Independent Loss of Methylthioadenosine Phosphorylase (MTAP) in Primary Cutaneous T-Cell Lymphoma

Abstract

Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are frequently deleted in malignancies. The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fungoides (MF) and Sézary syndrome (SS), is unknown. In 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2A (12%) in all cutaneous T-cell lymphoma stages using quantitative reverse transcription PCR. Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% of samples. In peripheral blood mononuclear cells from patients with SS, codeletion with CDKN2A occurred in 18% of samples but loss of MTAP alone was uncommon. In CD4(+) cells from SS, reduced MTAP mRNA expression correlated with MTAP copy number loss (P < 0.01) but reduced MTAP expression was also detected in the absence of copy number loss. Deep sequencing of MTAP/CDKN2A-CDKN2B loci in 77 peripheral blood mononuclear cell DNA samples from patients with SS did not show any nonsynonymous mutations, but read-depth analysis suggested focal deletions consistent with MTAP and CDKN2A copy number loss detected with quantitative reverse transcription PCR. In a cutaneous T-cell lymphoma cell line, promoter hypermethylation was shown to downregulate MTAP expression and may represent a mechanism of MTAP inactivation. In conclusion, our findings suggest that there may be selection in early stages of MF for MTAP deletion within the cutaneous tumor microenvironment.

Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma

“…A handful of clinical studies have found deletions of the MTAP gene without concordant loss of CDKN2A or CDKN2B , and its deletion rate is higher than that of CDKN2A in certain cancers. 18,23 In this study, we verified an indispensable role of MTAP loss in RCC progression. In our clinical observations, we show that a significant percentage of RCC tumors have low MTAP expression and that MTAP expression is inversely associated with tumor grade and shortens patient survival.…”

“…Many studies have reported a lack of MTAP in numerous human tumors, including melanoma, gliomas, hepatocellular carcinoma, and pancreatic, lung, breast, and blood-related cancers. 18,20–27 However, the molecular mechanisms underlying MTAP-mediated tumor suppression have yet to be elucidated. Alarmingly, the function of MTAP in various cancers has been conflicting.…”

TP53 alterations in primary and secondary Sézary syndrome: A diagnostic tool for the assessment of malignancy in patients with erythroderma

“…Several whole exome sequencing analysis reported a high rate of C>T transition in SS point mutations suggesting a causal role for UV exposure [ 25 , 37 ]. In our cohort, 6 out of 7 point mutations corresponded to a C>T transition.…”

Cutaneous T-cell lymphomas: modern data of pathogenesis, clinics and therapy

“…Имеютсясведенияодисрегуляциинекоторыхгенов и их сигнальных путей при ТКЛК, но точно их роль впатогенезезаболеваниянеизвестна [4,5,17,23,[42][43][44][45][46][47][48][49][50][51][52][53][54][55].Нарушениеэкспрессииилифункциинегативных регуляторов,включаяSOCS3ипротеинтирозинфосфатазы,такиекакSHP1,вовлеченовдисрегуляциюпути Jak-3 / STATиинтерлейкиннезависимойпролиферации злокачественныхТ-клеток.АктивностьпутиJak-3 / STAT препятствуетразвитиюТКЛКчерезстимуляциюсинте-заIL-5,IL-10,IL-17AиIL-17F,регулированиефакторов ангиогенезаипрепятствуетрезистентностиктерапии ингибитором гистоновой дезацетилазы (histone deacetylaseinhibitor,HDACI) [48,51,56,57].Дополнительно сообщается о вовлечении в патогенез СС сиг-нальногопутиNOTCH1 [23,58].NOTCHвключаетсемейство трансмембранных рецепторов, которые регулируюттранскрипциюгенов,участвующихвэмбриональном развитии, гомеостазе тканей, дифференцировкеклетокиихвыживаемости [45].…”