The repertoire of genetic alterations in salivary duct carcinoma including a novel HNRNPH3-ALK rearrangement

Abstract

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with limited treatment options and poor outcome. Twenty-nine primary resected SDC, including 15 SDC de novo (SDCDN), and 14 SDC ex pleomorphic adenoma (SDCXPA) were subjected to the massive parallel sequencing assay (MSK-IMPACT™) targeting 287-468 cancer-related genes. TP53 was the most frequently altered gene (69%). TP53 mutations and ERBB2 amplification were more frequent in SDCXPA than in SDCDN (p=0.0007 and p=0.01, respectively). Potentially targetable mutations were detected in 79% (23/29) SDC involving ERBB2 (31%), PIK3CA (28%), HRAS (21%), ALK (7%) and BRAF (3%), and 22% (5/23) of those cases harbored possible primary resistance mutations involving CCNE1, NF1 and PTEN. A novel HNRNPH3-ALK rearrangement was found in one SDCDN. In another case, EML4-ALK fusion detected in the primary tumor was associated with ALK G1202R secondary resistance mutation in the post-treatment metastasis. A germline analysis of the DNA repair genes revealed a case with a pathogenic BRCA1 E23fs germline variant.

ALK alterations in salivary gland carcinomas

“…Immunohistochemistry (IHC) can be used as a screening method for ALK aberrations, although confirmatory genetic testing is recommended [23,24]. This is also supported by findings in the recent papers [19,21] in which ALK-CTTNA1 and HNRNPH3-ALK translocations were associated with membranous and cytoplasmic ALK staining, respectively. However, neither IHC nor FISH analysis provides information on the exact breakpoint and on the respective fusion partner.…”

“…Genomic ALK aberrations are rare in SGCs. Recently, its alterations have been reported in five tumors of this group [ 18 – 21 ]. Out of 182 SGCs we screened by IHC, only eight samples expressed ALK in more than 10% of tumor cells with moderate to strong staining intensity.…”

“…These alterations have been identified, among others, in benign fibrous histiocytoma [13], papillary thyroid carcinoma [14,15], sarcomatoid carcinoma of the head and neck [16], and pediatric kidney carcinoma [17]. Likewise, there have been described five SGCs with ALK alterations until now: a myoepithelial carcinoma with MSN-ALK rearrangement [18], a secretory carcinoma with CTNNA1-ALK rearrangement [19], an intraductal carcinoma with STRN-ALK rearrangement [20], and two salivary gland carcinomas-one with HNRNPH3-ALK and another with EML4-ALK gene fusion [21]. Therefore, we systematically evaluated ALK by immunohistochemistry (IHC) followed by dual color fluorescence in situ hybridization (FISH) and new generation sequencing (NGS) in IHCpositive cases in a large, well-characterized series of salivary gland carcinomas.…”

A case of metachronous bilateral secretory carcinoma

“…Literature in the area of salivary malignancy genomics is sparse, but an association between BRCA gene mutations and salivary cancer has been described. 20 , 21 Given SC’s similarity to secretory carcinoma of the breast, this association may warrant further investigation.…”

Genetic diversity in alveolar soft part sarcoma: A subset contain variant fusion genes, highlighting broader molecular kinship with other MiT family tumors

“…The HNRNPH3 (heterogeneous nuclear ribonucleoprotein H3) gene is a member of the heterogeneous nuclear ribonucleoprotein H protein family, with important roles in RNA splicing . This gene was recently reported to fuse with ALK in a salivary duct carcinoma, whereby ALK expression is brought under the control of the HNRNPH3 promoter . In the HNRNPH3‐TFE3 fusion transcript, a similar mechanism is presumed whereby the HNRNPH3 regulates TFE3 expression; the presence of strong TFE3 immunoreactivity appears to confirm active translation of the fusion protein.…”