Sequential progression Vs. Heterogeneity

Roylance R, Gorman P, Papior T, Wan YL, Ives M, Watson JE, et al. A comprehensive study of chromosome 16q in invasive ductal and lobular breast carcinoma using array CGH. Oncogene. 2006 May;25(49):6544-6553. Available from: http://dx.doi.org/10.1038/sj.onc.1209659.

• Conventional CGH suggested that 16q deletions were much less common in Grade II and Grade III Invasive Ductal Cancer than in Grade I Invasive Ductal Cancers and Invasive Lobular Cancers.
• Further support is through morphological data (Millis et al., 1998)
• Led to the hypothesis that for the majority of breast tumours there were parallel pathways of tumour development, with Grade I tumours having a separate pathway from the higher grade tumours (Buerger et al., 1999; Roylance et al., 1999).
• For a minority of high-grade tumours with 16q loss, a progression from low-grade tumours was thought likely and mathematical modelling seemed to support this hypothesis (Korsching et al., 2004).
• It was further hypothesized, from the pattern of genetic changes in Grade I IDCs and ILCs, that ILCs developed along a similar pathway to GI IDCs with loss of E-cadherin leading to the ILC phenotype (Roylance et al., 1999, 2003; Cleton-Jansen, 2002).

Results

• Using the 16q-specific array, although we still found a differential loss of 16q, there was a higher frequency of changes on 16q in the higher grade lesions than expected.
• Furthermore, there were more complex changes seen in all cancers, but especially in the higher grade ductal lesions.
• Interestingly, the peaks and troughs of the frequencies of gains and losses tended to occur at the same sites in each of the four tumour types.
• Cluster analysis showed that most cancers with predominant loss on 16q clustered into a single group, but that, in the other two groups, ILCs were underrepresented compared with IDCs.
• We suspect, therefore, that the relationship between different morphological types of breast cancer is complex and that the previous hypothetical model needs refining.
• Our data remain consistent with a model in which ILCs and Grade I IDCs have a common progenitor and in which the lineages diverge at or soon after 16q loss owing to E-cadherin mutation or silencing causing the lobular phenotype to develop.
• However, unlike in the previous model, our aCGH data are more consistent with a significant number of IDCs showing progression through grades, with subsequent accumulation of segmental gains (and, perhaps, further losses) in the higher grade lesions.
• The fact that aCGH continues to find a lower frequency of any 16q loss in higher grade IDCs compared to GI tumours continues to support the hypothesis that some Grade II/Grade III IDCs develop along a pathogenic pathway which does not involve a precursor stage as a Grade I cancer.

Some high grade tumours have 16q losses - are these products of tumour progression from low grade lesions? Or the ADDITIONAL mutational changes have made them high grade tumours. Maybe the 16q loss becomes irrelevant when the tumours have other mutations tacked on.