Abstract
IntroductionYounger women with breast carcinoma (BC) exhibits more aggressive pathologic features compared to older women; young age could be an independent predictor of adverse prognosis. To find any existing differences in the molecular pathogenesis of BC in both younger and older women, alterations at chromosomal (chr.) 9q22.32-22.33 region were studied owing to its association in wide variety of tumors. Present work focuses on comparative analysis of alterations of four candidate genes; PHF2, FANCC, PTCH1 and XPA located within 4.4 Mb region of the afore-said locus in two age groups of BC, as well as the interrelation and prognostic significance of alterations of these genes.MethodsDeletion analysis of PHF2, FANCC, PTCH1 and XPA were examined in a subset of 47 early-onset (group-A: ≤ 40 years) and 59 late-onset (group-B: > 40 years) breast carcinomas using both microsatellite and exonic markers. Methylation Sensitive Restriction analysis (MSRA) was done to check for promoter methylation. Quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemisty (IHC) was done in some genes to see their relative mRNA and protein expressions respectively. Clinico-pathological correlation of different parameters as well as patient survival was calculated using different statistical softwares like EpiInfo 6.04b, SPSS 10.0 etc.ResultsEither age group exhibited high frequency of overall alterations in PHF2, FANCC and PTCH1 compared to XPA. Samples with alteration (deletion/methylation) in these genes showed reduced level of mRNA expression as seen by Q-PCR. Immunohistochemical analysis of FANCC and PTCH1 also supported this observation. Poor patient survival was noted in both age groups having alterations in FANCC. Similar result was also seen with PTCH1 and XPA alterations in group-A and PHF2 alterations in group-B. This reflected their roles as prognostic tools in the respective groups in which they were altered.ConclusionOverall alterations of PHF2, FANCC and PTCH1 were comparatively higher than XPA. Differential association of alterations in FANCC and PTCH1 with that of PHF2, XPA and two breast cancer susceptibility genes (BRCA1/BRCA2) in the two age groups suggests differences in their molecular pathogenesis and dysregulation of multiple DNA repair pathways as well as hedgehog dependent stem cell renewal pathway.
Highlights
Younger women with breast carcinoma (BC) exhibits more aggressive pathologic features compared to older women; young age could be an independent predictor of adverse prognosis
We focused primarily on a 4.4 Mb region between the chr.9q22.32-22.33 where DNA-damage repair genes like FANCC (Fanconi anaemia Complementation-group C), XPA (Xeroderma Pigmentosum A) as well as the hedgehog (HH) pathway associated gene PTCH1 are localized [13,14,15,16]
Compared to XPA, high deletion was seen in the PHF2, FANCC and PTCH1 loci in both age groups of BC [Figure 2; Additional Files 1 and 2]
Summary
Younger women with breast carcinoma (BC) exhibits more aggressive pathologic features compared to older women; young age could be an independent predictor of adverse prognosis. To find any existing differences in the molecular pathogenesis of BC in both younger and older women, alterations at chromosomal (chr.) 9q22.32-22.33 region were studied owing to its association in wide variety of tumors. Another report showed that in Asian population, BC patients below 40 years have tumors with a poorer prognostic profile This did not translate into a poorer overall survival, and this might be attributable to more aggressive adjuvant treatment of younger patients [5]. All these reports suggested early-onset BC to be a biologically separate disease and independently predict more adverse outcomes.
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