Genotypic phenotypic correlation in male breast cancer
AffiliationSir Peter MacCallum Department of Oncology
Document TypePhD thesis
Access StatusOpen Access
© 2018 Dr. Siddhartha Deb
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.
Keywordsmale breast cancer; familial breast cancer; breast cancer
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