Gynecologic Oncology 134 (2014) 1–2
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Editorial
Mutations in oncogenes: Context matters
Malignant melanoma is a rare gynecological cancer of the vulva, vagina, cervix and, rarely, ovary, associated with a very poor prognosis. The nomenclature of this tumor reflects the convention of naming tumors based on cell of origin, as it is derived from the melanocytes that migrate from the neural crest to sites throughout the body during embryonic development. Diagnostic criteria and reporting guidelines are derived from the much more common cutaneous melanomas, although it should be noted that “more common” is the perspective of someone who practices in an area with a patient population of largely northern European extraction, and the ratio of cutaneous:mucosal melanomas is subject to wide variations world-wide. Thus, melanocytic neoplasms vary dramatically based on host genetic (ethnic) context. Cutaneous melanomas are mostly superficially invasive (b1 mm) and associated with a favorable prognosis but for more aggressive/advanced tumors no effective treatments were available until recently. The identification of BRAF mutations in more than 50% of cases opened the possibility of targeted therapy with inhibitors of BRAF, which have entered clinical practice for patients whose melanomas test positive for mutant BRAF [1,2]. In this issue of the journal, van Engen-van Grunsven et al. report on molecular studies in genitourinary melanomas [3]. None of the 24 cases in their series were found to have BRAF exon 15 mutations, in keeping with the observation that melanomas of mucosal/non-sun-exposed sites have a different molecular phenotype than cutaneous melanomas [4]. Melanocytic neoplasms, then, vary significantly based on the etiologic factors i.e. actinic damage. They also looked at NRAS mutations (present in 4 of 24 cases) and KIT mutations (1 of 24 cases). This study illustrates a number of points of broader interest, beyond the rare gynecological melanomas studied. From a technical standpoint, they have pooled cases from five centers, and still have a small case series. For rare tumors studies of smaller series with careful consideration of cases from other published studies, as was done by the authors, are the only way forward. We have already seen that there is significant heterogeneity in melanomas, making it inappropriate to draw conclusions about vulvar melanomas from studies of melanomas arising in sun-exposed skin. Only through these sorts of smaller and narrowly focused studies will we accrue the information we need to improve the outcomes for women with vulvar or vaginal melanomas. A second technical aspect of the study is that they used Sanger sequencing of hot spots to look at oncogenic mutations. The era of next-generation sequencing, allowing sequencing of many genes at low cost, is around the corner. The ability to characterize mutational hot-spots from formalin-fixed paraffin-embedded material with this technology is relevant for studies of rare tumor types, where the lack of available frozen tumor samples, and the high-quality DNA that can be obtained from such samples, make studies from archival formalin-fixed paraffin-embedded samples
http://dx.doi.org/10.1016/j.ygyno.2014.05.023 0090-8258/© 2014 Elsevier Inc. All rights reserved.
necessary for the foreseeable future. This technical development will allow studies of series of rare tumor types, with samples derived from pathology archives, to generate more data, at less cost, in the future. It will also make such testing affordable for clinical use, for those tumor types where mutations that can be successfully targeted pharmacologically have been identified. There is abundant evidence indicating the importance of tumor cell type in the interpretation of molecular abnormalities. BRAF mutations are common in cutaneous melanomas and are a target for therapy. In low-grade serous neoplasia BRAF mutations are relatively common but it appears that BRAF mutations are associated with a favorable prognosis [5], such that the presence of this targetable mutation renders the tumor, quite unexpectedly, less likely to progress, and therefore not needing adjuvant treatment. In colon cancer, BRAF mutations are associated with a poor prognosis and predict unresponsiveness to targeted therapy [6]. They also, in patients whose tumors have lost expression of the MLH1 mismatch repair enzyme, provide evidence that such loss is not due to a germline MLH1 mutation (i.e. Lynch Syndrome) [7]. This bewildering complexity flies in the face of suggestions that we would soon move to a purely molecular taxonomy of cancer (HER2 mutant cancer, BRAF mutant cancer etc.). The clinical significance of oncogenic mutations is critically dependent on cell of origin, and within a given cell type, the other molecular abnormalities present within the tumor cells. This study makes another point that is surely disheartening for those inclined to be lumpers rather than splitters. Although they found only one KIT mutation, it was in a vaginal melanoma. Their study included very few vulvar melanomas (n = 1), so a comparison of the frequency of KIT mutations in vulvar and vaginal melanomas is not possible based on their data, however, in their review of the literature they found that KIT mutations are rare in vaginal melanomas (3 of 55 or 5.4% of cases, inclusive of the cases in their series) and significantly more common in vulvar melanomas (20 of 79 cases, 25%; p = 0.0024), indicating variation between melanomas arising in vulvar skin and vaginal squamous mucosa, even though the cell of origin and etiologic factors are probably the same. It will be important to take differences between vulvar and vaginal melanomas into account in future studies, by analyzing such cases separately, as these authors have done. In contrast to KIT, NRAS mutations were found to be equally frequent in vulvar and vaginal melanomas. NRAS is a potential therapeutic target in mucosal melanoma [8]. New targeted therapies have emerged slowly, however, with many promising preclincial or phase 1 trial results not carrying through to the introduction of effective treatments, and it remains to be seen whether NRAS mutations in genital melanomas can be specifically targeted. The finding of NRAS mutations in 80% of benign congenital melanocytic nevi [9] indicates that NRAS mutations alone are
2
Editorial
non-transforming; therapy may then have to target other pathways, in addition to those affected by NRAS mutations, to be effective, as suggested by van Engen-van Grunsven et al. [3]. We are progressing towards personalized medicine incrementally; for the present, we will be investigating single targets or small numbers of targets, and the significance of those mutations will be highly dependent on context: host genetic factors, etiologic factors, cell type, body site, and other genetic abnormalities present in the tumor. References [1] Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:1893–901. [2] Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012;18:3242–9. [3] van Engen-van Grunsven Adriana CH, Küsters-Vandevelde Heidi VN, De Hullu Joanne, van Duijn Lucette M, Rijntjes Jos, Bovée Judith VMG, et al. NRAS mutations are more prevalent than KIT mutations in melanoma of the female urogenital tract — a study of 24 cases from the Netherlands. Gynecol Oncol 2014;134:10–4.
[4] Cohen Y, Rosenbaum E, Begum S, et al. Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res 2004;10:3444–7. [5] Wong KK, Tsang YT, Deavers MT, et al. BRAF mutation is rare in advanced-stage lowgrade ovarian serous carcinomas. Am J Surg Pathol 2010;177:1611–7. [6] Chen D, Huang JE, Liu K, et al. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One 2014;9:e90607. [7] Parsons MT, Buchanan DD, Thomson B, Young JP, Spurdle AB. Correlation of tumor BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) status: a literature review assessing utility of tumor features for MMR variant classification. J Med Genet 2012;49:151–7. [8] Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249–56. [9] Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127(1):179–82.
C. Blake Gilks Rm 1259, 1st Floor JPPN, Dept of Pathology, Vancouver General Hospital, 910 W 10th Ave., Vancouver, BC V5Z 4E3, Canada E-mail address: [email protected].
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Editorial
Mutations in oncogenes: Context matters
Malignant melanoma is a rare gynecological cancer of the vulva, vagina, cervix and, rarely, ovary, associated with a very poor prognosis. The nomenclature of this tumor reflects the convention of naming tumors based on cell of origin, as it is derived from the melanocytes that migrate from the neural crest to sites throughout the body during embryonic development. Diagnostic criteria and reporting guidelines are derived from the much more common cutaneous melanomas, although it should be noted that “more common” is the perspective of someone who practices in an area with a patient population of largely northern European extraction, and the ratio of cutaneous:mucosal melanomas is subject to wide variations world-wide. Thus, melanocytic neoplasms vary dramatically based on host genetic (ethnic) context. Cutaneous melanomas are mostly superficially invasive (b1 mm) and associated with a favorable prognosis but for more aggressive/advanced tumors no effective treatments were available until recently. The identification of BRAF mutations in more than 50% of cases opened the possibility of targeted therapy with inhibitors of BRAF, which have entered clinical practice for patients whose melanomas test positive for mutant BRAF [1,2]. In this issue of the journal, van Engen-van Grunsven et al. report on molecular studies in genitourinary melanomas [3]. None of the 24 cases in their series were found to have BRAF exon 15 mutations, in keeping with the observation that melanomas of mucosal/non-sun-exposed sites have a different molecular phenotype than cutaneous melanomas [4]. Melanocytic neoplasms, then, vary significantly based on the etiologic factors i.e. actinic damage. They also looked at NRAS mutations (present in 4 of 24 cases) and KIT mutations (1 of 24 cases). This study illustrates a number of points of broader interest, beyond the rare gynecological melanomas studied. From a technical standpoint, they have pooled cases from five centers, and still have a small case series. For rare tumors studies of smaller series with careful consideration of cases from other published studies, as was done by the authors, are the only way forward. We have already seen that there is significant heterogeneity in melanomas, making it inappropriate to draw conclusions about vulvar melanomas from studies of melanomas arising in sun-exposed skin. Only through these sorts of smaller and narrowly focused studies will we accrue the information we need to improve the outcomes for women with vulvar or vaginal melanomas. A second technical aspect of the study is that they used Sanger sequencing of hot spots to look at oncogenic mutations. The era of next-generation sequencing, allowing sequencing of many genes at low cost, is around the corner. The ability to characterize mutational hot-spots from formalin-fixed paraffin-embedded material with this technology is relevant for studies of rare tumor types, where the lack of available frozen tumor samples, and the high-quality DNA that can be obtained from such samples, make studies from archival formalin-fixed paraffin-embedded samples
http://dx.doi.org/10.1016/j.ygyno.2014.05.023 0090-8258/© 2014 Elsevier Inc. All rights reserved.
necessary for the foreseeable future. This technical development will allow studies of series of rare tumor types, with samples derived from pathology archives, to generate more data, at less cost, in the future. It will also make such testing affordable for clinical use, for those tumor types where mutations that can be successfully targeted pharmacologically have been identified. There is abundant evidence indicating the importance of tumor cell type in the interpretation of molecular abnormalities. BRAF mutations are common in cutaneous melanomas and are a target for therapy. In low-grade serous neoplasia BRAF mutations are relatively common but it appears that BRAF mutations are associated with a favorable prognosis [5], such that the presence of this targetable mutation renders the tumor, quite unexpectedly, less likely to progress, and therefore not needing adjuvant treatment. In colon cancer, BRAF mutations are associated with a poor prognosis and predict unresponsiveness to targeted therapy [6]. They also, in patients whose tumors have lost expression of the MLH1 mismatch repair enzyme, provide evidence that such loss is not due to a germline MLH1 mutation (i.e. Lynch Syndrome) [7]. This bewildering complexity flies in the face of suggestions that we would soon move to a purely molecular taxonomy of cancer (HER2 mutant cancer, BRAF mutant cancer etc.). The clinical significance of oncogenic mutations is critically dependent on cell of origin, and within a given cell type, the other molecular abnormalities present within the tumor cells. This study makes another point that is surely disheartening for those inclined to be lumpers rather than splitters. Although they found only one KIT mutation, it was in a vaginal melanoma. Their study included very few vulvar melanomas (n = 1), so a comparison of the frequency of KIT mutations in vulvar and vaginal melanomas is not possible based on their data, however, in their review of the literature they found that KIT mutations are rare in vaginal melanomas (3 of 55 or 5.4% of cases, inclusive of the cases in their series) and significantly more common in vulvar melanomas (20 of 79 cases, 25%; p = 0.0024), indicating variation between melanomas arising in vulvar skin and vaginal squamous mucosa, even though the cell of origin and etiologic factors are probably the same. It will be important to take differences between vulvar and vaginal melanomas into account in future studies, by analyzing such cases separately, as these authors have done. In contrast to KIT, NRAS mutations were found to be equally frequent in vulvar and vaginal melanomas. NRAS is a potential therapeutic target in mucosal melanoma [8]. New targeted therapies have emerged slowly, however, with many promising preclincial or phase 1 trial results not carrying through to the introduction of effective treatments, and it remains to be seen whether NRAS mutations in genital melanomas can be specifically targeted. The finding of NRAS mutations in 80% of benign congenital melanocytic nevi [9] indicates that NRAS mutations alone are
2
Editorial
non-transforming; therapy may then have to target other pathways, in addition to those affected by NRAS mutations, to be effective, as suggested by van Engen-van Grunsven et al. [3]. We are progressing towards personalized medicine incrementally; for the present, we will be investigating single targets or small numbers of targets, and the significance of those mutations will be highly dependent on context: host genetic factors, etiologic factors, cell type, body site, and other genetic abnormalities present in the tumor. References [1] Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:1893–901. [2] Menzies AM, Haydu LE, Visintin L, et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 2012;18:3242–9. [3] van Engen-van Grunsven Adriana CH, Küsters-Vandevelde Heidi VN, De Hullu Joanne, van Duijn Lucette M, Rijntjes Jos, Bovée Judith VMG, et al. NRAS mutations are more prevalent than KIT mutations in melanoma of the female urogenital tract — a study of 24 cases from the Netherlands. Gynecol Oncol 2014;134:10–4.
[4] Cohen Y, Rosenbaum E, Begum S, et al. Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res 2004;10:3444–7. [5] Wong KK, Tsang YT, Deavers MT, et al. BRAF mutation is rare in advanced-stage lowgrade ovarian serous carcinomas. Am J Surg Pathol 2010;177:1611–7. [6] Chen D, Huang JE, Liu K, et al. BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One 2014;9:e90607. [7] Parsons MT, Buchanan DD, Thomson B, Young JP, Spurdle AB. Correlation of tumor BRAF mutations and MLH1 methylation with germline mismatch repair (MMR) status: a literature review assessing utility of tumor features for MMR variant classification. J Med Genet 2012;49:151–7. [8] Ascierto PA, Schadendorf D, Berking C, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol 2013;14:249–56. [9] Bauer J, Curtin JA, Pinkel D, Bastian BC. Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. J Invest Dermatol 2007;127(1):179–82.
C. Blake Gilks Rm 1259, 1st Floor JPPN, Dept of Pathology, Vancouver General Hospital, 910 W 10th Ave., Vancouver, BC V5Z 4E3, Canada E-mail address: [email protected].
