Sir Peter MacCallum Department of Oncology - Theses
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ItemIdentification and validation of novel breast cancer predisposition genes( 2019)The genetic causes of the majority of hereditary breast cancer families remain unresolved (BRCAx families) and lack of this information compromises primary and secondary cancer prevention for the affected women and their family members. Despite intensive efforts, no major new breast cancer predisposition genes with equivalent impact have been discovered since the identification of BRCA1 and BRCA2 in the 1990s. Research from our laboratory provided direct demonstration that the remaining hereditary causes of breast cancer are not due to a few BRCA1-like genes (high penetrance and high carrier frequency) but instead by numerous moderate penetrance genes, each accounting for only a small fraction of families. This finding highlighted the need for very large case-control studies as the only way of resolving the missing breast cancer heritability. In this thesis I aimed to carry out such a study. Using existing germline whole exome and targeted sequencing data, 162 candidate genes were selected for validation in ~8,000 unrelated BRCAx cases and cancer-free controls. Combined with the existing targeted sequencing data of ~4,000 cases and controls, this analysis represents one of the largest targeted sequencing studies of its kind. A significant association with breast cancer predisposition was confirmed for known breast cancer genes PALB2, CHEK2 and ATM. Among the 162 candidate genes, nearly twice as many had more LoF variants in the cases than the controls, compared to those with more variants in the controls than the cases, demonstrating a high enrichment for genuine breast cancer predisposition genes. Most novel candidate genes appeared to convey only low to moderate risks, with a total of 35 genes identified that had an OR>2. Despite the very large sample size, the number of carriers of LoF variants for any candidate gene was still small, further demonstrating the extreme genetic heterogeneity of BRCAx families, and that case-control data is still insufficient on its own to claim the discovery of a specific new breast cancer gene. Nevertheless, this large-scale case-control data will be a valuable guide for future validation. Many of the candidate genes such as NTHL1, WRN, BAP1, PARP2 and CDK9 play essential roles in DNA damage repair, consistent with the function of all the established breast cancer genes. An intriguing exception is CTH which is involved in the trans-sulfuration pathway, and if confirmed, would be the first moderate penetrance breast cancer predisposition not involved in DNA repair. This study also re-evaluated some contentious genes and provided strong evidence to reject RINT1 and RECQL as breast cancer predisposition genes. On the other hand, by combining both case-control data with tumour sequencing data, RAD51C was identified as a triple-negative breast cancer predisposition gene. This study has shown that because of the high genetic heterogeneity of BRCAx families, future validation studies will require either an extremely large sample size (>10,000 subjects), and/or the inclusion of approaches providing independent evidence, such as tumour sequencing to identify bi-allelic inactivation and specific mutational signatures.
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ItemGenotypic phenotypic correlation in male breast cancer( 2018)Male breast cancers (MBCs) are rare cancers, comprising less than 1% of all breast cancers and less than 1% of all cancers in men. As a result, these cancers have not been well characterized with almost all management extrapolated from the treatment of female breast cancers. More recent studies, however, have demonstrated differences from female breast cancers. This thesis has examined genotypic and phenotypic correlation in a group of 61 familial MBCs (kConFab) and 225 mixed familial and sporadic MBCs (Lund University, Sweden) with robust clinical and pathological data. The hypothesis is that: 1) male and female breast cancer (FBC) is different, 2) familial male and familial FBC is different and 3) familial and sporadic MBCs are different with possible differences within familial MBC subgroups. The penetrance of familial MBCs is different to that of familial FBC, showing an increased proportion of BRCA2 male carriers and underrepresentation of BRCA1 male tumours. Histopathology showed a paucity of lobular and medullary male breast cancers, with less frequent HER2 and Basal phenotypes. An association between BRCA2 mutation carrier status and invasive micropapillary subtype was seen. A BRCA1 associated medullary phenotype was not demonstrated and accordingly TP53 somatic mutations and associated hypoxic drive was not seen in these tumours, highly suggestive of a redundant role for BRCA1 in MBC. The somatic mutation profile in familial MBCs was similar to that seen in luminal A FBCs, with the rare E547K PIK3CA seen several times in MBCs suggesting a possible gender correlation. Methylation of the ERβ/eNOS complex associated tumour suppressor gene, GSTP1, was frequently seen in MBCs, more so in familial than sporadic MBCs. The clinical significance of this may be useful in screening for MBCs in these high-risk populations and may also be a risk modifier as high levels of GSTP1 methylation have also been seen in BRCA2-associated prostate cancers. Similar to familial FBCs, there was observed clustering of tumors by methylation patterns into different BRCA subgroups, albeit with small numbers. Compared to sporadic MBCs, familial MBCs overall showed an earlier median and mean age of onset, with more frequent multifocality or bilateral disease, Familial MBCs also showed a higher proportion of high grade tumours and invasive papillary carcinomas. Familial MBCs also showed a higher amount of gene losses and higher levels of candidate gene methylation. The study demonstrated several differences between male and female breast cancers and sporadic and familial MBCs.