Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis

Dorian R. A. Swarts, Quirinus J. M. Voorham, Annina P. van Splunter, Saskia M. Wilting, Daoud Sie, Divera Pronk, Marc van Beurden, Daniëlle A. M. Heideman, Peter J. F. Snijders, Chris J. L. M. Meijer, Renske D. M. Steenbergen, Maaike C. G. Bleeker

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow-up (VINno VSCC). HPV-testing resulted in 41 HPV-positive (16 VINVSCC, 14 VINno VSCC, and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P =.009), but shared chromosome 8 alterations. HPV-positive VINno VSCC had less CNA than VINVSCC (P =.022). Interestingly, 1pq gain was detected in 81% of HPV-positive VINVSCC and only in 21% of VINno VSCC (P =.001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.
Original languageEnglish
Pages (from-to)4542-4553
JournalCancer Medicine
Volume7
Issue number9
Early online date20 Jul 2018
DOIs
Publication statusPublished - 2018

Cite this

Swarts, Dorian R. A. ; Voorham, Quirinus J. M. ; van Splunter, Annina P. ; Wilting, Saskia M. ; Sie, Daoud ; Pronk, Divera ; van Beurden, Marc ; Heideman, Daniëlle A. M. ; Snijders, Peter J. F. ; Meijer, Chris J. L. M. ; Steenbergen, Renske D. M. ; Bleeker, Maaike C. G. / Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis. In: Cancer Medicine. 2018 ; Vol. 7, No. 9. pp. 4542-4553.
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title = "Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis",
abstract = "Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow-up (VINno VSCC). HPV-testing resulted in 41 HPV-positive (16 VINVSCC, 14 VINno VSCC, and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P =.009), but shared chromosome 8 alterations. HPV-positive VINno VSCC had less CNA than VINVSCC (P =.022). Interestingly, 1pq gain was detected in 81{\%} of HPV-positive VINVSCC and only in 21{\%} of VINno VSCC (P =.001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.",
author = "Swarts, {Dorian R. A.} and Voorham, {Quirinus J. M.} and {van Splunter}, {Annina P.} and Wilting, {Saskia M.} and Daoud Sie and Divera Pronk and {van Beurden}, Marc and Heideman, {Dani{\"e}lle A. M.} and Snijders, {Peter J. F.} and Meijer, {Chris J. L. M.} and Steenbergen, {Renske D. M.} and Bleeker, {Maaike C. G.}",
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Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis. / Swarts, Dorian R. A.; Voorham, Quirinus J. M.; van Splunter, Annina P.; Wilting, Saskia M.; Sie, Daoud; Pronk, Divera; van Beurden, Marc; Heideman, Daniëlle A. M.; Snijders, Peter J. F.; Meijer, Chris J. L. M.; Steenbergen, Renske D. M.; Bleeker, Maaike C. G.

In: Cancer Medicine, Vol. 7, No. 9, 2018, p. 4542-4553.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Molecular heterogeneity in human papillomavirus-dependent and -independent vulvar carcinogenesis

AU - Swarts, Dorian R. A.

AU - Voorham, Quirinus J. M.

AU - van Splunter, Annina P.

AU - Wilting, Saskia M.

AU - Sie, Daoud

AU - Pronk, Divera

AU - van Beurden, Marc

AU - Heideman, Daniëlle A. M.

AU - Snijders, Peter J. F.

AU - Meijer, Chris J. L. M.

AU - Steenbergen, Renske D. M.

AU - Bleeker, Maaike C. G.

N1 - © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

PY - 2018

Y1 - 2018

N2 - Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow-up (VINno VSCC). HPV-testing resulted in 41 HPV-positive (16 VINVSCC, 14 VINno VSCC, and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P =.009), but shared chromosome 8 alterations. HPV-positive VINno VSCC had less CNA than VINVSCC (P =.022). Interestingly, 1pq gain was detected in 81% of HPV-positive VINVSCC and only in 21% of VINno VSCC (P =.001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.

AB - Vulvar squamous cell carcinoma (VSCC) and precancerous vulvar intraepithelial neoplasia (VIN) can develop through human papillomavirus (HPV)-dependent and -independent pathways, indicating a heterogeneous disease. Only a minority of VIN progress, but current clinicopathological classifications are insufficient to predict the cancer risk. Here we analyzed copy number alterations (CNA) to assess the molecular heterogeneity of vulvar lesions in relation to HPV and cancer risk. HPV-status and CNA by means of whole-genome next-generation shallow-sequencing were assessed in VSCC and VIN. The latter included VIN of women with associated VSCC (VINVSCC) and women who did not develop VSCC during follow-up (VINno VSCC). HPV-testing resulted in 41 HPV-positive (16 VINVSCC, 14 VINno VSCC, and 11 VSCC) and 24 HPV-negative (11 VINVSCC and 13 VSCC) lesions. HPV-positive and -negative VSCC showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. In contrast, amplification of 11q13/cyclinD1 was exclusively found in HPV-negative lesions. HPV-negative VINVSCC had less CNA than HPV-negative VSCC (P =.009), but shared chromosome 8 alterations. HPV-positive VINno VSCC had less CNA than VINVSCC (P =.022). Interestingly, 1pq gain was detected in 81% of HPV-positive VINVSCC and only in 21% of VINno VSCC (P =.001). In conclusion, HPV-dependent and -independent vulvar carcinogenesis is characterized by distinct CNA patterns at the VIN stage, while more comparable patterns are present at the cancer stage. Cancer risk in VIN seems to be reflected by the extent of CNA, in particular chromosome 1 gain in HPV-positive cases.

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