IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity

Abstract

Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment.

Breast Tumours Resembling the Tall Cell Variant of Thyroid Papillary Carcinoma: Are They Part of the Papillary Carcinoma Spectrum or a Distinct Entity?

“…Some also appeared to be composed mainly of follicles rather than of papillae [21]. The majority had a triple-negative profile [15,16]; some, however, were positive for ER. Of note, the only case previously described to have distant metastasis (to the bone) was positive for ER [17].…”

“…These tumours are characterised by the presence of tall, columnar cells arranged in nests, papillae, and follicle-like structures, and are filled with eosinophilic colloid-like material. Nuclear grooves, nuclear overlap and stratification, nuclei with a ground-glass appearance, nuclear pseudoinclusions, and psammoma bodies are typically present, in addition to reverse polarity and a lack of hormone receptor expression [12,13,[15][16][17].…”

“…They were originally designated "breast tumour resembling the tall cell variant of papillary thyroid carcinoma" [12,13,16,17]. In a recent study of 13 cases, a different term was used "solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms" [16]; in line with Chiang et al [15], the authors used the term "solid papillary carcinoma," which is a variant of papillary carcinoma with well-characterised histological features and is considered as in situ disease for management purposes [3].…”

“…However, reflecting the uncertainty as to the nature and existence of this tumour as a distinct entity, several of its features are also seen in otherwise conventional PC variants [14], and variable terminology has been used to describe it [12][13][14][15][16]. Furthermore, despite being described as an oestrogen receptor (ER)-negative entity [16], a review of the literature reveals the existence of cases described as being ER-positive [13,15,17,18]. Finally, specific mutations involving the IDH2 gene have been reported in this entity [15,19], although it is not clear whether this gene mutation is a prerequisite for its diagnosis and is restricted to BTRTPC.…”

“…Furthermore, despite being described as an oestrogen receptor (ER)-negative entity [16], a review of the literature reveals the existence of cases described as being ER-positive [13,15,17,18]. Finally, specific mutations involving the IDH2 gene have been reported in this entity [15,19], although it is not clear whether this gene mutation is a prerequisite for its diagnosis and is restricted to BTRTPC. Foschini et al [16] described these tumours as being invasive.…”