The genetic landscape of breast carcinomas with neuroendocrine differentiation

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• 作者：Caterina Marchiò ; Felipe C Geyer ; Charlotte KY Ng ; Salvatore Piscuoglio ; Maria R De Filippo ; Marco Cupo ; Anne M Schultheis ; Raymond S Lim ; Kathleen A Burke ; Elena Guerini-Rocco ; Mauro Papotti ; Larry Norton ; Anna Sapino ; Britta Weigelt and Jorge S Reis-Filho
• 刊名：The Journal of Pathology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：241
• 期：3
• 页码：405-419
• 全文大小：2626K
• ISSN：1096-9896

文摘

Neuroendocrine breast carcinomas (NBCs) account for 2–5% of all invasive breast cancers, and are histologically similar to neuroendocrine tumours from other sites. They typically express oestrogen receptor (ER), and are HER2-negative and of luminal 'intrinsic' subtype. Here, we sought to define the mutational profile of NBCs, and to investigate whether NBCs and common forms of luminal (ER⁺/HER2⁻) breast carcinoma show distinct repertoires of somatic mutations. Eighteen ER⁺/HER2⁻ NBCs, defined as harbouring >50% of tumour cells expressing chromogranin A and/or synaptophysin, and matched normal tissues were microdissected and subjected to massively parallel sequencing targeting all exons of 254 genes most frequently mutated in breast carcinomas and/or related to DNA repair. Their mutational repertoire was compared with that of ER⁺/HER2⁻ breast carcinomas (n = 240), PAM50-defined luminal breast carcinomas (luminal A, n = 209; luminal B, n = 111) and invasive lobular carcinomas (n = 127) from The Cancer Genome Atlas. NBCs were found to harbour a median of 4.5 (range 1–11) somatic mutations, similar to that of luminal B breast carcinomas (median = 3, range 0–17) but significantly higher than that of luminal A breast carcinomas (median = 3, range 0–18, p = 0.02). The most frequently mutated genes were GATA3, FOXA1, TBX3, and ARID1A (3/18, 17%), and PIK3CA, AKT1, and CDH1 (2/18, 11%). NBCs less frequently harboured PIK3CA mutations than common forms of ER⁺/HER2⁻, luminal A and invasive lobular carcinomas (p < 0.05), and showed a significantly higher frequency of somatic mutations affecting ARID1A (17% versus 2%, p < 0.05) and the transcription factor-encoding genes FOXA1 (17% versus 2%, p = 0.01) and TBX3 (17% versus 3%, p < 0.05) than common-type ER⁺/HER2⁻ breast carcinomas. No TP53 somatic mutations were detected in NBCs. As compared with common forms of luminal breast carcinomas, NBCs show a distinctive repertoire of somatic mutations featuring lower frequencies of TP53 and PIK3CA mutations, enrichment for FOXA1 and TBX3 mutations, and, akin to neuroendocrine tumours from other sites, ARID1A mutations. Copyright