The role of biochemical markers and genetic susceptibility in the pathogenesis of hormone dependent malignancies

Abstract

Introduction: Multiple studies have associated the global increase of postmenopausal breast and endometrial cancer with the worldwide increase in obesity and the metabolic syndrome. The Maltese population has also been repeatedly shown to have markedly increased obesity, metabolic syndrome and insulin resistance, with increasing trends of breast and endometrial cancers. Aims: To evaluate which markers - metabolic/hormonal and genetic markers related to the metabolic syndrome – are associated with increased risk of breast and/or endometrial cancer. Also, it aims to compare the performance of polygenic risk scores relative to anthropometric/clinical predictors in classifying cancer from control patients. Method: A random sample of three study populations was recruited: Study Group 1- Patients with a history of endometrial carcinoma; Study Group 2 - Patients with a history of breast carcinoma; and Study Group 3: A control group including women with histologically confirmed absence of endometrial carcinoma (after hysterectomy) and no history of breast carcinoma. All the patients recruited were postmenopausal patients of Maltese ethnicity. Each subject was interviewed and anthropometric data measured. Blood was collected for biochemical and hormonal tests. The risk factors were associated with breast/endometrial cancer risk and logistic regression was done. DNA was extracted from whole blood and genetic profiling by LP-WGS was then carried out. Association of genetic risk scores of single nucleotide polymorphisms known to be association with diabetes mellitus type II and insulin resistance were determined by logistic regression. Results: 300 patients have been recruited - 132 patients were diagnosed with breast cancer, 90 patients with endometrial cancer (four patients had both endometrial and breast cancer) and 82 patients controls. The study observed a positive association between early menarche, nulliparity and high BMI with both breast (p=0.02, p=0.049, and p=0.04 respectively] and endometrial cancer risk (p=0.01, p=0.017, p<0.01) respectively. Family history of breast cancer and high SHBG level were also found to be associated with increased breast cancer risk (p=0.009 and p=0.02 respectively) while a positive association between history of hypertension (p<0.01), diabetes mellitus type 2 (p<0.01), presence of the metabolic syndrome (p<0.01), family history of hypertension (p=0.007), high serum triglycerides (p<0.01), HbA1C (p<0.01), HOMA-IR (p=0.01) were found with endometrial cancer. History of breastfeeding was observed to be negatively associated with both breast (p<0.01) and endometrial cancer risk (p<0.01). Serum FSH and LH levels were also found to be negatively associated with breast cancer (p<0.01 and p<0.01 respectively) while serum SHBG and progesterone showed a negative association with endometrial cancer (p=0.01 and p=0.01 respectively). The logistic regression models showed that that BMI was the best predictor of breast and endometrial cancers - for every 1 kg/m2 increase in BMI, the odds of having breast cancer increased by 3.9% (OR=1.039) while the odds of having endometrial cancer increased by 8.4% (OR=1084). Genetic profiling showed that a greater number of alleles from genetic risk scores with loci for diabetes mellitus type 2 and insulin resistance were significantly present in the breast and endometrial cancer cohorts. After adjustment for age, fasting insulin, fasting glucose, WHR and serum triglycerides level, quintile 5 of GRS 1 was found to have an OR for cancer risk (breast/endometrial) of 21.738 (p<0.01). Conclusion: This study gave better understanding on the risk significance of various factors related to breast and endometrial carcinogenesis in the Maltese population. By determining risk factors, women can be risk-stratified and individualised intervention/s can be implemented according to their risk for developing breast/endometrial cancer.