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Mariapun, Shivaani (2024) Mammographic density and breast cancer risk in Asian women. PhD thesis, University of Nottingham.

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Abstract

Breast cancer is the most common cancer worldwide and in 2020, nearly half of the cases globally were from Asia. The mortality-to-incidence ratio in Asia is higher than the world average, and there is an urgent need to improve early detection of breast cancer and access to curative therapies. Today, early detection of breast cancer is possible through population-based mammography screening, but this is largely unavailable in low- and middle-income countries because of the lack of resources. An alternative approach is to provide screening to those at highest risk, and to explore this possibility, the starting step is to have accurate risk assessment tools for the Asian population.

The best performing risk assessment tool today incorporates classical lifestyle risk factors and genetic factors. Mammographic density (MD) reflects the amount of radiologically dense tissue in the breast, and is a strong risk factor for breast cancer after accounting for age and body mass index (BMI). Recent studies have shown that incorporating MD into models for risk prediction improves the accuracy of risk assessment models. However, little is known about mammographic density and breast cancer risk for women in Asian populations. In addition, MD is also a highly heritable risk factor of breast cancer and dissecting the role of genetics in MD and breast cancer risk could uncover new understanding in the etiology of breast cancer as well as improve accuracy of risk prediction. To date, 55 independent genetic loci have been identified from genome-wide association studies (GWASs) in women of European descent, none of which have been conducted in women of Asian ancestry.

This thesis sought to fill the gaps in the understanding of MD in the Asian population, by evaluating the association between MD and breast cancer risk in a case-control analysis of Asian women from Malaysia, and by identifying common genetic variants that are associated with MD in Asian women from Malaysia. First, this study found that both area and volume-based MD measures are associated with breast cancer risk. Strongest associations were observed for percent dense area (OR=2.06) and percent dense volume (OR=2.21) for all women, and postmenopausal women (OR=1.89 and 1.96 for percent dense area and volume, respectively) when comparing women in the top versus bottom quartiles of density. For premenopausal women, having very low amounts of densities (< 5 % or < 9 cm2) or being in the lowest percent density quartile, were associated with a lower risk of disease compared to having moderate to high MD. Furthermore, greater non-densities, appear to be protective of disease in all women and premenopausal women, but not postmenopausal women. Second, the associations of single nucleotide polymorphisms (SNPs) identified in women of European descent were evaluated. This study found that 21 were associated with MD at a nominal threshold of P value < 0.05, all in consistent directions with those reported in European ancestry populations. Moreover, nine of the MD-associated SNPs in this study were also associated with breast cancer risk in Asian women (P < 0.05), seven of which showed a direction of associations that was consistent with that reported for MD. Finally, to identify novel MD-associated loci, a genome wide association study (GWAS) in 2,450 Asian women was conducted, and this GWAS identified 175 novel loci that were associated with at least one MD phenotype at P < 5 x 10-6. Of these, 7 were associated with MD in 27,900 women of European ancestry, of which one (rs279075 at 13q14.3 (DLEU1)) was associated with MD at the Bonferroni corrected P value threshold, and six more variants had nominally significant associations (P < 0.05). In addition, 8 of the 175 SNPs (including rs279075) were also found to be associated with breast cancer risk in an Asian GWAS meta-analysis of 24,925 cases and 91,089 controls. Notably, more than half (52.3%) of the sub-genome wide significant variants identified in this study were either monomorphic or had extremely low minor allele frequencies (< 1%) in the European population and require replication in an independent Asian cohort.

Together, this study confirms the associations of MD with breast cancer risk in Asian women, identifies known and novel SNPS associated with MD, and further supports the evidence of a shared genetic basis through common genetic variants for MD and breast cancer risk. As one of the first and largest studies in the Asian population, this study highlights the value of automated methods in defining disease-associated MD and demonstrates the value of GWAS studies in diverse populations.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Ho, Weang Kee Teo, Soo Hwang
Keywords:	mammographic density, breast cancer, Asian population, genetic variants, genome-wide association study
Subjects:	R Medicine > RG Gynecology and obstetrics
Faculties/Schools:	University of Nottingham, Malaysia > Faculty of Science and Engineering — Engineering > Department of Chemical and Environmental Engineering
Item ID:	77342
Depositing User:	Mariapun, Shivaani
Date Deposited:	09 Mar 2024 04:40
Last Modified:	26 Mar 2024 07:48
URI:	https://eprints.nottingham.ac.uk/id/eprint/77342

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