung 

cancer risk both before (OR: 0.64, 95% C.I. 0.31-

1.32) and after adjustment for potential 

confounders (OR: 0.55, 95% C.I. 0.28-1.48) (Table 

3). As African Americans are an admixed 

population, we also adjusted our analysis for 

global genetic ancestry, however, this adjustment 

did not alter the coefficients (Table 3). 

Table 3. Relationship between rs1800371 with lung cancer risk among African Americans. 

rs1800371 OR (95% C.I.)
a
 P-value OR (95% C.I.)

b
 P-value OR (95% C.I.)

c
 P-value 

Proline/Proline Reference  Reference  Reference  

Proline/Serine 0.64 (0.31-1.32) 0.23 0.65 (0.28-1.48) 0.30 0.65 (0.28-1.50) 0.32 

Serine/Serine NA  NA  NA  

a
 Unadjusted 

b
 Adjusted for age at diagnosis, gender, smoking status, pack-years of smoking, bmi 

c
 Adjusted for age at diagnosis, gender, smoking status, pack-years of smoking, bmi, West African ancestry, European ancestry and Native 

American ancestry 

 

 



 
 
 
 
 

 

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RESEARCH 

Relationship between rs1800371 with lung cancer 

survival 

We tested the relationship between rs1800371 with 

lung cancer specific survival among the African 

American cases for whom we had survival data 

(n=439). We observed a non-significant 

relationship between the serine allele with 

prognosis (HR: 0.82, 95% C.I. 0.34-2.00). 

 

Table 4. Relationship between rs1800371 and lung cancer survival among African Americans. 

rs1800371 HR (95% C.I.)
a
 

N=439 

P-value HR (95% C.I.)
b
 

N=360 

P-value 

Proline/Proline Reference  Reference  

Proline/Serine 0.82 (0.34-2.00) 0.67 0.56 (0.23-1.38) 0.21 

Serine/Serine NA  NA  

 

DISCUSSION 

Animal and experimental studies using human 

cells have suggested that the serine allele of 

rs1800371 predisposes individuals to risk of cancer 

(Basu et al., 2016; Jennis et al., 2016). In this study, 

we examined whether carriers of the serine allele 

had an increased risk of lung cancer. However, we 

did not find evidence for an association, neither 

did we find an association with survival. 

Mostaid et al. did not find an association between 

S47 and lung cancer risk in a Bangladeshi 

population. (Mostaid et al., 2014). Similarly, no risk 

associations were observed in esophageal, breast, 

colorectal and bladder cancer studies (Alawadi et 

al., 2011; Jaiswal et al., 2011; Kaur et al., 2014; 

Sameer et al., 2010; Santos et al., 2011). In contrast, 

Singamsetty et al., focusing on a south Indian 

population, observed a significant difference in the 

proportion of S47 alleles in cases which had a 

protective effect on CRC risk (Singamsetty et al., 

2014). Furthermore, one study has demonstrated 

an association with increased risk and the S47 

variant. In 2013, an extra-axial brain tumor study 

revealed a small increase in risk for tumor 

development in a Brazilian population (Almeida et 

al., 2009). In breast cancer, particularly among pre-

menopausal women, the serine allele is associated 

with increased risk among African Americans 

(Murphy et al., 2017). 

The CT genotype, conferring one copy of the 

serine allele and one copy of the proline allele, was 

observed in 42/1435 (2.9%) of African Americans. 

This frequency is somewhat lower than the 

occurrence of the CT genotype in African 

populations (~6-8%) previously reported, but the 

lower frequency in our cohort could reflect genetic 

admixture. Of note, the minor allele frequency of 

the T allele in this study (1.5%) is similar to that 

reported in a recent report of African American 

women (~1.4%) (Murphy et al., 2017). 

P53 mediates its tumor suppressive function by 

inhibiting cell growth, inducing senescence and 

modulating cell metabolism. It accomplishes these 

functions via transcriptional activation of target 

genes, some of which is driven by post-

translational modifications such as 

phosphorylation. For example, phosphorylation of 

serine 46, the amino acid next to proline 47 is 

required for efficient p53-mediated cell death in 

several cell line systems and in mice (Bulavin et al., 

1999; Jennis et al., 2016). Phosphorylation of serine 

46 requires the presence of a proline at 47, thus 



 
 
 
 
 

 

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RESEARCH 

serine 47 significantly impairs the induction of cell 

death in cell line models (Li et al., 2005). However, 

the impact of this variant on the p53 signaling 

pathway and cancer risk in an intact animal has 

never been assessed. In a follow up study, Jennis 

and colleagues found that the S47 variant is 

modestly impaired for most p53 functions, and 

that it is significantly impaired for the ability to 

transactivate a subset of p53 target genes to 

induce cell death following cisplatin or ferroptosis 

in a mouse model (Jennis et al., 2016). 

We had hypothesized that rs1800371 would be 

associated with increased risk of lung cancer. This 

hypothesis was primarily based on the observation 

that 80% of mice carrying two copies of the serine 

allele developed spontaneous cancers. There are 

several possible reasons why an observation with 

cancer risk was not observed in our study. First, it 

is possible that this SNP is not associated with lung 

cancer. In the mouse study, the main tumor type 

observed was hepatocellular carcinoma. This is 

possibly related to the fact that one of the main 

gene targets disrupted by serine 47 is GLS2 (Jennis 

et al., 2016). While some penetrance of 

spontaneous tumors was observed among mice 

carrying one serine allele, the frequency was lower. 

Also, our study population did not identify any 

individuals carrying two serine alleles and it is 

possible that both alleles are needed for higher 

disease penetrance. Moreover, smoking is the 

main etiological cause of lung cancer in our 

population and it is possible that the mechanism 

of smoking-induced lung carcinogenesis does not 

involve ferroptosis. TP53 has many splice variants, 

and one key difference between the human and 

mouse is the presence and absence of the 

dominant negative delta133 isoform in human and 

mice, respectively. However, given that this variant 

occurs in codon 47, and delta133 is missing the 

first 133 codons of the full-length gene, it seems 

unlikely that these differences in isoform 

expression could impact function. Finally, as shown 

in previous studies, TP53-related variants do not 

always function in isolation. For example, the two 

promoter variants SNP309 and SNP285 of the 

MDM2 gene, negative regulator of p53, 

functionally interact; SNP285 acts as an antagonist 

to SNP309 by overriding the effect of SNP309 on 

SP1-mediated transcription (Knappskog et al., 2011; 

Ryan et al., 2012). Therefore, it is possible that the 

tumor suppressive function of serine 47 interacts 

with another human polymorphism in the TP53 

pathway. 

Our study suggests that rs1800371 is not 

associated with increased lung cancer risk among 

African Americans, but we cannot rule out the 

possibility that carriers of two serine alleles would 

have increased susceptibility. However, given the 

penetrance of hepatocellular carcinoma in mice 

carrying the serine allele, and disparities in liver 

cancer incidence in the US (Islami et al., 2017), case 

control studies of this cancer type and rs1800371 

should be considered. 

 

Acknowledgements 

Community Health Representative(s), Community 

Partners, and community members who 

participated in the study. This work was supported 

by the intramural research program of the Center 

for Cancer Research, National Cancer Institute. 

Conflict of interest statement 
The author has declared that no competing or 

conflict of interests exists. The funders had no role 

in study design, writing of the manuscript and 

decision to publish.  

 



 
 
 
 
 

 

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Authors’ contributions 

Conceptualization: BMR, Formal analysis: NN, AZ, 

BMR, KM, CM Methodology: AZ, NN, 

EBSupervision: AZ, BMR Writing ± original draft: 

NN, BMR Writing ± review & editing: NN, KM, 

BMR, AZ, EB, CM,  

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