The proliferation marker Chromatin Assembly Factor-1 is of clinical value in predicting the biological behaviour of salivary gland tumours

Abstract

Abstract. Salivary gland tumours (SGT) constitute a diagnostically challenging group of neoplasms with frequently unpredictable clinical outcome. The proliferation rate facilitates the identification of aggressive SGT. The Chromatin Assembly Factor-1 (CAF-1) is a major epigenetic regulator of nuclear chromatin organization during DNA replication. It plays a critical function in human tumourigenesis and has been proposed as a new proliferation and prognostic marker for some malignancies. This study focused on the role of CAF-1/p60 protein as a marker of clinical value for SGT. The expression of CAF-1/p60 was evaluated by immunohistochemistry on a retrospective series of 362 surgically excised benign and malignant SGT with different histogenesis and, when available, on fine-needle pre-surgical cytological biopsies. The resulting data were compared with traditional prognostic parameters, including the expression of the routine proliferation marker ki67/MIB1. CAF-1/p60 was detectable in all SGT, with highest degree of expression in metastasizing malignant tumours. Moreover, the cases of benign tumours which progressed to carcinoma during the follow-up, showed significantly higher CAF-1/p60 expression than nonprogressing benign SGT, both on histological sections and cytological smears of the primary tumour. Cox's multiple regression analysis selected CAF-1/p60 expression as the best independent predictor of cancer development for benign SGT (p<0.0001), and the best independent predictor of metastasis onset for malignant tumours (p<0.0004). Overexpression of CAF-1/p60, on histological and/or cytological samples, characterizes malignant SGT with aggressive behaviour, irrespective of their specific histotype, and allows the early diagnosis of progression toward malignancy of morphologically benign tumours.

Overexpression of chromatin assembly factor-1/p60 predicts biological behaviour of laryngeal carcinomas

“…In fact, several recent reports have highlighted the strict relationship between CAF-1/p60 over-expression and adverse behaviour of different malignant tumours, including prostate, tongue, salivary glands carcinomas and cutaneous melanoma 28 - 31 . These studies have confirmed the hypothesis that CAF-1/p60 is heavily involved in tumoural and metastatic processes, constituting an independent prognostic biomarker of tumour evolution 8 25 32 - 34 .…”

Clinical implications of epigenetic regulation in oral cancer

“…A histone chaperone, chromatin assembly factor-1 (CAF-1), acts as an epigenetic regulator of nuclear chromatin organization during DNA replication. CAF-1 is composed of subunits p150, p60 and p48, with concomitant overexpression of p60 and down regulation of p150 correlated with clinicopathological profile indicating advanced stages, local recurrence, metastasis, overall survival, thus enables prognosis in oral cancer patients [106,107]. The data emphasizes the complex mechanisms with genetic and epigenetic regulation playing a critical role in oral carcinogenesis.…”

Overexpression of chromatin assembly factor‐1 p60, poly(ADP‐ribose) polymerase 1 and nestin predicts metastasizing behaviour of oral cancer

“…For each case, double immunolabelling of routine tissue sections and corresponding tissue microarrays (TMAs) was performed with the EnVision ™ G/2 Doublestain System (Dako, Carpinteria, CA, USA) 45,46 . Immunohistochemistry was carried out as previously described 32–35,47 . Briefly, sections were heated at 55°C for 60 min, deparaffinized, and processed for antigen retrieval by microwaving in 1% sodium citrate buffer, pH 6.0.…”

“…Knocking down p60 disrupts the activity of CAF‐1 in nucleosome assembly, causing replication fork arrest, activation of the intra‐S‐phase checkpoint, and global defects in chromatin structure 28–31 . The nuclear expression of CAF‐1/p60 is increased in multiple types of cancer, proportionally to their adverse clinical behaviour 23,31–34 . On account of these postulates, we examined the expression of the stem cell‐associated antigens CD133, CD166, CD44 with the v6 variant and nestin (frequently associated with CSCs of solid malignancies) in a series of primary and metastatic OSCCs 35 .…”