Merkel Cell Polyomavirus Causes Skin Cancer

IARC 2012

Carcinogenicity of malaria and of some polyomaviruses. V Bouvard, RA Baan, Y Grosse, B Lauby-Secretan, F El Ghissassi, L Benbrahim-Tallaa, N Guha, K Straif; WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol 2012 Apr;13(4):339-340. "An aetiological role of MCV for MCC is supported by a few case—control studies and several case series. Case—control studies reported odds ratios of 2·4—6·6 for serological markers of MCV infection and of 16·9—63·2 for serological markers of viral early gene expression. Because knowledge of other risk factors for MCV infection and MCC is limited, potential confounding could not be ruled out. However, a large number of case series in different populations consistently show the presence of MCV DNA in tumour tissue of most MCC cases (prevalence range, 59—100%)... In most MCV-positive MCCs analysed, the MCV genome was present in one or more copies per cell, was integrated into the cellular genome, and integration appeared to precede clonal expansion of tumour cells. Most MCCs contained mutations within large T-antigen sequences leading to the expression of a C-terminal truncated protein deficient for viral replication.22 Expression of the small and large T-antigens, shown in vitro to have oncogenic properties, has been repeatedly reported in MCC cell lines. Based on “limited evidence” in humans, “inadequate evidence” in experimental animals, and strong mechanistic evidence in humans, MCV was classified as “probably carcinogenic to humans” (Group 2A)."

Bouvard / Lancet Oncol 2012 full article

Merkel Cell Polyomavirus and Merkel Cell Carcinoma

Clonal integration of a polyomavirus in human Merkel cell carcinoma. H Feng, M Shuda, Y Chang, PS Moore. Science 2008 Feb 22;319(5866):1096-1100. "MCV sequences were detected in 8 of 10 (80%) MCC tumors but only 5 of 59 (8%) control tissues from various body sites and 4 of 25 (16%) control skin tissues. In six of eight MCV-positive MCCs, viral DNA was integrated within the tumor genome in a clonal pattern, suggesting that MCV infection and integration preceded clonal expansion of the tumor cells."

Feng - Science 2008 abstract / PubMed

Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. A Kassem, A Schöpflin, C Diaz, W Weyers, E Stickeler, M Werner, A Zur Hausen. Cancer Res 2008 Jul 1;68(13):5009-5013. Merkel cell polyomavirus was found in 30 of 39 (77%) Merkel cell carcinomas.

Kassem - Cancer Res 2008 abstract / PubMed

Merkel cell polyomavirus and Merkel cell carcinoma, France. V Foulongne, N Kluger, O Dereure, N Brieu, B Guillot, M Segondy. Emerg Infect Dis 2008 Sep;14(9):1491-1493. MCPyV was found in 8 of 9 patients with MCC, of whom 2 were immunocompromised.; versus 0 of 15 patients with diverse proliferative or inflammatory skin or mucosa lesions as controls.

Foulongne / Emerg Infect Dis 2008 full article
Foulongne - Emerg Infect Dis 2008 full article / PubMed Central

Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. KM Garneski, AH Warcola, Q Feng, NB Kiviat, JH Leonard, P Nghiem. J Invest Dermatol 2009 Jan;129(1):246-248. "16 of 37 Merkel cell carcinoma tumor tissues were positive for Merkel cell polyomavirus DNA (43%)," 11/16 (69%) from North America, versus 5/21 (24%) from Australia. "We observed MCPyV in 5 of 8 primary tumors, 3 of 13 recurrences, 7 of 15 nodal metastases, and in the single studied distant metastasis... The majority of Australian samples were nodal metastases, whereas most North American samples were primaries." Also, "most of the Australian tumor specimens were collected in the 1990’s and most North American specimens were collected after the year 2000." "MCPyV was not detected in any of the normal skin DNA, but was present in 2 of 15 SCC tumors (13%)."

Garneski - J Invest Dermatol 2009 author manuscript / PubMed Central

Ultrastructural proof of polyomavirus in Merkel cell carcinoma tumour cells and its absence in small cell carcinoma of the lung. CT Wetzels, JG Hoefnagel, JM Bakkers, HB Dijkman, WA Blokx, WJ Melchers. PLoS ONE 2009;4(3):e4958. MCPyV was found in 2/5 Merkel cell carcinomas and 0/10 small cell lung carcinomas.

Wetzels / PLoS ONE 2009 full article
Wetzels - PLoS ONE 2009 full article / PubMed Central

Prevalence of Merkel cell polyomavirus in Merkel cell carcinoma. EJ Duncavage, BA Zehnbauer, JD Pfeifer. Mod Pathol 2009 Apr;22(4):516-521. 41 cases of Merkel cell carcinoma (from 29 different patients). Of these, 20 cases were primary cutaneous tumors, 4 were local recurrences, and 17 were metastases. 22/29 (76%) were positive for MCVPS1 (109 bp amplicon).

Duncavage - Mod Pathol 2009 abstract / PubMed

Merkel cell carcinoma of the skin: pathological and molecular evidence for a causative role of MCV in oncogenesis. X Sastre-Garau, M Peter, MF Avril, H Laude, J Couturier, F Rozenberg, A Almeida, F Boitier, A Carlotti, B Couturaud, N Dupin. J Pathol 2009 May;218(1):48-56. "MCV DNA sequences were found in all ten cases of MCC and in none of the 1241 specimens of other tumour types. Clonal integration of MCV into the host genome was seen in all MCC cases and was checked by FISH in one case. A recurrent pattern of conserved viral sequences which encompassed the replication origin, the small tumour (ST), and the 5' part of the large tumour (LT) antigen DNA sequences was observed. Both ST and LT viral sequences were found to be significantly expressed in all MCCs. Neither recurrent site of integration nor alteration of cellular genes located near the viral sequences was observed. The tight association of MCV with MCC, the clonal pattern of MCV integration, and the expression of the viral oncoproteins strongly support a causative role for MCV in the tumour process."

Sastre-Garau - J Pathol 2009 abstract / PubMed

Merkel cell polyomavirus strains in patients with merkel cell carcinoma. A Touzé, J Gaitan, A Maruani, E Le Bidre, A Doussinaud, C Clavel, A Durlach, F Aubin, S Guyétant, G Lorette, P Coursaget. Emerg Infect Dis 2009 Jun;15(6):960-962. 21 of 32 (66%) samples of Merkel cell carcinoma with suitable quality DNA were positive for Merkel cell polyomavirus DNA. All 12 frozen samples were positive versus only 9/20 (45%) of formalin-fixed and paraffin-embedded samples. "MCPyV DNA was not detected for any of the 9 patients with non-MCC neuroendocrine carcinomas," which were 5 small-cell lung carcinomas, 3 well-differentiated intestinal carcinomas, and 1 high-grade neuroendocrine carcinoma of the cervix.

Touzé / Emerg Infect Dis 2009 full article

Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc. KG Paulson, BD Lemos, B Feng, N Jaimes, PF Peñas, X Bi, E Maher, L Cohen, JH Leonard, SR Granter, L Chin, P Nghiem. J Invest Dermatol 2009 Jun;129(6):1547-1555. "Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions."

Paulson - J Invest Dermatol 2009 abstract / PubMed

Clinical Factors Associated With Merkel Cell Polyomavirus Infection in Merkel Cell Carcinoma. H Sihto, H Kukko, V Koljonen, R Sankila, T Böhling, H Joensuu. J Natl Cancer Inst 2009 Jul 1;101(13):938-45. 79.8 % of 114 patients with Merkel cell carcinoma in Finland were positive for Merkel cell polyomavirus DNA."Compared with MCPyV DNA-negative cancers, MCPyV DNA-positive cancers were more often located in a limb (40.7% vs 8.7%, P = .015) and less frequent in patients who had regional nodal metastases at diagnosis (6.6% vs 21.7%, P = .043). Patients with MCPyV DNA-positive tumors had better overall survival than those with MCPyV DNA-negative tumors (5-year survival: 45.0% vs 13.0%, respectively; P < .001, two-sided log-rank test)."

Shito - J Natl Cancer Inst 2009 abstract / PubMed

Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. A Kassem, K Technau, AK Kurz, D Pantulu, M Löning, G Kayser, E Stickeler, W Weyers, C Diaz, M Werner, D Nashan, A Zur Hausen. Int J Cancer 2009 Jul 15;125(2):356-361. 56 nonmelanoma skin cancers (squamous cell carcinoma, basal cell carcinoma, and Bowen's disease) from 11 immunosuppressed patients and 147 NMSCs of 125 immunocompetent patients; normal skin and 89 colorectal cancers as comparison. "MCPyV specific sequences were significantly more frequently found in NMSC of immunosuppressed patients compared to immunocompetent patients (p < 0.001). In particular BD and BCC revealed a significant increased association of MCPyV of immunosuppressed patients (p = 0.002 and p = 0.006). Forty-seven of 147 (32%) sporadic NMSC were MCPyV positive. Interestingly, 37.5% (36/96) of sporadic BCC of immunocompetent patients were MCPyV positive. No MCPyV was detected within normal skin and only 3 out of 89 of additionally tested colorectal cancers were MCPyV positive."

Kassem - Int J Cancer 2009 abstract / PubMed

Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. H Sihto, H Kukko, V Koljonen, R Sankila, T Böhling, H Joensuu. J Natl Cancer Inst 2009 Jul 1;101(13):938-945. 114 Merkel cell carcinoma tissue samples in Finland from 1979 to 2004. MCPyV DNA was present in 91 carcinomas (79.8%), and positive tumors were more often located in a limb.

Sihto - J Natl Cancer Inst 2009 abstract / PubMed

Merkel cell polyomavirus expression in merkel cell carcinomas and its absence in combined tumors and pulmonary neuroendocrine carcinomas. KJ Busam, AA Jungbluth, N Rekthman, D Coit, M Pulitzer, J Bini, R Arora, NC Hanson, JA Tassello, D Frosina, P Moore, Y Chang. Am J Surg Pathol 2009 Sep;33(9):1378-1385. 15 of 17 (88%) frozen Merkel cell carcinoma samples were positive for MCV by PCR. "A tissue microarray of 36 MCCs, 7 combined squamous and neuroendocrine carcinomas of the skin, and 26 pulmonary neuroendocrine carcinomas were also examined by IHC. Of the 36 MCCs assembled on a microarray, 32 (89%) tumors expressed CK20, and 27 (75%) were immunoreactive with CM2B4. The skin tumors with a combined squamous and neuroendocrine phenotype and all pulmonary neuroendocrine carcinomas failed to react with CM2B4."

Busam - Am J Surg Pathol 2009 abstract / PubMed

Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays. YL Tolstov, DV Pastrana, H Feng, JC Becker, FJ Jenkins, S Moschos, Y Chang, CB Buck, PS Moore. Int J Cancer 2009 Sep 15;125(6):1250-1256. "Among MCC patients, all 21 (100%) patients tested with MCV-positive tumors had high serum MCV IgG but not high MCV IgM levels. Only 3 of 6 (50%) MCC patients with MCV-negative tumors were positive for MCV antibodies. Sera from most adults, including 107 of 166 (64%) blood donors, 63 of 100 (63%) commercial donors and 37 of 50 (74%) systemic lupus erythematosus patients, show evidence for prior MCV exposure... Although past exposure to MCV is common among all adult groups, MCC patients have a markedly elevated MCV IgG response compared with control patients."

Tolstov - Int J Cancer 2009 author manuscript / PubMed Central

Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma. H Katano, H Ito, Y Suzuki, T Nakamura, Y Sato, T Tsuji, K Matsuo, H Nakagawa, T Sata. J Med Virol 2009 Sep 22;81(11):1951-1958. MCPyV-DNA was detected in 6 of 11 (55%) cases of Merkel cell carcinoma by nested PCR and real-time PCR. MCPyV-positive cases had different histology from MCPyV-negative cases.

Katano - J Med Virol 2009 abstract / PubMed

Detection of Merkel cell polyomavirus DNA in Merkel cell carcinomas. E Varga, M Kiss, K Szabó, L Kemény. Br J Dermatol 2009 Oct;161(4):930-2. "Nine primary or recurrent MCCs from seven patients were examined; 29 other tumours (squamous cell, basal cell and basosquamous carcinomas and malignant melanomas) were examined for comparative purposes... The presence of viral T antigen and/or viral capsid DNA sequences was demonstrated in seven of the eight MCC lesions. None of the comparative samples contained MCV DNA."

Varga - Br J Dermatol 2009 abstract / PubMed

Frequent occurrence of RASSF1A promoter hypermethylation and merkel cell polyomavirus in merkel cell carcinoma. P Helmbold, C Lahtz, A Enk, P Herrmann-Trost, WC Marsch, H Kutzner, RH Dammann. Mol Carcinog 2009 Oct;48(10):903-9. "MCPyV was found in 90 of 98 (92%) MCC, however, no SV40 signal was detected. No correlation between TSG hypermethylation and viral infection was found."

Helmbold - Mol Carcinog 2009 abstract / PubMed

Merkel cell polyomavirus in cutaneous squamous cell carcinoma of immunocompetent individuals. AM Dworkin, SY Tseng, DC Allain, OH Iwenofu, SB Peters, AE Toland. J Invest Dermatol 2009 Dec;129(12):2868-74. "We detected MCPyV in 15% (26/177) of SCC DNA samples and 17% (11/63) of adjacent skin DNA samples from 21 of 58 (36%) individuals studied... All sequenced SCC samples had a common mutation truncating the LT antigen that provides indirect evidence of viral integration."

Dworkin - J Invest Dermatol 2009 abstract / PubMed

Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. V Foulongne, O Dereure, N Kluger, JP Molès, B Guillot, M Segondy. Br J Dermatol 2010 Jan;162(1):59-63. "MCPyV DNA was detected in 14 of 18 (78%) patients with MCC, five of 18 (28%) patients with other skin diseases (P = 0.007) and one of six (17%) clinically healthy subjects. In patients with MCC, viral DNA was detected in nine of 11 (82%) tumours and in 10 of 14 (71%) nontumoral skin samples (P = 0.66). MCPyV DNA levels were higher in MCC tumours than in nontumoral skin from patients with MCC, and than in lesional or nonlesional skin from patients with other cutaneous disorders. Signature mutations in the T antigen gene were not identified in the two MCC tumour specimens analysed."

Foulongne - Br J Dermatol 2010 abstract / PubMed

Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. C Andres, B Belloni, U Puchta, CA Sander, MJ Flaig. J Cutan Pathol 2010 Jan;37(1):28-34. 33 MCC samples and 33 age- and sex-matched samples of sun exposed non-MCC tumors (12 seborrheic keratoses, 11 basal cell carcinomas, and 10 lentigo maligna melanomas). "MCPyV sequences were detected in 21 MCC samples (64%) and in 2 non-MCC tumors of sun exposed skin (6%; both SK-patients). Neither the tissue samples from BCC nor LMM proved positive for MCPyV sequences."

Andres - J Cutan Pathol 2010 abstract / PubMed

Prevalence of Merkel cell polyomavirus among Swiss Merkel cell carcinoma patients. J Mangana, P Dziunycz, K Kerl, R Dummer, A Cozzio. Dermatology 2010;221(2):184-188. "We detected viral DNA in 20 out of 30 cases of MCC and in 0 out of 19 control samples."

Mangana - Dermatology 2010 abstract / PubMed

Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. K Bhatia, JJ Goedert, R Modali, L Preiss, LW Ayers. Int J Cancer 2010 May 1;126(9):2240-2246. "MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06-1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p </= 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p </= 0.08)."

Bhatia - Int J Cancer 2010 abstract / PubMed

Distinct Merkel Cell Polyomavirus Molecular Features in Tumour and Non Tumour Specimens from Patients with Merkel Cell Carcinoma. HC Laude, B Jonchère, E Maubec, A Carlotti, E Marinho, B Couturaud, M Peter, X Sastre-Garau, M-F Avril, N Dupin, F Rozenberg. PLoS Pathog 2010 Aug. 31 / 33 tumors were positive for markers of MPyV. "Patients with MCC containing more than 1 viral genome copy per cell had a longer period in complete remission than patients with less than 1 copy per cell (34 vs 10 months, P = 0.037)" "However, in two models of adenovirus and polyomavirus-induced oncogenesis, the dependence of transformed cells on viral oncoproteins was reversed upon time, since cells conserved an oncogenic phenotype while viral expression was shut-down in one case and viral sequences were lost in the other. These findings suggest that transformed cells acquire subsequent genetic alterations which circumvent their need for a continued expression of viral oncoproteins. Therefore, more cellular genetic alterations may be necessary in virus-unrelated than in virus-related oncogenesis."

Laude / PLoS Pathog 2010 full article

Lack of evidence for basal or squamous cell carcinoma infection with Merkel cell polyomavirus in immunocompetent patients with Merkel cell carcinoma. DM Reisinger, JD Shiffer, AB Cognetta Jr, Y Chang, PS Moore. J Am Acad Dermatol 2010 Sep;63(3):400-403. "MCV T antigen was readily detected in 15 (75%) of 20 MCC tumors including 11 MCC tumors from patients with secondary SCC or BCC. In contrast to MCC, none of these secondary BCC or SCC was MCV T-antigen positive.

Reisinger - J Am Acad Dermatol 2010 abstract / PubMed

Antibodies to Merkel Cell Polyomavirus T Antigen Oncoproteins Reflect Tumor Burden in Merkel Cell Carcinoma Patients. KG Paulson, JJ Carter LG Johnson, KW Cahill, JG Iyer, D Schrama, JC Becker, MM Madeleine, P Nghiem, Galloway. Cancer Res 2010 Nov 1;70(21):8388-97. "Among 530 population control subjects, these antibodies were present in only 0.9% and were of low titer. In contrast, among 205 MCC cases, 40.5% had serum IgG antibodies that recognize a portion of T-Ag shared between small and large T-Ags. Among cases, titers of T-Ag antibodies fell rapidly (∼8-fold per year) in patients whose cancer did not recur, whereas they rose rapidly in those with progressive disease. Importantly, in several patients who developed metastases, the rise in T-Ag titer preceded clinical detection of disease spread."

Paulson - Cancer Res 2010 abstract / PubMed

The new polyomavirus (MCPyV) does not affect the clinical course in MCCs. J Handschel, D Müller, RA Depprich, MA Ommerborn, NR Kübler, C Naujoks, J Reifenberger, KL Schäfer, S Braunstein. Int J Oral Maxillofac Surg 2010 Nov;39(11):1086-1090. "59 samples from 44 patients were analysed for the presence of MCPyV using the primers LT3, VP1 and LT1... 58% of specimens were positive for MCPyV. Of these, LT3 was positive in 53%, VP1 in 37% and LT1 in 10%."

Handschel - Int J Oral Maxillofac Surg 2010 abstract / PubMed

Merkel cell carcinoma: Our experience with seven patients in Korea and a literature review. KJ Woo, YL Choi, HS Jung, G Jung, YK Shin, KT Jang, J Han, JK Pyon. J Plast Reconstr Aesthet Surg 2010 Dec;63(12):2064-70. All seven patients were positive for Merkel cell polyomavirus.

Woo - J Plast Reconstr Aesthet Surg 2010 abstract / PubMed

Homo- and heterotypic cell-cell contacts in Merkel cells and Merkel cell carcinomas: heterogeneity and indications for cadherin switching. AM Werling, Y Doerflinger, JM Brandner, F Fuchs, JC Becker, D Schrama, H Kurzen, S Goerdt, WK Peitsch. Histopathology 2011 Jan;58(2):286-303. 84% of 52 MCCs were positive for MCV DNA.

Werling - Histopathology 2011 abstract / PubMed

Presence of Merkel cell polyomavirus in Japanese cutaneous squamous cell carcinoma. M Murakami, M Imajoh, T Ikawa, H Nakajima, M Kamioka, Y Nemoto, T Ujihara, J Uchiyama, S Matsuzaki, S Sano, M Daibata. J Clin Virol 2011 Jan;50(1):37-41. 30 squamous cell carcinomas and 10 basal cell carcinomas in Japanese. Viral sequences of the LT3 gene were found in 4 of 30 (13%) of SCCs. BCCs were all negative for MCPyV.

Murakami - J Clin Virol 2011 abstract / PubMed

Merkel cell polyomavirus in Merkel cell carcinoma of Italian patients. F Paolini, P Donati, A Amantea, S Bucher, E Migliano, A Venuti. Virol J 2011 Mar 7;8:103. "The presence of viral T antigen and/or viral capsid DNA sequences was demonstrated in eight of the nine MCC lesions, whereas RNA transcripts were detected in three MCCs."

Paolini - Virol J 2011 full article / PubMed Central

Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma. S Kuwamoto, H Higaki, K Kanai, T Iwasaki, H Sano, K Nagata, K Kato, M Kato, I Murakami, Y Horie, O Yamamoto, K Hayashi. Hum Pathol 2011 May;42(5):632-640. "Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm."

Kuwamoto - Hum Pathol 2011 abstract / PubMed

Human polyomaviruses and other human viruses in neuroendocrine tumors. M Schmitt, D Höfler, N Koleganova, M Pawlita. Cancer Epidemiol Biomarkers Prev 2011 Jul;20(7):1558-1561. 2 of 3 MCCs (67%) were positive for MCV. Neuroendocrine tumors from other entities were negative for all human polyomaviruses.

Schmitt - Cancer Epidemiol Biomarkers Prev 2011 abstract / PubMed

Association of Merkel cell polyomavirus infection with tumor p53, KIT, stem cell factor, PDGFR-alpha and survival in Merkel cell carcinoma. M Waltari, H Sihto, H Kukko, V Koljonen, R Sankila, T Böhling, H Joensuu. Int J Cancer 2011 Aug 1;129(3):619-628. "Most (77.0%) of the 87 tumors contained MCPyV DNA and 37 (42.5%) expressed KIT, whereas PDGFRα, p53, SCF and pKIT expression was less common (31.9%, 22.8%, 8.6% and 4.8%, respectively)."

Waltari - Int J Cancer 2011 abstract / PubMed

Merkel cell polyomavirus status is not associated with clinical course of merkel cell carcinoma. D Schrama, WK Peitsch, M Zapatka, H Kneitz, R Houben, S Eib, S Haferkamp, PS Moore, M Shuda, JF Thompson, U Trefzer, C Pföhler, RA Scolyer, JC Becker. J Invest Dermatol 2011 Aug;131(8):1631-1638. 86% of 174 MCC patients from Australia and Germany were positive for MCC, with no significant difference in prevalence between the countries.

Schrama - J Invest Dermatol 2011 abstract / PubMed

Detection of Merkel cell polyomavirus in Merkel cell carcinomas and small cell carcinomas by PCR and immunohistochemistry. HS Jung, YL Choi, JS Choi, JH Roh, JK Pyon, KJ Woo, EH Lee, KT Jang, J Han, CS Park, YS Park, YK Shin. Histol Histopathol 2011 Oct;26(10):1231-1241. 14 MCCs, 24 SCCs, 7 Ewing sarcoma/primitive neuroectodermal tumors (ES/PNETs) and 5 neuroblastomas; and a variety of other cancers. "In total, 12 of 14 (85.7%) MCC cases were positive for MCPyV by PCR, which was consistent with published data. Some SCC specimens were also positive for MCPyV (37.5%) by PCR. PCR products from MCC and SCC cases showed premature truncation and frameshift mutation. Furthermore, one case of ES/PNET and one gastric carcinoma showed MCPyV DNA. However, MCPyV DNA and transcript were only detected in MCCs with quantitative real-time PCR analysis. In addition, 11 of 13 (84.6%) MCC cases and 6 of 23 (26.1%) SCC cases showed immunoreactivity with monoclonal antibodies against MCPyV large T-antigen. Considering both PCR and IHC results, MCPyV was detected in all MCCs tested. The presence of MCPyV in all MCC cases tested and in some SCC cases suggests that MCPyV may be involved in the malignant transformation."

Jung - Histol Histopathol 2011 abstract / PubMed

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I-II) Merkel cell carcinomas. S Asioli, A Righi, D de Biase, L Morandi, V Caliendo, F Picciotto, G Macripò, F Maletta, LV di Cantogno, L Chiusa, V Eusebi, G Bussolati. Mod Pathol 2011 Nov;24(11):1451-1461. "Presence of Merkel cell polyomavirus DNA sequences was detected in 86% (60/70) of Merkel cell carcinomas and did not emerge as a significant prognostic parameter."

Asioli - Mod Pathol 2011 abstract / PubMed

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites. TY Ly, NM Walsh, S Pasternak. Hum Pathol 2012 Apr;43(4):557-566. "Merkel cell polyomavirus large T antigen was detected in 17 (63%) of 27 pure Merkel cell carcinomas and absent in all 15 (0%) combined Merkel cell carcinomas. Furthermore, complete concordance (100%) of Merkel cell polyomavirus large T antigen expression was observed in 10 cases of primary Merkel cell carcinoma and subsequent tumor metastases. We also evaluated 70 non-Merkel cell carcinoma lesions including 15 cases each of pulmonary and gastrointestinal neuroendocrine tumors. All 70 non-Merkel cell carcinoma lesions were negative for Merkel cell polyomavirus by CM2B4 immunohistochemistry, irrespective of any known Merkel cell carcinoma diagnosis and immune status."

Ly - Hum Pathol 2012 abstract / PubMed

P-cadherin expression in Merkel cell carcinomas is associated with prolonged recurrence-free survival. L Vlahova, Y Doerflinger, R Houben, JC Becker, D Schrama, C Weiss, M Goebeler, P Helmbold, S Goerdt, WK Peitsch. Br J Dermatol 2012 May;166(5):1043-1052. 148 samples from 106 patients. "MCV DNA was detected in 78·2% of all MCC, more frequently in P-cadherin-positive MCC (P = 0·0008)."

Vlahova - Br J Dermatol 2012 abstract / PubMed

Genetic variability and integration of Merkel cell polyomavirus in Merkel cell carcinoma. C Martel-Jantin, C Filippone, O Cassar, M Peter, G Tomasic, P Vielh, J Brière, T Petrella, MH Aubriot-Lorton, L Mortier, G Jouvion, X Sastre-Garau, C Robert, A Gessain. Virology 2012 May 10;426(2):134-142. 113 lesions from 97 patients. "MCPyV detection was higher in fresh-frozen (FF) biopsies (94%) than in formalin-fixed paraffin-embedded biopsies (39-47%). Mean viral load in FF tumor was of 7.5 copies per cell with a very wide range (0.01-95.4)." 19 / 27 had integrated virus.

Martel-Jantin - Virology 2012 abstract / PubMed

Detection of Merkel Cell Polyomavirus and Human Papillomaviruses in Merkel Cell Carcinoma Combined With Squamous Cell Carcinoma in Immunocompetent European Patients. C Mitteldorf, KD Mertz, MT Fernández-Figueras, M Schmid, M Tronnier, W Kempf. Am J Dermatopathol 2012 Jul;34(5):506-510. 2 combined tumors of MCC and SCC were positive for MCPyV DNA, and HPV DNA was also detected in one.

Mitteldorf - Am J Dermatopathol 2012 abstract / PubMed

Extracutaneous Merkel cell carcinomas harbor polyomavirus DNA. D de Biase, M Ragazzi, S Asioli, V Eusebi. Hum Pathol 2012 Jul;43(7):980-985. "Cases studied were 5 primary Merkel cell carcinomas in lymph nodes, 1 in the parotid gland, and 12 in the skin. Twelve cases of primary and metastatic small cell carcinoma of the lung were also investigated... Cytokeratin 20 and Merkel cell polyomavirus were detected in all cases of primary Merkel cell carcinoma irrespective of their site of origin. On the contrary, all cases of pulmonary small cell carcinoma were negative for both Merkel cell polyomavirus and cytokeratin 20."

de Biase - Hum Pathol 2012 abstract / PubMed

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus. SJ Rodig, J Cheng, J Wardzala, A DoRosario, JJ Scanlon, AC Laga, A Martinez-Fernandez, JA Barletta, AM Bellizzi, S Sadasivam, DT Holloway, DJ Cooper, TS Kupper, LC Wang, JA DeCaprio. J Clin Invest 2012 Dec 3;122(12):4645-4653. "Here we report that a novel monoclonal antibody detected MCPyV large T antigen expression in 56 of 58 (97%) unique MCC tumors. PCR analysis specifically detected viral DNA in all 60 unique MCC tumors tested. We also detected inactivating point substitution mutations of TP53 in the two MCC specimens that lacked large T antigen expression and in only 1 of 56 tumors positive for large T antigen. These results indicate that MCPyV is present in MCC tumors more frequently than previously reported and that mutations in TP53 tend to occur in MCC tumors that fail to express MCPyV large T antigen."

Rodig - J Clin Invest 2012 full article / PubMed Central

Merkel cell polyomavirus is frequently detected in korean patients with merkel cell carcinoma. SM Chun, SJ Yun, SC Lee, YH Won, JB Lee. Ann Dermatol 2013 May;25(2):203-207. "MCPyV sequences were detected in six of seven MCC tissue specimens (85.7%)." One small cell carcinoma of the lung and 32 tissue specimens of other skin tumors were negative.

Chun - Ann Dermatol 2013 full article / PubMed Central
Chun - Ann Dermatol 2013 full article

The prevalence of Merkel cell polyomavirus in Japanese patients with Merkel cell carcinoma. T Hattori, Y Takeuchi, T Takenouchi, A Hirofuji, T Tsuchida, T Kabumoto, H Fujiwara, M Ito, A Shimizu, E Okada, SI Motegi, A Tamura, O Ishikawa. J Dermatol Sci 2013 May;70(2):99-107. "Twenty-three out of 26 cases (88.5%) were positive for MCPyV DNA by PCR... The LT antigen was expressed in various degrees in 20 of 26 cases (76.9%) by immunohistochemistry."

Hattori - J Dermatol Sci 2013 abstract / PubMed

Prevalence and viral DNA loads of three novel human polyomaviruses in skin cancers from Japanese patients. M Imajoh, Y Hashida, H Nakajima, S Sano, M Daibata. J Dermatol 2013 Aug;40(8):657-660. "MCPyV, HPyV6 and HPyV7 were detected in 22.2%, 3.2% and 1.6% of squamous cell carcinomas, 18.0%, 2.0% and 4.0% of basal cell carcinomas, and 19.1%, 4.3% and 4.3% of melanomas, respectively. Quantitative real-time polymerase chain reaction showed that their DNA loads were low."

Imajoh - J Dermatol 2013 abstract / PubMed

Prospective study of merkel cell polyomavirus and risk of merkel cell carcinoma. H Faust, K Andersson, J Ekström, M Hortlund, TE Robsahm, J Dillner. Int J Cancer 2014 Feb;134(4):844-848. 22 cases from cancer registries of Sweden and Norway, and 88 controls. "An increased risk for future MCC was associated both with high levels of MCV antibodies (OR 4.4, 95% CI 1.3-17.4) and with MCV neutralizing activity (OR 5.3, 95% CI 1.3-32.3). In males, MCV seropositivity was not associated to MCC risk, whereas the risk was strongly increased in females, both for high levels of MCV antibodies (OR 7.0, 95% CI 1.6-42.8) and for MCV neutralizing activity (OR 14.3, 95% CI 1.7-677)."

Faust - Int J Cancer 2013 abstract / PubMed

T-cell responses to oncogenic Merkel cell polyomavirus proteins distinguish Merkel cell carcinoma patients from healthy donors. R Lyngaa, NW Pedersen, D Schrama, CA Thrue, D Ibrani, O Met, P Thor Straten, P Nghiem, JC Becker, SR Hadrup. Clin Cancer Res 2014 Apr 1;20(7):1768-1778. "In peripheral blood from 38 MCC patients and 30 healthy donors we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in MCC patients, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells towards MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor infiltrating lymphocytes further substantiated the relevance of the identified epitopes."

Lyngaa - Clin Cancer Res 2014 abstract / PubMed

Merkel cell polyomavirus detection in Merkel cell cancer tumors in Northern Germany using PCR and protein expression. M Leitz, K Stieler, A Grundhoff, I Moll, JM Brandner, N Fischer. J Med Virol 2014 Oct;86(10):1813-1819. For MCPyV sequences and viral early gene expression in 32 cases, "40-57% of the cases were identified as MCPyV positive with 40.6% of the cases positive by immunohistochemical staining and 51.6-57.6% positive by PCR."

Leitz - J Med Virol 2014 abstract / PubMed

Fluorescence in situ hybridization and qPCR to detect Merkel cell polyomavirus physical status and load in Merkel cell carcinomas. AM Haugg, D Rennspiess, AZ Hausen, EJ Speel, G Cathomas, JC Becker, D Schrama. Int J Cancer 2014 Dec 15;135(12):2804-2815. 62 samples from 42 patients. "MCPyV-FISH and qPCR data were highly correlated, i.e. 83% for FISH-positive and 93% for FISH-negative cores. Accordingly, the mean of the qPCR values of all MCPyV-positive cores differed significantly from the mean of the negative cores (p = 0.0076). Importantly, two hybridization patterns were definable in the MCPyV-FISH: a punctate pattern (85%) indicating viral integration, which correlated with a moderate viral abundance and a combination of the punctate with a diffuse pattern (15%), suggesting a possible coexistence of integrated and episomal virus which was associated with very high viral load and VP1 expression."

Haugg - Int J Cancer 2014 abstract / PubMed

Frequent detection of human polyomavirus 6 in keratoacanthomas. J Beckervordersandforth, S Pujari, D Rennspiess, EJ Speel, V Winnepenninckx, C Diaz, W Weyers, AM Haugg, AK Kurz, A Zur Hausen. Diagn Pathol 2016 Jul 7;11(1):58. 299 non-melanoma skin cancer cases, including 59 keratoacanthomas, 25 of which (42.3%) were positive for MCPyV.

Beckervordersandforth - Diagn Pathol 2016 full article / PubMed Central
Beckervordersandforth - Diagn Pathol 2016 full article


A specific signature of Merkel cell polyomavirus persistence in human cancer cells. H zur Hausen. Proc Natl Acad Sci USA. 2008 Oct 21;105(42):16063-16064. Mutations in the helicase part of the large T antigen of MCpyV result in replication incompetence. These types of mutation in other polyomaviruses have been shown to increase their transformation potential.

zur Hausen / Proc Natl Acad Sci USA 2008 full article
zur Hausen - Proc Natl Acad Sci USA 2008 full article / PubMed Central

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. M Shuda, H Feng, HJ Kwun, ST Rosen, O Gjoerup, PS Moore, Y Chang. Proc Natl Acad Sci USA 2008 Oct 21;105(42):16272-16277. "Nine MCC tumor-derived LT genomic sequences have been examined, and all were found to harbor mutations prematurely truncating the MCV LT helicase. In contrast, four presumed episomal viruses from nontumor sources did not possess this T antigen signature mutation." The mutations "do not affect retinoblastoma tumor suppressor protein (Rb) binding by LT but do eliminate viral DNA replication capacity." "Only WT LT expression activates replication of integrated MCV DNA in MKL-1 cells. Our findings suggest that MCV-positive MCC tumor cells undergo selection for LT mutations to prevent autoactivation of integrated virus replication that would be detrimental to cell survival. Because these mutations render the virus replication-incompetent, MCV is not a "passenger virus" that secondarily infects MCC tumors."

Shuda / Proc Natl Acad Sci USA 2008 full article
Shuda - Proc Natl Acad Sci USA 2008 full article / PubMed Central

Merkel cell polyomavirus infected Merkel cell carcinoma cells require expression of viral T antigens. R Houben, M Shuda, R Weinkam, D Schrama, H Feng, Y Chang, PS Moore, JC Becker. J Virol 2010 Jul;84(14):7064-7072. "We knocked down MCV T antigen (TA) expression in MCV-positive MCC cell lines using three different shRNA-expressing vectors targeting exon 1 of the TAs... Notably, all MCV-positive MCC cell lines underwent growth arrest and/or cell death upon TA knock down, whereas proliferation of MCV-negative cell lines remained unaffected... Our study provides the first direct experimental evidence for TA expression being necessary for maintenance of MCV-positive MCC and thereby identifies the TAs as possible targets for future therapies."

Houben - J Virol 2010 abstract / PubMed

Merkel cell polyomavirus small T antigen mRNA level is increased following in vivo UV-radiation. A Mogha, A Fautrel, N Mouchet, N Guo, S Corre, H Adamski, E Watier, L Misery, MD Galibert. PLoS One 2010 Jul 2;5(7):e11423. "Two patients were infected with two new variants of MCPyV, present in their episomal form and RT-QPCR analyses on SSR-irradiated skin samples showed a specific and unique dose-dependent increase of MCPyV small t antigen transcript. A luciferase based in vitro assay confirmed that small t promoter is indeed UV-inducible."

Mogha / PLoS One 2010 full article
Mogha - PLoS One 2010 full article / PubMed Central

Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator. M Shuda, HJ Kwun, H Feng, Y Chang, PS Moore. J Clin Invest 2011 Sep;121(9):3623-3634. "Unlike the closely related SV40 sT, MCV sT transformed rodent fibroblasts to anchorage- and contact-independent growth and promoted serum-free proliferation of human cells... MCV sT was found to act downstream in the mammalian target of rapamycin (mTOR) signaling pathway to preserve eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) hyperphosphorylation, resulting in dysregulated cap-dependent translation. MCV sT-associated 4E-BP1 serine 65 hyperphosphorylation was resistant to mTOR complex (mTORC1) and mTORC2 inhibitors. Steady-state phosphorylation of other downstream Akt-mTOR targets, including S6K and 4E-BP2, was also increased by MCV sT."

Shuda - J Clin Invest 2011 full article / PubMed Central

Merkel cell carcinoma and Merkel cell polyomavirus: evidence for hit-and-run oncogenesis. R Houben, J Grimm, C Willmes, R Weinkam, JC Becker, D Schrama. J Invest Dermatol 2012 Jan;132(1):254-256. (Letter.) A cell line from an MCV-positive tumor did not require T-antigen for growth. "Thus, in some MCC cases, MCV may only be necessary for tumor initiation, whereas additional mutations during tumor progression render T-antigen expression dispensable for them. This might lead on one hand to the loss of MCV within these tumors and on the other to a different biological behavior including a more aggressive phenotype."

Houben / J Invest Dermatol 2012 full article

Association of Merkel cell polyomavirus infection with clinicopathological differences in Merkel cell carcinoma. H Higaki-Mori, S Kuwamoto, T Iwasaki, M Kato, I Murakami, K Nagata, H Sano, Y Horie, Y Yoshida, O Yamamoto, K Adachi, E Nanba, K Hayashi. Hum Pathol 2012 Dec;43(12):2282-2291. 20 Merkel cell polyomavirus-positive and 6 Merkel cell polyomavirus-negative Merkel cell carcinoma cases. TP53 expression was higher in positive cases. "Interestingly, frequency of TP53 non-ultraviolet signature mutation was significantly higher in Merkel cell polyomavirus-negative Merkel cell carcinomas than in Merkel cell polyomavirus-positive Merkel cell carcinomas (P = .036), whereas no significant difference was detected in TP53 ultraviolet signature mutations between two groups."

Higaki-Mori - Hum Pathol 2012 abstract / PubMed

C-terminal deletions of Merkel cell polyomavirus large T-antigen, a highly specific surrogate marker for virally induced malignancy. M Schmitt, U Wieland, A Kreuter, M Pawlita. Int J Cancer 2012 Dec 15;131(12):2863-2868. "MCPyV ΔC-TAg was used to assess the physical state of MCPyV TAg in a large series of 55 MCCs, 15 cutaneous lymphomas and 47 forehead smears of healthy individuals. Neither DNA positivity nor viral load was able to discriminate MCCs from the other different types of samples. However, deleted TAg C-terminus sequences were detected only in MCPyV positive MCCs (39%)."

Schmitt - Int J Cancer 2012 abstract / PubMed

Merkel cell polyomavirus infection in both components of a combined Merkel cell carcinoma and basal cell carcinoma with ductal differentiation; each component had a similar but different novel Merkel cell polyomavirus large T antigen truncating mutation. T Iwasaki, H Kodama, M Matsushita, N Kuroda, Y Yamasaki, I Murakami, O Yamamoto, K Hayashi. Hum Pathol 2013 Mar;44(3):442-447. Case report of a combined tumor with Merkel cell carcinoma and basal cell carcinoma with ductal differentiation. "Both tumors and intermingled Merkel cells in basal cell carcinoma expressed Merkel cell polyomavirus large T antigen, and 17 and 240 copies of Merkel cell polyomavirus/cell were detected in the microdissected Merkel cell carcinoma and basal cell carcinoma specimens, respectively. Mutation analysis of Merkel cell polyomavirus large T antigen revealed a novel truncating mutation in Merkel cell carcinoma and a similar but different mutation in the basal cell carcinoma."

Iwasaki - Hum Pathol 2013 abstract / PubMed

Merkel Cell Polyomavirus Large T Antigen Disrupts Host Genomic Integrity and Inhibits Cellular Proliferation. J Li, X Wang, J Diaz, SH Tsang, CB Buck, J You. J Virol 2013 Aug;87(16):9173-9188. "In this study, we show that MCV infection leads to activation of host DNA damage responses (DDR). This activity was mapped to the C-terminal helicase-containing region of MCV LT. The MCV LT-activated DNA damage kinases, in turn, led to enhanced p53 phosphorylation, up-regulation of p53 downstream target genes and cell cycle arrest. Compared to the N-terminal MCV LT fragment that is usually preserved in mutants isolated from MCC tumors, full-length MCV LT shows a decreased potential to support cellular proliferation, focus formation and anchorage-independent cell growth. These apparently anti-tumorigenic effects can be reversed by a dominant-negative p53 inhibitor... This study also explains, in part, why truncation mutations that remove the MCV LT C-terminal region are necessary for the oncogenic progression of MCV-associated cancers."

Li - J Virol 2013 abstract / PubMed

Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. JH Lai, KE Fleming, TY Ly, S Pasternak, M Godlewski, S Doucette, NM Walsh. Hum Pathol 2015 Sep;46(9):1290-1296. 51 MCV-positive and 24 MCV-negative. "Virus-positive tumors (all pure) exhibit high retinoblastoma protein and low p53 expression, whereas virus-negative cases (few pure and all combined) show high p53 and relatively high c-kit expression."

Lai - Hum Pathol 2015 abstract / PubMed

The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma. PW Harms, P Vats, ME Verhaegen, DR Robinson, YM Wu, SM Dhanasekaran, N Palanisamy, J Siddiqui, X Cao, F Su, R Wang, H Xiao, LP Kunju, R Mehra, SA Tomlins, DR Fullen, CK Bichakjian, TM Johnson, AA Dlugosz, AM Chinnaiyan. Cancer Res 2015 Sep 15;75(18):3720-3727. "MCPyV-negative tumors also displayed high overall mutation burden (10.09 +/- 2.32 mutations per Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 +/- 0.09 mutations per Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways."

Harms - Cancer Res 2015 abstract / PubMed


Seroepidemiology of Human Polyomaviruses. JM Kean, S Rao, M Wang, RL Garcea. PLoS Pathogens 2009 Mar;5(3). Seroprevalence in 1501 healthy adult blood donors was SV40 (9%), BKV (82%), JCV (39%), LPV (15%), KIV (55%), WUV (69%), MCV strain 350 (25%), and MCV strain 339 (42%). Seroprevalence in 721 pediatric patients (<21 y) was similar.

Kean / PLoS Pathogens 2009 full article

Age-specific seroprevalence of Merkel cell polyomavirus, BK virus, and JC virus. RP Viscidi, DE Rollison, VK Sondak, B Silver, JL Messina, AR Giuliano, W Fulp, A Ajidahun, D Rivanera. Clin Vaccine Immunol 2011 Oct;18(10):1737-1743. 947 outpatients aged 1 to 93 years. "MCPyV seroprevalence was 45% in children under 10 years of age, increased to 60% in the next decade of life, and peaked at 81% among those 60 to 69 years of age. Levels of MCPyV capsid antibodies were positively correlated with age (P = 0.007)."

Viscidi - Clin Vaccine Immunol 2011 abstract / PubMed

Molecular epidemiology of Merkel cell polyomavirus: evidence for geographically-related variant genotypes. C Martel-Jantin, C Filippone, P Tortevoye, PV Afonso, E Betsem, S Descorps-Declere, JT Nicol, A Touzé, P Coursaget, M Crouzat, N Berthet, O Cassar, A Gessain. J Clin Microbiol 2014 May;52(5):1687-1690. "DNAs from skin swabs of 255 adults, originating from the 5 continents, were subjected to MCPyV PCRs. Phylogenetic analyses demonstrated the existence of 5 major geographically-related MCPyV genotypes (Europe/North America, Africa (Sub-Saharan), Oceania, South America, Asia/Japan)."

Martel-Jantin - J Clin Microbiol 2014 abstract / PubMed

See Also:

HPVs Cause Skin Cancer
Merkel Cell Polyomavirus Is Implicated in Small Cell Lung Cancer


cast 08-06-16