Frequency of the phosphatidylinositol3-kinase, catalytic, α-polypeptide gene amplification in ovarian cancer among Sudanese women: a cross-sectional study

Introduction

Universally, ovarian carcinoma (OC) is the deadliest gynecological tumor. It is ranted as the fifth most prevalent disease causing mortality in women^1,2. In 2018, there were 14,070 associated deaths and 22,240 new cases reported in the USA^3,4. In Sudan, OC ranked as the fourth most common malignancy in women with 188 in every 100,000 people recorded; 8 in every 100,000 people at a gender-specific rate and 7 in every 100,000 people at an age-standardized rate^5,6. In addition, a common issue for OC is that more often a higher stage of carcinoma is seen at diagnosis; resulting in a poorer prognosis for this cancer and the 5-year survival rate of advanced-stage OC remains low^7,8.

The phosphatidylinositol-3-kinases (PI3Ks) are a member of the kinase family^9,10 and have regulatory functions in cell survival, proliferation, and migration^11,12. They also have a crucial role in cellular tumorigenesis, cancer development, and drug conflicts^13,14. Mechanisms for pathway activation in cancer are mostly due to PIK3Ca or AKT (serine/ threonine-protein kinase B) mutation or amplification^11,12. PI3Ks have three classes: class I, class II, and class III^14,15; class I is most frequently linked to cancers^15,16. Class I is a heterodimer and consists of two main subunits; the regulatory (p85a, p55a, p50a, p85b, p55c, or p101 isoforms) subunit and catalytic (p110a, p110b, p110d, or p110c isoforms) subunit^16,17. Among the four catalytic isoforms, only phosphatidylinositol3-kinase, catalytic, α-polypeptide (PIK3CA) gene, which is found on chromosome 3q26.3¹⁸, is frequently altered in cancer^19,20.

In OC, PIK3CA gene mutation or amplification is present in >20% of women²¹. To the best of our knowledge, there are no published reports about PIK3CA gene amplification among Sudanese women with OC in Sudan. Therefore, the present study reports the amplification of the PIK3CA gene and its relationship with tumor type, grade, and ages in Sudanese women with OC.

Methods

Results

This study included 90 ovarian samples. Among the 90 cases, the median age was 50 years (range, 18–75 years). All cases were distributed into two age groups: ≤ 50 years (range, 18–50 years), 48.2% (n = 40); > 50 years (range, 51–75 years), 38.6% (n = 32).

Amplification of the PIK3CA was common in 33.7% of OC samples (n = 28/83). The results of the amplification rate in different OC types is presented in Figure 1. A higher frequency of amplification was seen in high grade (39.5%; n = 17/43) rather than low grade (27.5%; n = 11/40) carcinoma (Figure 2). In addition, a higher frequency of amplification was seen in older (43.4%; n = 11/32) rather than younger (30.0%; n = 12/40) women. However, there was no significant association between carcinoma type or grade and age of women, and amplification of PIK3CA (Fisher’s Exact test p = 0.660, 0.698 and 0.687, respectively).

Figure 1. The amplification rate of the phosphatidylinositol3-kinase, catalytic, α-polypeptide (PIK3CA) gene in ovarian carcinoma samples according to carcinoma type among Sudanese women.

Figure 2. The amplification rate of the phosphatidylinositol3-kinase, catalytic, α-polypeptide (PIK3CA) gene in ovarian carcinoma samples according to carcinoma grade among Sudanese women.

Discussion

The phosphatidylinositol-3-kinase (PI3K) pathway plays a regulatory role in common physiological processes; when mutated, it contributes to cellular tumorigenesis, cancer evolution, and drug conflict¹⁴. In addition, it has a decisive role in the progression of OC². Mechanisms for pathway activation are principally due to PIK3CA or AKT mutation or amplification^11,12. Earlier studies from developed countries established that amplification was seen in the range of 13 to 24.5% of patients with OC^24–28. A single study from a developed country with a small sample size (n=12) reported a higher frequency (40%)²⁹. However, Abubaker et al. revealed a high-frequency level (35.5%) in individuals from the Middle Eastern with OC²², which supports the present study. This dissimilarity of the former study with the current study in the frequency may be due to the variation in sample size, ethnic background, the cancer biology in the Sudanese population or the sensitivity of the methods used.

Regarding the association of amplification with tumor grade; we observed an increased amplification frequency in higher grade carcinoma compared with low-grade carcinoma. Our observation implies that PIK3CA gene amplification is an early result in the progress of poorly differentiated (high grade) OC. However, amplification was not significantly associated with tumor type or grade in the present study. Our results are supportive of previous studies^22,30 where no significant outcome was detected between histological tumor type or grade and PIK3CA amplification.

Conclusions

The present study revealed that amplification of the PIK3CA gene occurs in about one-third of Sudanese women with OC, more frequently in high grade carcinoma and women of older ages. In support of recently published literature, our observations foster early reports that imply that oncogenic PIK3CA gene has a significant role in the progression and activation of OC and might offer a new strategy for specific targeted therapy and prognostic assessment in OC patients.

Data availability