TP53 genetic alterations in Arab breast cancer patients: Novel mutations, pattern and distribution

  • Authors:
    • Abeer J. Al-Qasem
    • Mohamed Toulimat
    • Abdelmoneim M. Eldali
    • Asma Tulbah
    • Nujoud Al-Yousef
    • Sooad K. Al-Daihan
    • Nada Al-Tassan
    • Taher Al-Tweigeri
    • Abdelilah Aboussekhra
  • Corresponding author:
  • View Affiliations

  • Published online on: Tuesday, January 18, 2011
  • Pages: 363-369 DOI: 10.3892/ol.2011.236

Abstract

Breast cancer remains a worldwide public health concern. The incidence and mortality of breast cancer varies significantly in ethnically and geographically distinct populations. In the Kingdom of Saudi Arabia (KSA) breast cancer has shown an increase in incidence and is characterized by early onset and aggressiveness. The tumor suppressor TP53 gene is a crucial genetic factor that plays a significant role in breast carcinogenesis. Furthermore, studies have shown a correlation between certain p53 mutations and response to therapy in breast cancer. In the present study, TP53 mutations were identified by direct sequencing of the gene (exons 4-9) from 119 breast cancer tissues. The prevalence of TP53 mutations in Arab breast cancer patients living in the KSA is among the highest in the world (40%). Notably, 73% of the patients whose tumors harbored p53 mutations were less than 50 years of age. Furthermore, for the first time, we identified 7 novel mutations and 16 mutations in breast cancer tissues. Notably, all the novel point mutations were found in exon 4, wherein 29% of the mutations were localized. Furthermore, an excess of G:C→A:T transitions (49%) at non-CpG sites was noted, suggesting exposure to particular environmental carcinogens such as N-nitroso compounds. The results indicate that the TP53 gene plays a significant role in breast carcinogenesis and the early onset of the disease among Arab female individuals.

Introduction

Breast cancer has a major impact on the health of women worldwide. It is the most frequently diagnosed cancer and a leading cause of cancer-related death, ranking second in Caucasian (1) and Saudi female patients (Cancer Incidence Report, NCR, 2004). The incidence and mortality rates vary between various ethnically and geographically distinct populations, with the lowest incidence reported among Asians and the highest among North Americans (2). Multiple causes characterize breast carcinomas, which may be either familial or sporadic. Genetic predisposition accounts for only about 5–10% of breast cancer, whereas 90% of breast cancer cases are sporadic and their origin remains to be determined (3). The Saudi population comprises more than 50% of females younger than 20 years old. In this population, the majority of breast cancer cases diagnosed are at advanced stages and at an early age (4). Similar characteristics have been found in African-American female individuals (5,6).

Breast carcinogenesis is associated with various types of somatic genetic alterations, such as mutations in oncogenes and tumor suppressor genes (7). The most frequently mutated gene in human malignancies, including breast cancer, is the TP53 gene (8). This important tumor suppressor gene is a multifunctional transcription factor involved in the control of cell cycle progression, DNA repair, apoptosis and angiogenesis (9). The proportion of TP53 mutations in various cancer tissues ranges from 10 to 80% (10), while that of TP53 mutations reported in breast tumors ranges from 15 to 71%, with significant differences among populations. Over 1,400 TP53 mutations have been identified in breast cancer (11). Of these mutations, 80% are clustered within exons 5–8 (12). Notably, the proportion of TP53 mutations is higher in younger patients and those with advanced breast cancer (13); these patients comprise the prevalent breast cancer patient group among the Saudis. Furthermore, variations in patterns and distribution of p53 mutations in breast cancer occur according to ethnicity and geographical location, indicating the effect of genetic and environmental factors (14).

Cells lacking normal p53 function have a selective growth advantage and are more resistant to ionizing radiation and frequently used anticancer drugs compared to cells with wild-type p53 protein (15). TP53 gene mutations predict the response of breast cancer patients to treatment with various chemotherapeutic agents (16,17). Furthermore, it has been shown that the TP53 mutation status is a crucial survival marker of breast cancer that may provide prognostic data which complements clinical variables (18).

In the present study, the prevalence of TP53 mutations in Arab breast cancer patients was among the highest in the world (40%), and occurred more frequently in young patients. Notably, 7 novel mutations, including a 15-bp deletion, were identified in these sporadic breast cancer patients.

Materials and methods

Sample collection

A total of 119 archived breast tumor samples were collected from Arab patients living in Saudi Arabia and suffering invasive ductal carcinoma. All of these patients were diagnosed at King Faisal Specialist Hospital and Research Center in Riyadh. The experimental protocol was approved by the institutional Basic research and Ethics Protocol Committees (RAC proposal no. 2040037). The age of the patients at the time of diagnosis ranged from 22 to 80 years (median 51). A total of 108 fresh blood samples (5 ml) were collected from volunteer healthy Arab female individuals, and used as controls. The age of the healthy Saudi female individuals (controls) ranged from 17 to 76 years (median 47).

DNA purification

Genomic DNA was purified using the Gentra Puregen kit according to the manufacturer’s instructions (Gentra Puregene blood kit; Qiagen, Valencia, CA, USA; cat. no D-50K1–4).

DNA amplification and sequencing of the TP53 gene

Standard PCR was performed to amplify exons 4–9 and their intron/exon borders of the TP53 gene, using the HotStar Taq polymerase kit (Qiagen, Chatsworth, CA, USA). The primers used for this amplification are listed in Table I. Each PCR reaction was performed in a total volume of 25 μl containing 4 ng of genomic DNA, 0.5 mM dNTPs, 1 mM primers, 0.04 units Taq DNA polymerase and MgCl2 (1.5–3 mM). MgCl2 concentrations were optimized according to the different primers (Table I). Following a denaturation step of 10 min at 94°C, the PCR amplification consisted of 35 cycles of 45 sec at 94°C, 45 sec at 62°C, 45 sec at 72°C, followed by a final extension step of 10 min at 72°C. The PCR products were then directly sequenced using the ABI Prism BigDye Terminator v3.1 cycle sequencing kit (Applied Biosystems, Foster City, CA, USA). The unincorporated dye labeled terminators were removed using the DyeEx 96 kit (Qiagen). The reaction product was resuspended in a formamide loading buffer, and then separated and detected in the ABI 3730x1 DNA analyzer (Applied Biosystems). The analysis of the obtained sequence was carried out using the GeneBank database, NT_010718. TP53 somatic mutations were confirmed by two independent experiments.

Table I

TP53 primers used in the PCR reactions.

Table I

TP53 primers used in the PCR reactions.

PrimerLength (bp)Sequence (5′ to 3′)SizeAnnealing temperature (°C)MgCl2 (mM)
Exon 4370621.5
 Forward20TGA GGA CCT GGT CCT CTG AC
 Reverse20CGG CCA GGC ATT GAA GTC TC
Exon 5330623.0
 Forward20TGT TCC AGT TGC TTT ATC TG
 Reverse20AGA GCA ATC AGT GAG GAA TC
Exon 618056–622.0
 Forward20GGC CTC TGA TTC CTC ACT GA
 Reverse20GGT CCC CTA AGC AGC AGG AG
Exon 7257622.5
 Forward20CAG GTC TCC CCA AGG CGC AC
 Reverse20TGG AAG AAA TCG GTA AGA GG
Exon 8,939156–622.5
 Forward20CCT TAC TGC CTC TTG CTT CT
 Reverse20TGT TAG ACT GGA AAC TTT CC
Statistical analysis

Statistical analysis was carried out using the SPSS program version 17. The Chi-square test (χ2) was used to test for an association between categorical data. P≤0.05 was considered to be statistically significant.

Results

Prevalence of TP53 mutations is high among Arab breast cancer patients

Screening for TP53 mutations was carried out on exons 4–9.

DNA from 119 breast carcinoma tumor samples was amplified and sequenced. A total of 40 of 119 (33.61%) patients harbored mutations in the TP53 gene; with 6 patients harboring more than one mutation. Subsequently, 47 substitutions were identified in the samples obtained from these 40 patients. Notably, only 19 exonic mutations of these substitutions were previously identified in breast cancer patients (Table II). Different types of mutations were detected: 28 (59.57%) were missense mutations, 6 (12.77%) were silent, 5 (10.64%) were nonsense (stop) mutations, and 3 (6.38%) deletions and 5 mutations (10.64%) were found in the intron-exon intersections (Fig. 1A). Two of the 3 deletions led to a premature stop codon (frame shift) (Table II).

Table II

Summary of TP53 mutations and their nature/location found in breast cancer tissues.

Table II

Summary of TP53 mutations and their nature/location found in breast cancer tissues.

Base changeStructural changeMutation typeExon/IntronCoding DescriptionMut _ ID
GAC>GGCaD48GTransitionE4c.143A>G449
TGG>TAGaW53XTransitionE4c.158G>A502
ACT>CCTcT55PTransversionE4c.163A>C
CCA>CTAcP58STransitionE4c.173C>T
CCC>CCTcP64LTransitionE4c.192C>T
GCA>GGAaA76GTransversionE4c.227C>G753
GCA>GCGcA78ATransitionE4c.234A>G
GCC>GCTaA84ATransitionE4c.252C>T843
Del of CaA88TdelfsX33DeletionE4c.263del1887
CCC>CCTaP89PTransitionE4c.267C>T899
TAC>TCCcY107STransversionE4c.320A>C
GGG>AGGaG117RTransitionE4c.349G>A1209
C>TNo changeTransitionIVS 4-3c.376-3C>T5820
C>T-TransitionIVS 4–14c.376-14C>T
TCC>TTCbS127FTransitionE5c.380C>T1341
Del CAAc L130-N131delLfsX15DeletionE5c.390–392del3
GTG>GCGbV143ATransitionE5c.428T>C1590
CCC>CCTbP153PTransitionE5c.459C>T1761
ACC>ATCbT155ITransitionE5c.464C>T1794
ACC>ACTbT155TTransitionE5c.465C>T1799
ACC>AACaT155NTransversionE5c.464C>A1792
Del 15 bpcV157-A161delDeletionE5c.469–483del15
ATC>ATTbI162ITransitionE5c.486C>T1932
CAG>TAGb,dQ165XTransitionE5c.493C>T1972
TGC>TACbC176YTransitionE5c.527G>A2166
CAT>CGTbH193RTransitionE6c.578A>G2410
CAT>TATbH193YTransitionE6c.577C>T2408
TAT>GATaY220DTransversionE6c.658T>G2819
TAT>TGTbT220CTransitionE6c.659A>G2821
GAG>GCGa,dE221DTransversionE6c.662A>C2833
TAC>TAGb,dY234XTransversionE7c.702C>G3029
TAC>AACbY234NTransversionE7c.700T>A3020
TGT>TTTbC238FTransversionE7c.713G>T3108
C>T-TransitionIVS 7–15c.783-15C>T
GTG>TTGbV272LTransversionE8,9c.814G>T3713
AGA>GGAbR280GTransitionE8,9c.838A>G3844
AGA>ACAaR280TTransversionE8,9c.839G>C3850
CCT>CTTbP295LTransitionE8,9c.884C>T4084
CAC>TACaH297YTransitionE8,9c.889C>T4106
CCC>CTCaP316LTransitionE8,9c.947C>T4348
CAG>CGGaQ317RTransitionE8,9c.950A>G4363
ACC>ATCaT329ITransitionE8,9c.986C>T4501
G>A-TransitionIVS 8+18c.919+18G>A
G>A-TransitionIVS 9+28c.993+28G>A

{ label (or @symbol) needed for fn[@id='tfn1-ol-02-02-0363'] } Mut, mutations.

a Mutations reported in cancers other than breast cancer.

b Mutations reported in breast cancer.

c Mutations not previously reported.

d TP53 mutations reported more than once. International Agency for Research on Cancer database, TP53 genetic variation in human cancer, IARC release R13 (2008), used as a reference.

The majority of the identified mutations were transitions (Fig. 1B). Only one transition mutation of proline-153 occurred at a CpG site. Furthermore, various base changes were identified in the 47 TP53 mutations with 24 (51.1%) C:G→T:A transitions (at the CpG and non-CpG sites) representing the most frequent one (Fig. 1C). The frequency of this transition reached 48.93% at the non-CpG sites (Fig. 1C).

Fig. 2 shows the distribution of the TP53 mutations within exons 4–9 of the gene. The majority of the mutations were identified in exons 4 and 5 (12 mutations, representing 29%, in each). However, only 4 mutations were identified in exon 7, while exons 6 and 8,9 harbored 6 and 8 mutations, respectively. This finding shows that exon 4 is a hot-spot for TP53 mutations in the Saudi Arabian population. Furthermore, 9 of the 47 mutations were found within the conserved regions (II, III, IV and V) of the TP53 gene. Of the 9 mutations, 3 were identified in conserved region V at valine 272 and argenine 280 (Table II). Argenine 280 is a significant amino acid involved in direct DNA binding. Another 2 mutations were found at cysteine 176 and 238, in conserved regions III and IV, respectively. These cysteines are also directly involved in the binding of the zinc molecule (Table II). Six (12.8%) mutations were identified within the zinc-binding loop domains L2 and L3 (codons 163–195 and 236–251, respectively) (Table II). No mutation was detected at the 3 hot-spot codons 248, 273 and 175, nor at the highly mutagenic codons 245, 249 and 282 (14). Furthermore, only one mutation was identified at codon 176 and 2 at codon 220.

Identification of novel mutations in the TP53 gene

In the present study, 16 new mutations were identified in the TP53 gene. These mutations were found in 14 different patients. One of these patients harbored 3 mutations. The majority of these mutations were transitional (10 transitions vs. 6 transversions) (Table II). In addition, 7 novel changes were identified in the TP53 gene (not previously reported in breast cancer or any other tumor type, IARC database, 2008). These changes (5 base substitutions and 2 deletions) were found in 6 different patients, since the tumor from one patient had 2 of these novel mutations at codons 58 and 64 (Table II). All of the 5 base substitutions were located in exon 4 at codons 58, 64, 55, 78 and 107 (3 transitions and 2 transversions) (Table II). The 2 novel deletions of 3 and 15 bp were identified in exon 5 (Table II). The second deletion did not lead to a premature stop codon, whereas the first one did following the addition of 15 new amino acids.

The frequency of the 7 novel changes was <1%. Therefore, they were considered as mutations. To verify this, we sequenced exon 4 which encompassed the 5 base substitutions from 108 DNA blood samples from healthy Arab female controls. No substitutions were identified at these sites, confirming that the substitutions identified in the breast cancer tissues were novel mutations. Therefore, the frequency of p53 mutations in the Arab breast cancer patients was 39.49%.

Association between TP53 mutations and the age of Arab breast cancer patients

The potential link between TP53 mutations and the age of breast cancer patients was investigated. The patients were divided into two subgroups depending on their age; the first group included patients younger than 50 years of age (young patients), and the second included patients of 50 years or older (‘old’ patients). As expected, most of the Arab breast cancer patients (68%) were under 50 years of age, confirming the early onset of breast cancer in this population. Notably, among 33 patients that harbored TP53 mutations in their tumors, 24 (73%) were young patients, whereas only 9 (27%) were considered older patients. In each subgroup, patients with tumors harboring TP53 mutations were compared with those patients with tumors without TP53 mutations. Table III shows that the TP53 gene mutations were more frequent in tumors from younger patients with a prevalence of 35%, whereas in the older patients the TP53 mutations were only 27%. However, the difference was not statistically significant (p=0.45).

Table III

Association of TP53 gene mutations with the clinicopathological characteristics of Arab breast cancer patients.

Table III

Association of TP53 gene mutations with the clinicopathological characteristics of Arab breast cancer patients.

Total (n)Positive n (%)Negative n (%)P-value
Age
 <506924 (34.8)45 (65.2)0.4480
 ≥50339 (27.3)24 (72.0)
Menopausal status
 Premenopausal6824 (23.08)44 (42.31)0.1690
 Postmenopausal368 (7.69)28 (26.92)
ER status
 Positive4813 (18.31)35 (49.30)0.7690
 Negative237 (9.86)16 (22.54)
PR status
 Positive10 (0.00)1 (7.69)0.7640
 Negative121 (7.69)11 (84.62)
ErbB2 status
 Positive4518 (17.48)27 (26.21)0.0850
 Negative5814 (13.59)44 (42.72)
Involvement of lymph nodes
 Positive4616 (17.20)30 (32.26)0.4590
 Negative4713 (13.98)34 (36.56)
Clinical stage of tumors
 I163 (3.19)13 (13.83)
 II3511 (11.70)24 (25.53)0.0447
 III2212 (12.77)10 (10.64)
 IV214 (4.26)17 (18/09)
Histopathological grade of tumors
 I93 (2.88)6 (5.77)
 II5314 (13.46)39 (37.50)0.6120
 III4215 (14.42)27 (25.96)
Association between TP53 mutations and the clinocopathological characteristics of Arab breast cancer patients

To investigate the potential role of p53 in the development and progression of primary breast tumors, the clinicopathological characteristics of the patients with tumors harboring p53 mutations were compared with those of patients that had tumors without p53 mutations. A statistically significant correlation between the presence of p53 mutations and the clinical stage of the tumors was found (p=0.0447). Patients with locally advanced breast cancer stage III A+B showed the highest proportion of p53 mutations. On the other hand, no statistically significant correlation was found with the other characteristics, such as the menopausal status, the histopathological grade, the presence or absence of lymphatic or vascular invasion, ER/PR status and Her2neu.

Discussion

In the present study, the frequency of TP53 mutations in Arab breast cancer patients living in Saudi Arabia was found to be 39.49%. This frequency is considered to be relatively high, since it is significantly higher than the previously reported mean proportion of 25% (range 15–71%; examined in 1425 breast tumor samples worldwide) (19). It is also higher than the prevalence of p53 mutations in breast tumors determined in a meta-analysis (18%) (20) and in the IARC mutation prevalence database on all breast cancers, R9 release (28%) (21). Therefore, the frequency of TP53 mutations in the KSA is one of the highest in the world. It is similar to the frequency found in Kashmir (44%) (22), the USA (45%) (21), Japan (47.5%) (21), the UK (34.5%) (21), and in African-Americans (34.5%) (23). However, it is higher than the prevalence reported in patients from Delhi, India (3%) (24), France (19%) (25), Tokyo (25%) (26) and US midwestern Caucasians (30%) (27). This variation in p53 mutations in breast cancers may be due to factors such as the ethno-geographically diverse populations studied, exposure to various carcinogens, size of the studied population, life-style and dietary habits. Notably, 7 novel mutations (not previously reported in the TP53 gene) were identified during this study; 5 of the 7 mutations were found in exon 4. Therefore, tumors from Arab breast cancer patients have a high prevalence (28.57%) of TP53 mutations in exons 4 and 5, whereas the smallest proportion of TP53 mutations (9.52%) was found in exon 7. However, in the IARC database, exon 5 has the highest proportion of TP53 mutations in breast cancer (30.6%) followed by exon 7 (23.5%), while exon 4 represents only 4.2% of mutations (IARC TP53 Database, R14 release, November 2009, http://www.iarc.fr/p53/homepage.htm/). Therefore, even the distribution of TP53 mutations in the various exons of the gene appears to be population-dependent. Brazilian women of African descent have a higher proportion of mutations in exons 5 and 7, whereas Brazilian women of Caucasian descent have more mutations in exon 8. No mutations were found in Brazilian patients of African descent in exon 4 (29). In the Kashmiri population, no mutation was found in exon 5, and 52.9% of mutations were identified in exon 6 (22). To the best of our knowledge, this study is the first to report a high proportion of mutations in exon 4 of the TP53 gene.

When we compared the TP53 mutational pattern in the Arab breast cancer population to the patterns of 15 other populations from low and high breast cancer-risk countries, we found that the Saudi population is characterized by a low frequency (2.1%) of the G:C→A:T transition (at CpG sites) and a high frequency (48.9%) of the mutational type G:C→A:T transition (at non-CpG sites). Thus, the Arab population living in Saudi Arabia possesses the second highest frequency of G:C→A:T transitions at non-CpG sites after a New Orleans population of African or Caucasian descent (57%) (23). On the other hand, the frequency of G:C→A:T transitions at CpG sites in the KSA is the lowest in the world. IARC mutation spectrum data on all breast cancer cases reported frequencies of 17.7% at the non-CpG sites and 21.3% at the CpG sites (21). This variation in the TP53 mutation pattern among different populations may be due to exposure to various environmental mutagens (23). The association between mutations and specific exogenous mutagens has been observed in the TP53 gene. The best example is the CC→TT tandem dipyrimidine transition associated with UV light and G→T transversions associated with benzo(a)pyrene (14). In the Saudi breast cancer patients, the most distinguishing feature of the TP53 mutation pattern was the excess of G:C→A:T transition at the non-CpG sites, which was rarely found at the CpG sites. The transition of cytosine to thymine at the CpG sites may result from spontaneous deamination of methylated cytosine (29). Therefore, the low frequency of this transition in the Saudi breast cancer patients is likely to be due to the low cytosine methylation at the CpG sites. On the other hand, the G:C→A:T transitions at the non-CpG sites is induced by various carcinogens, in particular oxidizing agents and alkylating agents such as N-nitroso compounds (e.g., nitrosoamines and N-nitrosodimethylamine ‘NDMA’) (14). The carcinogenic effect of the N-nitroso compounds on the mammary gland of laboratory animals is well established, suggesting that human mammary epithelial cells contain DNA adducts due to exposure to these chemicals (30,31). N-nitroso compounds (e.g., N-nitrosdimethylamines) are procarcinogenic agents that are bioactivated by enzymatic metabolism (32,33). These agents lead to guanine alkylation generating o6-alkylguanine (e.g., o6-methylguanine), which typically results in G:C→A:T transitions (34). This adduct can be directly repaired by alkylguanine alkyltransferase enzymes (e.g. o6-methylguanine DNA methyl transferase enzymes) (35). This enzyme has been detected in breast tissue with large inter-individual variations in activity (36). Zaidi et al demonstrated that the presence of estrogen increased the amount of o6-methylguanine in the DNA of breast xenografts (34). Therefore, high exposure to nitrosamines (or NDMA) with insufficient capacity for DNA repair or high levels of estrogen may lead to the accumulation of DNA damage and the formation of mutations that trigger cellular transformation and then breast carcinogenesis. These mutagens and the type of mutations they induce have been shown to play a role in the etiopathogenesis of oesophageal and gastric carcinomas (3739).

Findings of our study showed that among the 33 patients with tumors harboring TP53 mutations, 24 (73%) were young patients (<50 years of age), while only 9 (27%) were older patients (≥50 years of age). Furthermore, TP53 mutations occurred more frequently in tumors from young patients with a prevalence of 34.8% than in the older patients with a prevalence of 27.3%. However, this difference was not statistically significant (p=0.45). Studies have reported the presence of an association between TP53 mutations and the age of breast cancer onset (13). However, Nagai et al who reported on the Brazilian population, found no significant correlation between the age of breast cancer patients and p53 mutations (28).

In the present study, the frequency of p53 mutations in the Arab breast cancer patients was found to be among the highest in the world (40%), with a high proportion of these mutations localized in exon 4 of the gene. Five out of these 12 mutations were identified for the first time. We also identified 2 novel deletions in exon 5. In addition, 16 mutations were identified for the first time in these breast cancer patients. A total of 70% of the patients harboring p53 mutations in their tumors were younger than 50 years of age. Therefore, it can be concluded that the TP53 gene plays a signficant role in breast carcinogenesis and the early onset of the disease among Arab female individuals.

Acknowledgements

We are very thankful to KACST for their financial help. We also thank the KFSH & RC administration as well as the Training and Education and ORA offices for their continuous assistance. This study was performed under the RAC proposal #2040037 and KACST #LPG 10-9.

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Journal Cover

March 2011
Volume 2 Issue 2

Print ISSN: 1792-1074
Online ISSN:1792-1082

2013 Impact Factor: 0.987
2014 I.F. (Expected) ≥ 1.785 Ranked #149/202 Oncology
(total number of cites)

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APA
Al-Qasem, A.J., Toulimat, M., Eldali, A.M., Tulbah, A., Al-Yousef, N., Al-Daihan, S.K. ... Aboussekhra, A. (2011). TP53 genetic alterations in Arab breast cancer patients: Novel mutations, pattern and distribution. Oncology Letters, 2, 363-369. http://dx.doi.org/10.3892/ol.2011.236
MLA
Al-Qasem, A. J., Toulimat, M., Eldali, A. M., Tulbah, A., Al-Yousef, N., Al-Daihan, S. K., Al-Tassan, N., Al-Tweigeri, T., Aboussekhra, A."TP53 genetic alterations in Arab breast cancer patients: Novel mutations, pattern and distribution". Oncology Letters 2.2 (2011): 363-369.
Chicago
Al-Qasem, A. J., Toulimat, M., Eldali, A. M., Tulbah, A., Al-Yousef, N., Al-Daihan, S. K., Al-Tassan, N., Al-Tweigeri, T., Aboussekhra, A."TP53 genetic alterations in Arab breast cancer patients: Novel mutations, pattern and distribution". Oncology Letters 2, no. 2 (2011): 363-369. http://dx.doi.org/10.3892/ol.2011.236