【皮膚】悪性黒色腫の分子生物学的分類

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities

J Pathol. 2019 Apr;247(5):539-551.

悪性黒色腫の分子生物学的分類が話題となって数年が経っている。直接的に病理診断に関わることは少ないが、背景知識としてもっていることは必要だと思う。具体的には日光曝露＝ cumulative sun damage（CSD）と背景遺伝子異常によって分類されている。
ここで取り上げる論文は従来の部位的分類と背景遺伝子の関係を整理したレビューであり、free article なので、その内容を一部引用する。したがって、Spitz 腫瘍における融合遺伝子などについては言及されていない。なお、この分類の元となった初めの論文および最新の論文は free ではないので、本記事の後半で Abstract のみ紹介する。

Abstract
Melanoma is characterised by its ability to metastasise at early stages of tumour development. Current clinico-pathologic staging based on the American Joint Committee on Cancer criteria is used to guide surveillance and management in early-stage disease, but its ability to predict clinical outcome has limitations. Herein we review the genomics of melanoma subtypes including cutaneous, acral, uveal and mucosal, with a focus on the prognostic and predictive significance of key molecular aberrations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Keywords: 31-gene expression profile; acral; biomarkers; cutaneous; desmoplastic; driver genes; melanoma; mucosal; mutations; predictive; prognostic; uveal.

従来の悪性黒色腫の分類について以下のように書かれている。そして、日光曝露が多い部位ほど遺伝子変異が多く、TBM（tumor mutation burden）が大きい。これは紫外線によるＣ→Ｔ変異のためである。

Historically, melanoma has been classified into subtypes based on the tissue from which the primary tumour arises. The major such subtypes are cutaneous melanoma (CM), which arises in non-glabrous skin;
acral melanoma (AM), a distinct form that originates in glabrous skin of the palms, soles and nail beds; mucosal melanoma (MM), the rarest subtype, which arises from melanocytes in the mucosal lining of internal tissues; and uveal melanoma (UM) which develops from melanocytes in the uveal tract of the eye.

遺伝子変異との関係が表にまとめられている。また、主たる分子経路が図示されている。

【主な４型とその概要】

１．CM (cutaneous melanoma): dominated by ultraviolet-induced mutations
１’．DM (Desmoplastic melanoma: a CM subtype with an elevated mutational load
２．AM (acral melanoma): numerous copy number changes and low point mutation burden
３．UM (uveal melanoma): a sparsely mutated melanoma subtype with poor responses to modern systemic therapies
４．MM (mucosal melanoma): a rare and aggressive subtype

【SANOTIC SUMMARY】
１．最もメジャーな CM では 日光曝露により高頻度の遺伝子変異がみられ（高 TMB）、特に Big 3（BRAF, NRAS, NF1）の異常が多い
２．DM は CM の一型で、特に高 TMB を示し、NF1 の異常が特に多い
３．AM は比較的日光曝露が少なく、triple wild-type （TWT）が多い
４．UM と MM は稀なので、ここでは言及しない

PubMedのリンクはこちら👇

Melanoma subtypes: genomic profiles, prognostic molecular markers and therapeutic possibilities - PubMed

▶ From melanocytes to melanomas

Nat Rev Cancer. 2016 Jun;16(6):345-58.

こちらが有名な Bastian の論文である。ここからメラノサイト系腫瘍が日光曝露と遺伝子異常の関連で整理されるようになった。

Abstract
Melanomas on sun-exposed skin are heterogeneous tumours, which can be subtyped on the basis of their cumulative levels of exposure to ultraviolet (UV) radiation. A melanocytic neoplasm can also be staged by how far it has progressed, ranging from a benign neoplasm, such as a naevus, to a malignant neoplasm, such as a metastatic melanoma. Each subtype of melanoma can evolve through distinct evolutionary trajectories, passing through (or sometimes skipping over) various stages of transformation. This Review delineates several of the more common progression trajectories that occur in the patient setting and proposes models for tumour evolution that integrate genetic, histopathological, clinical and biological insights from the melanoma literature.

From melanocytes to melanomas - PubMed

▶ The genomic landscapes of individual melanocytes from human skin

Nature. 2020 Oct;586(7830):600-605.

こちらが最新の論文である。

Abstract
Every cell in the human body has a unique set of somatic mutations, but it remains difficult to comprehensively genotype an individual cell1. Here we describe ways to overcome this obstacle in the context of normal human skin, thus offering a glimpse into the genomic landscapes of individual melanocytes from human skin. As expected, sun-shielded melanocytes had fewer mutations than sun-exposed melanocytes. However, melanocytes from chronically sun-exposed skin (for example, the face) had a lower mutation burden than melanocytes from intermittently sun-exposed skin (for example, the back). Melanocytes located adjacent to a skin cancer had higher mutation burdens than melanocytes from donors without skin cancer, implying that the mutation burden of normal skin can be used to measure cumulative sun damage and risk of skin cancer. Moreover, melanocytes from healthy skin commonly contained pathogenic mutations, although these mutations tended to be weakly oncogenic, probably explaining why they did not give rise to discernible lesions. Phylogenetic analyses identified groups of related melanocytes, suggesting that melanocytes spread throughout skin as fields of clonally related cells that are invisible to the naked eye. Overall, our results uncover the genomic landscapes of individual melanocytes, providing key insights into the causes and origins of melanoma.

The genomic landscapes of individual melanocytes from human skin - PubMed

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