mRNA subtypes in lung squamous cell carcinoma

With all the recent studies looking at various distinct histological and molecular subtypes in lung adenocarcinoma, lung squamous cell carcinoma has been somewhat neglected.  Pathologists have recognized variability in morphological appearances in squamous cell carcinomas and there is a wide range of clinical outcomes.  Although the recent WHO classification recognizes four uncommon histological variants, their biological and clinical significance is not clear.  Moreover, clinical differences between other less-defined morphological patterns are unknown.

A paper published online on July 19, 2010 on Clinical Cancer Research by Wilkerson et al. from University of North Carolina sheds a new light of lung squamous cell carcinoma (abstract).  They describe four novel reproducible mRNA expression subtypes different survival outcomes, histological features, functional biological processes or themes, and association with normal lung cell types.

The methodology of subtype discovery and validation is worth a separate blog itself (for someone else to tackle I'm afraid) but well-worth seeing for yourself because it is quite clever.  The four subtypes described in terms of their mRNA overexpression relative to other types are:

• Primitive: cellular proliferation theme.  Genes include minichromosome maintenance 10 (MCM10), E2F transcription factor 3 (E2F3), thymidylate synthase (TYMS), and polymerase alpha 1 (POLA1), and a previously published "proliferation signature."  PARP1 is also overexpressed--which may be a potential target for the new class of PARP inhibitors. Target genes for E2F transcription factor are also overexpressed.  Other functional themes of this subtype are RNA processing and DNA repair.
• Classical: xenobiotics metabolism theme.  Genes include GPX2, ALDH3A1, AKR1C3 which have been found in smokers' airway transcriptomes and lung cell lines exposed to smoke; TP63, a transcription factor essential to development of stratified squamous epithelium.  This subtype has the greatest percentage of smokers and the heaviest smokers compared to other subtypes.
• Secretory: immune response theme.  Genes include Rho GDP dissociation inhibitor beta (ARHGDIB) and tumor necrosis factor receptor 14 (TNFRSF14); also has a NF-kappaB regulation theme and expression of NF-kappaB target gene overexpression.  Also shows overexpression of lung secretory cell markers (MUC1 and pulmonary surfactant proteins).  TTF-1 (NKX2-1/TTF1)--which is highly expressed in adenocarcinomas--is overexpressed in this type relative to other subtypes.
• Basal: cell adhesion theme and epidermal development theme.  Genes relating to the cell adhesion theme include laminins, collagens, integrins, and claudin-1.  Genes relating to the epidermal development theme include keratin 5, psoriasin, and gap junction protein beta 5 (GJB5).  This subtype also shows overexpression of several S100 family genes.  Interestingly, several of the genes overexpressed in this subtype are also overexpressed in basal-like tumors from other organ sites: an head and neck SCC subtype identified by Chung et al (2004) and the basal-like breast cancer subtype. This suggests that these various "basal" subtypes may share some biological properties.

This is all interesting--but does it have any impact on clinical outcome?

The authors found that tumor subtype is significantly associated with grade: the primitive subtype has an overrepresentation of poorly-differentiated tumors, while the basaloid type has an overrepresentation of well-differentiated tumors.  However, subtype showed no association with tumor stage.  Nevertheless, overall and relapse-free survival was significantly different between different SqCC subtypes.  The primitive subtype was found to have the worst OS and RFS compared to other subtypes across all stages, whereas the classical, secretory and basal subtype all have similar outcomes.  In multivariate models, only subtype was significantly associated with OS and RFS.  The authors comment, however, that tumor stage was not have achieved significance because of an underrepresentation of higher stage tumors--which is the usual referral bias of tertiary-care single institution studies.

This paper is significant because one could use this data to evaluate an IHC panel to subtype SqCC not only for prognosis but also to identify patients who might respond to certain targeted therapies, like PARP inhibitors.