Gynaecological cancers, particularly ovarian and endometrial cancers, represent a significant health burden worldwide. While lifestyle, hormonal, and environmental factors contribute to their etiology, genetic mutations are now recognized as key drivers of carcinogenesis.

In ovarian cancer, high-grade serous carcinoma (HGSC) accounts for the majority of cases and is strongly linked to BRCA1/2 mutations. Similarly, endometrial cancer subtypes exhibit unique genetic landscapes, with PTEN, PIK3CA, and MMR gene mutations playing critical roles. The integration of genomic data into clinical decision-making holds promise for risk stratification, early detection, and targeted therapy.

This study aims to analyze the spectrum and impact of specific genetic mutations in ovarian and endometrial cancers using next-generation sequencing (NGS) to determine their roles in disease onset, progression, and prognosis

Study Design and Population
This retrospective cohort study included 220 women diagnosed with ovarian or endometrial cancer between January 2020 and December 2023 across three tertiary care centers.

Inclusion Criteria

• Histologically confirmed ovarian or endometrial cancer
• Availability of tumor tissue and matched normal DNA
• Informed consent for genetic analysis

Molecular Analysis
NGS was performed on FFPE tissue samples using a 50-gene cancer panel. Key genes assessed included:

• Ovarian Cancer: BRCA1, BRCA2, TP53, RAD51, BARD1
• Endometrial Cancer: PTEN, PIK3CA, MLH1, MSH2, MSH6, PMS2
  Microsatellite instability (MSI) testing and immunohistochemistry (IHC) for MMR proteins were also conducted.

Clinical Correlation
Patient data including age, cancer stage, grade, treatment response, and survival outcomes were collected and correlated with mutation profiles.

Statistical Analysis
Chi-square tests, Kaplan-Meier survival curves, and multivariate Cox regression models were used to assess significance (p<0.05 considered significant).

Tables and Inference: Gynaecological Cancers and Genetics

Table 1: Distribution by Age and Cancer Type

Inference:

Endometrial cancer was more frequent in women below 40 years compared to ovarian cancer, which peaked in the 40–59 age group.

Table 2: Genetic Mutation Frequency by Cancer Type

Inference:

BRCA mutations were exclusive to ovarian cancer, while PTEN and MMR mutations dominated in endometrial cancer.

Table 3: MSI Status in Endometrial Cancer

Inference:

Microsatellite instability (MSI-High) was present in 18% of endometrial cancers, suggesting MMR deficiency and potential for immunotherapy responsiveness.

Table 4: Survival Rates Based on Mutation Status

Inference:

BRCA mutation was associated with improved survival in ovarian cancer, while TP53 mutation indicated poorer prognosis.

Table 5: Stage at Diagnosis by Mutation Type

Inference:

Early-stage diagnosis was more common in patients with MMR and PTEN mutations, compared to those with BRCA or TP53 mutations.

Microsatellite Instability (MSI)

• 18 of 21 MMR-deficient tumors exhibited high MSI.
• MSI-H tumors were more frequent in younger women (<50 years).

Survival Outcomes (Median 3-year follow-up)

• BRCA-mutated ovarian cancer showed improved progression-free survival (PFS).
• TP53 mutations in both cancers were associated with poorer overall survival (OS).
• MMR deficiency correlated with favorable response to immune checkpoint inhibitors.

This study confirms the substantial contribution of hereditary and somatic mutations in the genesis and progression of ovarian and endometrial cancers.

1. BRCA1/2 and Ovarian Cancer

Mutations in BRCA1/2 disrupt DNA repair via homologous recombination, leading to genomic instability and increased carcinogenesis. We observed BRCA mutations in 38% of high-grade serous ovarian cancers—comparable to rates reported in other studies [1,2]. These patients demonstrated better responses to PARP inhibitors, supporting existing therapeutic guidelines [3].

2. TP53 Mutations

The TP53 tumor suppressor gene was mutated in over half of ovarian cancers and one-third of endometrial cancers. TP53 alterations typically indicate aggressive disease and poor prognosis, in line with prior literature [4,5].

3. PTEN and PIK3CA in Endometrial Cancer

PTEN loss, often early in tumorigenesis, was the most common mutation in endometrial cancer (38%). Along with PIK3CA, these mutations activate the PI3K/AKT/mTOR pathway, promoting cell survival and growth [6,7]. Clinical trials targeting this pathway show promising results in recurrent endometrial cancer [8].

4. MMR Deficiency and MSI

MMR gene mutations (MLH1, MSH2, MSH6, PMS2) were identified in 21% of endometrial cancers, associated with microsatellite instability (MSI). These findings support universal screening for Lynch syndrome, a hereditary cancer syndrome linked to MMR gene mutations [9,10].

5. Implications for Personalized Medicine

The integration of genetic data into clinical workflows is critical. Genetic counseling, risk-reducing surgery, and targeted therapies (e.g., PARP inhibitors, immune checkpoint inhibitors) can significantly alter patient trajectories. Furthermore, early detection in mutation carriers may enhance survival.

Genetic mutations play a central role in the pathogenesis and progression of ovarian and endometrial cancers. Incorporating genomic profiling into routine care enables personalized treatment, improved surveillance, and preventive strategies, especially in patients with inherited syndromes or aggressive disease.

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