Screening of microsatellite markers in penile cancer reveals differences between metastatic and nonmetastatic carcinomas

Abstract

Penile cancer, observed only rarely in the western world, represents a carcinoma that may be cured by resection of primary lesion and in case of lymph node metastasis by early lymph node dissection. This early inguinal lymphadenectomy bares a significant better survival even in cases of nonpalpable lymph nodes, but carries also a high risk of overtreatment, especially in lower tumor stages. Due to the low incidence, only few data are available on the molecular genetic background of this tumor, especially concerning tumor progression and metastasis. Therefore, we studied 62 microsatellite markers in 28 penile carcinomas searching for markers predicting progression or outcome. LOH in more than 25% of primary tumors was found on six different chromosomes, including 2q, 6p, 8q, 9p, 12q and 17p13. Statistically significant correlations could be established in D6S260 to clinical outcome and in markers from chromosomes 6, 9 and 12 to tumor stage and metastasis. These regions are worthy for further analysis concerning tumor suppressor genes and metastasis suppressor genes. Keywords: penile carcinoma; microsatellite marker; LOH; HPV; metastasis Penile squamous cell carcinoma (PSCC) is an uncommon tumor entity in North America and Europe (incidence of 1/100 000). PSCC is characterized by a slow regional tumor progression and frequent metastases of inguinal lymph nodes. The incidence of lymph node metastasis varies from 0-30% in T1 tumors to 25-50% in T2-T3 stages 1 and has been established as the main variable for the survival of patients. PSCC may be cured by resection of primary lesion and involved regional lymph nodes, but inguinal lymphadenectomy is associated with a high risk for complications, such as wound infection, necrosis and moderate to severe lymphedema and a higher mortality. 2,3 Therefore, accurate diagnosis of metastasis is required and the detection of reliable markers for the occurrence of metastasis would result in a great benefit for the patients. In this context, several histopathological factors of the primary penile tumor have been discussed, for example tumor stage, histopathological growth pattern, grade of differentiation, depth of invasion and presence of angioinvasion. [3][4][5][6][7] Additionally, the over-or underexpression of certain proteins has been examined for its importance in tumor progression. Martins et al 8 reported a prognostic significance of tumor suppressor gene p53 and a significant correlation between proliferation cell nuclear antigen and lymph node metastasis. A significant shorter survival in patients with positive p53 immunoreaction of their tumors in combination with detection of HPV DNA has also been demonstrated. 9 Nevertheless, only few studies searched for DNA aberrations in penile carcinoma. Alves et al 10 presented deletions in 13q21-22 and 4q21-32 by means of comperative genomic hybridization. Humbey et al 11 found genetic alterations in exon 4 of the p53 region. No further information about genetic imbalances in penile carcinomas is known until now. Therefore, we ...

Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival

“…Even fewer studies have described an association between genetic alterations and clinical findings. Allelic losses on chromosomes 4, 6, 9, 12, and 13 were associated with lower survival and T stage (12).…”

No Evidence of Microsatellite Instability and Loss of Mismatch-Repair-Protein Expression in Squamous Cell Carcinoma of the Penis

“…But to date, no analyses on this topic are available. Poetsch et al [10] described a screening of microsatellite markers in penile cancer. They described a frequent loss of heterozygosity but did not describe MSI in the analyzed tumors [10].…”

“…Poetsch et al [10] described a screening of microsatellite markers in penile cancer. They described a frequent loss of heterozygosity but did not describe MSI in the analyzed tumors [10]. Unfortunately, this study did not use the validated National Cancer Institute (NCI) marker panel for MSI detection, so the MSI status and the role of a possible defective MMR system are still unknown in penile cancer.…”

Alterations in the tumor suppressor gene p16 INK4A are associated with aggressive behavior of penile carcinomas

“…A significant role of LOH at chromosome 9p21 was reported for penile carcinomas in an earlier study [10]. Allelic loss in the p16 INK4A region was found in over 60%, and promoter hypermethylation was evident in over 40% of the tumors of our study.…”

“…Loss of heterozygosity (LOH) at chromosome 9p21, including the p16 and ARF region, is a frequent event in several tumor entities and has been described before for penile carcinomas [10]. Point mutations of p16 INK4A and-more frequently-silencing of the p16 INK4A gene by hypermethylation of the promoter have been reported for many human cancers [11,12].…”