Gene strong predictor of metastasis in melanoma

 

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

genes_photo_web.jpg

The study drew on a preselected list of 79 immunomodulatory genes that had been implicated in a broad spectrum of cancers, not just melanoma, based on a literature review. The researchers generated complimentary DNA samples from primary tumor specimens collected from 37 patients who had nonmetastatic primary melanoma. They followed those patients for a median of 38 months, ranging from 1 month to 12 years, in which time six developed metastases. They then compared differential gene expression of the 79 immunomodulatory genes in the patients who developed metastases and those who did not.

The rationale for analyzing the 79 genes implicated in cancer only rather than the entire array of 22,000 genes was to reduce the odds of a high false-discovery rate from 5% to 0.007%. “This is what strengthens our findings in a cohort of 37 patients,” Dr. Erdrich said.

The study analyzed pathological characteristics of the metastatic and nonmetastatic groups. Most characteristics were similar between the two groups, including location of the primary tumor in the trunk and extremities of 67% and 71%, respectively, and age of 60 years and older. The analysis noted two deviations: primary tumor size was thicker in the metastatic group (2.1 mm vs. 1.05 mm; P = .6), although Dr. Erdrich noted this was “not significantly different”; and a higher rate of ulceration in the metastatic group (50% vs. 13%; P = .05).

The genes CXCL1 and CXCL2 are both chemokines involved in growth and inflammation. “CXCL1 expression was 2.51 times greater in the metastatic group,” Dr. Erdrich said (P less than .001). Overexpression in the other three genes of interest was: CXCL2, 1.68 times greater (P less than .01); CD276, which is involved in T-cell immunity, 1.16 times greater (P = .04); and C-CBL, which is a photo-oncogene involved in the ubiquitin pathway, 1.15 times greater (P = .01). “The overexpression of all four of these was statistically significant,” she said.

Univariate analysis found ulceration of the primary along with overexpression of

 

the four genes to be significant predictors of metastasis. “However, in our multivariate model, three of the genes dropped out but CXCL1 remained robust,” she said.

Dr. Erdrich noted that CXCL1 is a cytokine located on chromosome 4, is secreted by macrophages, exerts its signal through CXCR2, and is one of five cytokines upregulated in lesions that respond to immunotherapy (Br J Dermatol. 2016;175:966-78).

CXCL1 compares favorably with S100, the existing blood-based biomarker for predicting recurrence in high-risk melanoma, as a predictor of metastases, Dr. Erdrich said, with an area under the curve of 0.80 versus 0.66; sensitivity of 67% versus 77%; specificity of 97% versus 61%; positive predictive value of 80% versus 40%; and negative predictive value of 94% versus 88% (Anticancer Res. 1999;19:2685-90; Cancer. 2003;97:1737-45).

The study also looked at overall survival in patients with low and high expression of CXCL1. “The patients with high expression had 5-year survival of only 50% compared to those of low expression, whose 5-year survival was 97%,” Dr. Erdrich said.

Dr. Erdrich and her coauthors reported having no financial relationships.

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.

 

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

genes_photo_web.jpg

The study drew on a preselected list of 79 immunomodulatory genes that had been implicated in a broad spectrum of cancers, not just melanoma, based on a literature review. The researchers generated complimentary DNA samples from primary tumor specimens collected from 37 patients who had nonmetastatic primary melanoma. They followed those patients for a median of 38 months, ranging from 1 month to 12 years, in which time six developed metastases. They then compared differential gene expression of the 79 immunomodulatory genes in the patients who developed metastases and those who did not.

The rationale for analyzing the 79 genes implicated in cancer only rather than the entire array of 22,000 genes was to reduce the odds of a high false-discovery rate from 5% to 0.007%. “This is what strengthens our findings in a cohort of 37 patients,” Dr. Erdrich said.

The study analyzed pathological characteristics of the metastatic and nonmetastatic groups. Most characteristics were similar between the two groups, including location of the primary tumor in the trunk and extremities of 67% and 71%, respectively, and age of 60 years and older. The analysis noted two deviations: primary tumor size was thicker in the metastatic group (2.1 mm vs. 1.05 mm; P = .6), although Dr. Erdrich noted this was “not significantly different”; and a higher rate of ulceration in the metastatic group (50% vs. 13%; P = .05).

The genes CXCL1 and CXCL2 are both chemokines involved in growth and inflammation. “CXCL1 expression was 2.51 times greater in the metastatic group,” Dr. Erdrich said (P less than .001). Overexpression in the other three genes of interest was: CXCL2, 1.68 times greater (P less than .01); CD276, which is involved in T-cell immunity, 1.16 times greater (P = .04); and C-CBL, which is a photo-oncogene involved in the ubiquitin pathway, 1.15 times greater (P = .01). “The overexpression of all four of these was statistically significant,” she said.

Univariate analysis found ulceration of the primary along with overexpression of

 

the four genes to be significant predictors of metastasis. “However, in our multivariate model, three of the genes dropped out but CXCL1 remained robust,” she said.

Dr. Erdrich noted that CXCL1 is a cytokine located on chromosome 4, is secreted by macrophages, exerts its signal through CXCR2, and is one of five cytokines upregulated in lesions that respond to immunotherapy (Br J Dermatol. 2016;175:966-78).

CXCL1 compares favorably with S100, the existing blood-based biomarker for predicting recurrence in high-risk melanoma, as a predictor of metastases, Dr. Erdrich said, with an area under the curve of 0.80 versus 0.66; sensitivity of 67% versus 77%; specificity of 97% versus 61%; positive predictive value of 80% versus 40%; and negative predictive value of 94% versus 88% (Anticancer Res. 1999;19:2685-90; Cancer. 2003;97:1737-45).

The study also looked at overall survival in patients with low and high expression of CXCL1. “The patients with high expression had 5-year survival of only 50% compared to those of low expression, whose 5-year survival was 97%,” Dr. Erdrich said.

Dr. Erdrich and her coauthors reported having no financial relationships.

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.

 

CHICAGO – Investigators have identified four genes that are overexpressed in primary melanoma, including one, CXCL1, that holds promise as a strong predictor of future metastatic disease, according to study results presented at the Society of Surgical Oncology Annual Cancer Symposium.

The study implicated four genes strongly expressed in primary melanoma tumors of patients who develop distant metastases – CXCL1, CXCL2, CBL, and CD276 – said Jennifer Erdrich, MD, MPH, of Cedars Sinai Medical Center, Los Angeles. However, CXCL1 stood out. “CXCL1 overexpression is an independent predictor of developing metastatic disease. Patients with CXCL1 overexpression in the primary tumor in our study had decreased overall 5-year survival.” CXCL1 may be a useful predictive marker in primary melanoma and a potential target for immunotherapy, she said.

genes_photo_web.jpg

The study drew on a preselected list of 79 immunomodulatory genes that had been implicated in a broad spectrum of cancers, not just melanoma, based on a literature review. The researchers generated complimentary DNA samples from primary tumor specimens collected from 37 patients who had nonmetastatic primary melanoma. They followed those patients for a median of 38 months, ranging from 1 month to 12 years, in which time six developed metastases. They then compared differential gene expression of the 79 immunomodulatory genes in the patients who developed metastases and those who did not.

The rationale for analyzing the 79 genes implicated in cancer only rather than the entire array of 22,000 genes was to reduce the odds of a high false-discovery rate from 5% to 0.007%. “This is what strengthens our findings in a cohort of 37 patients,” Dr. Erdrich said.

The study analyzed pathological characteristics of the metastatic and nonmetastatic groups. Most characteristics were similar between the two groups, including location of the primary tumor in the trunk and extremities of 67% and 71%, respectively, and age of 60 years and older. The analysis noted two deviations: primary tumor size was thicker in the metastatic group (2.1 mm vs. 1.05 mm; P = .6), although Dr. Erdrich noted this was “not significantly different”; and a higher rate of ulceration in the metastatic group (50% vs. 13%; P = .05).

The genes CXCL1 and CXCL2 are both chemokines involved in growth and inflammation. “CXCL1 expression was 2.51 times greater in the metastatic group,” Dr. Erdrich said (P less than .001). Overexpression in the other three genes of interest was: CXCL2, 1.68 times greater (P less than .01); CD276, which is involved in T-cell immunity, 1.16 times greater (P = .04); and C-CBL, which is a photo-oncogene involved in the ubiquitin pathway, 1.15 times greater (P = .01). “The overexpression of all four of these was statistically significant,” she said.

Univariate analysis found ulceration of the primary along with overexpression of

 

the four genes to be significant predictors of metastasis. “However, in our multivariate model, three of the genes dropped out but CXCL1 remained robust,” she said.

Dr. Erdrich noted that CXCL1 is a cytokine located on chromosome 4, is secreted by macrophages, exerts its signal through CXCR2, and is one of five cytokines upregulated in lesions that respond to immunotherapy (Br J Dermatol. 2016;175:966-78).

CXCL1 compares favorably with S100, the existing blood-based biomarker for predicting recurrence in high-risk melanoma, as a predictor of metastases, Dr. Erdrich said, with an area under the curve of 0.80 versus 0.66; sensitivity of 67% versus 77%; specificity of 97% versus 61%; positive predictive value of 80% versus 40%; and negative predictive value of 94% versus 88% (Anticancer Res. 1999;19:2685-90; Cancer. 2003;97:1737-45).

The study also looked at overall survival in patients with low and high expression of CXCL1. “The patients with high expression had 5-year survival of only 50% compared to those of low expression, whose 5-year survival was 97%,” Dr. Erdrich said.

Dr. Erdrich and her coauthors reported having no financial relationships.

SOURCE: Erdrich J et al. SSO 2018, Abstract 82.