Proliferating Pilar Tumors Are Characterized by Recurrent 15q, 6q, and 6p22.2 Alterations

Abstract

:Proliferating pilar tumors (PPTs) are rare neoplasms of external root sheath derivation, which most commonly occur on the scalp of elderly women. Although typically showing classic histologic features such as trichilemmal type keratinization, a lobular architecture and peripheral palisading, squamous cell carcinoma (SCC) remains a common diagnostic pitfall. Therefore, we sought to explore the molecular pathogenesis of PPTs and compare it with that of cutaneous squamous cell carcinoma (cSCC). Herein, we describe the use of a next-generation DNA sequencing platform to provide the most comprehensive molecular genetic analysis to date of a cohort of 5 PPTs and compare them to 5 head and neck cutaneous SCCs. Recurrent broad arm-level gains of 15q and concurrent single-copy losses of 6q and 6p22.2 were observed in 4 of 5 (80%) PPT cases. Other recurrent mutations or alterations of significance were not found in PPTs. Notably, these chromosomal changes were not identified in any of the 5 cutaneous SCCs, which instead showed recurrent alterations in the known SCC driver genes TP53, CDKN2A, and NOTCH1. Here, we show for the first time that PPTs are molecularly distinct from cutaneous SCC and provide evidence that recurrent alterations in chromosome 15 and chromosome 6 are central to the pathogenesis of PPTs.

Malignant Proliferating Pilar Tumor

“…On the contrary, low TMB and lack of UV signature were seen in MPPT. While mutations in TP53 have also been detected in some BPPT, alterations in CDKN2A and NOTCH1 were absent 15 . None of the cases of BPPT reported by Fischer et al 15 or the MPPT cases in our cohort demonstrated a UVA mutational signature, supporting UV-independent pathogenesis.…”

“…A retrospective search of the BWH molecular database yielded 19 cutaneous SCC with OncoPanel results for comparison. Previously sequenced BPPTs were included for comparison 15 . The molecular analyses of MPPT revealed frequent TP53 mutations (5/6 cases) as well as copy number gains of 15q and losses of 6p and 6q.…”

“…Although molecular data regarding BPPT and MPPT in the literature is limited, distinct molecular alterations (15q gain and 6q and 6p22.2 loss) may characterize BPPT 15 . These molecular alterations may allow BPPT/MPPT to be distinguished from SCC as SCC typically features high tumor mutational burden (TMB) as well as mutations in CDKN2A and NOTCH 1/2 16 .…”

“…14 Although molecular data regarding BPPT and MPPT in the literature is limited, distinct molecular alterations (15q gain and 6q and 6p22.2 loss) may characterize BPPT. 15 These molecular alterations may allow BPPT/MPPT to be distinguished from SCC as SCC typically features high tumor mutational burden (TMB) as well as mutations in CDKN2A and NOTCH 1/2. 16 These mutations were not identified in 5 BPPT cases analyzed by Fischer et al 15 In addition, TP53 alterations have been demonstrated in some BPPT and may play a role in the malignant transformation of BPPT to MPPT.…”

Deep‐penetrating‐nevus‐like melanoma arising in patients with familial adenomatous polyposis syndrome

“…Bap‐1 immunohistochemical expression was retained in both components. Next‐generation DNA sequencing (NGS) was performed using a targeted platform which includes 447 cancer‐related genes as previously described 15–17 . Sequencing confirmed the presence of a BRAF‐V600E mutation ( BRAF c.1799T>A) and a frameshift alteration in the APC gene (c.1657del, p.W553Gfs*5).…”