Fig. 5
Genetic progression of metaplastic carcinomas from ductal to heterologous differentiation. a Paired ductal carcinoma in situ, invasive ductal, and invasive squamous components of tumor Sq4 were microdissected and sequenced separately. Clonal PIK3R1 (p.579_582del), PTEN (p.Y240fs), and ZNF703 (p.179_181del) mutations were shared between all three components. A clonal pathogenic TP53 missense mutation (p.G266R) was shared only between invasive ductal and squamous components, whereas the sampled in situ component harbored two different TP53 missense mutations (p.K132N, p.R213L) at subclonal allele frequencies that were not present in the invasive cancer. Histologic progression to squamous cell carcinoma was associated with unique truncating pathogenic KMT2D (p.S2927*) and SMAD4 (p.Q334*) mutations. b Paired invasive ductal and invasive chondroid components of tumor C1 were microdissected and sequenced separately. FGFR1 and MCL1 amplifications, as well as frameshift NOTCH1 (p.P2514fs), missense TP53 (p.V173M), and missense NT5C2 (p.D306G) mutations, were shared between components. Pathogenic ATRX (p.E873*), RB1 (c.1128-2 A > G), and ARID1AI (p.E1904fs) mutations were unique to the chondroid component, along with numerous additional variants of unknown significance at clonal and subclonal allele frequencies. DCIS, ductal carcinoma in situ
