Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. Demographic/Pathologic Data
Characteristics | Males No. (%) | Females No. (%) | Total No. (%) |
---|---|---|---|
No. Of Patients | 57 (49.1) | 59 (50.9) | 116 (100) |
Mean Age in Years | 63 | 65.4 | – |
Age | |||
31–40 years | 1 (1.8) | 4 (6.8) | 5 (4.3) |
41–50 years | 8 (14.0) | 8 (13.6) | 16 (13.8) |
51–60 years | 15 (26.3) | 11 (18.6) | 26 (22.4) |
61–70 years | 14 (24.5) | 9 (15.2) | 23 (19.8) |
71–80 years | 18 (31.6) | 17 (28.8) | 35 (30.2) |
>81 years | 1 (1.8) | 10 (17.0) | 11 (9.5) |
Tumor Site | |||
Right side of colon | 16 (28.1) | 12 (20.3) | 28 (24.2) |
Left side of colon | 18 (31.6) | 29 (49.2) * | 47 (40.5) |
Rectum | 11 (19.3) | 12 (20.3) | 23 (19.8) |
Unspecified | 12 (21.0) | 6 (10.2) | 18 (15.5) |
Histological Grade | |||
Well-differentiated | 4 (7.0) | 9 (15.2) | 13 (11.2) |
Moderately-differentiated | 44 (77.2) | 40 (67.8) | 84 (72.4) |
Poorly-differentiated | 6 (10.5) | 5 (8.5) | 11 (9.5) |
Unspecified | 3 (5.3) | 5 (8.5) | 8 (6.9) |
Dukes’ Stage | |||
Stage B | 48 (84.2) | 48 (81.4) | 96 (82.8) |
Stage C | 8 (14.0) | 10 (16.9) | 18 (15.5) |
Stage D | 1 (1.8) | 1 (1.7) | 2 (1.7) |
Microsatellite Status—BRAF | |||
MSS—wild type BRAF | 41 (72.0) | 46 (77.9) | 87 (75.0) |
MSS—mutated BRAF | 2 (3.5) | 1 (1.7) | 3 (2.6) |
MSI—wild type BRAF | 6 (10.5) | 4 (6.8) | 10 (8.6) |
MSI—mutated BRAF | 4 (7.0) | 4 (6.8) | 8 (6.9) |
Unspecified | 4 (7.0) | 4 (6.8) | 8 (6.9) |
Follow-Up | |||
Relapse, local or metastatic | 7 (12.3) | 17 (28.8) ** | 24 (20.7) |
Relapse-free | 35 (61.4) | 28 (47.5) | 63 (54.3) |
Unknown | 15 (26.3) | 14 (23.7) | 29 (25.0) |
2.2. Array Comparative Genomic Hybridization (aCGH)
Locus | CNA | Candidate Genes | Females % | Males % | p-Value |
---|---|---|---|---|---|
1q21.2 | Gain | LINC00568, AF289612, AK023606, MIR4257, TSRC1, ADAMTSL4 | 50.8 | 17.5 | <0.0001 |
1q21.2–1q21.3 | Gain | U78576, PIP5K1A, BC007833, PSMD4, ZNF687, AK023105, PIK4CB, PI4KB, AJ011123, BC040300, RFX5, AK023875, SELENBP1, PSMB4, BX537561, POGZ, CGN, MIR554, TUFT1, AY358610 | 46.7 | 12.3 | <0.0001 |
4q13.2 | Gain | AF064819, UGT2B17 | 33.9 | 1.75 | <0.0001 |
6p21.31 | Gain | FKBP5, MIR5690 | 37.3 | 5.3 | <0.0001 |
6p21.1 | Gain | TBCC, AK096036, KIAA0240, GLTSCR1L, RPL7L1, C6orf226, LOC441150, PTCRA, CNPY3, TNRC5 | 35.6 | 3.5 | <0.0001 |
11q25 | Loss | FLJ45436, AY358331, NTM, BC050716, HNT | 47.45 | 14 | 0.0001 |
16p11.2 | Gain | QPRT, C16orf54, BC029149, ZG16, KIF22, BC004352, CR590954, AF489858, MAZ, L01420, BC041629, AK074572, PRRT2, LOC112476, AK092265, C16orf53, PAGR1, MVP, AK131349, CDIPT, LOC440356, BC000567, SEZ6L2, AJ245822, ASPHD1, LOC253982, KCTD13, TMEM219, LOC124446, TAOK2 | 54.2 | 20.8 | 0.0003 |
2.3. Feminization of Colorectal Cancer Cells in Males
Locus | CNA | Candidate Genes | Females % | Males % | p-Value |
---|---|---|---|---|---|
Xp22.32–p22.31 | Gain | NLGN4X, AK125309, MIR4770, VCX3A, HDHD1A, HDHD1, MIR4767, STS, VCX, PNPLA4, MIR651 | 9.3 | 42.3 | <0.01 |
Xp22.31–p22.2 | Gain | VCX-C, VCX3B, KAL1, FAM9A, AK097501, FAM9B, AY459291, TBL1X, GPR143, X83543, SHROOM2, APXL, CR749271, LOC100288814, KIAA1280, WWC3, BC035601, CLCN4, MID1, HCCS, AMELX, ARHGAP6, MSL3L1, MSL3, PDZK10, FRMPD4, PRPS2, TLR7, TLR8, AY358296, TLR8-AS1, TMSB4X, FAM9C, LOC100093698, ATXN3L, LOC100133123 | 10.7 | 45.8 | <0.01 |
Xp22.12–p22.11 | Gain | SH3KBP1, AL833278, CXorf23, AK094661, LOC729609, MIR23C, AK098768, MAP7D2, BC089400, FLJ14503, EIF1AX, SCARNA9L, RPS6KA3, CNKSR2, RP11-450P7.3, KLHL34, SMPX, BC036465, YY2, MBTPS2, SMS, PHEX, PHEX-AS1, ZNF645, LOC100873065, DDX53 | 12.5 | 46.2 | <0.01 |
Xp22.11–p21.2 | Gain | PDK3, BC045634, PCYT1B, SCARNA23, POLA, POLA1, ARX, MAGEB18, MGC33889, MAGEB6, MAGEB5, VENTXP1, SMEK3P, AK131475, AK057304, DCAF8L2, MAGEB10, DCAF8L1, IL1RAPL1, MAGEB2, MAGEB3, MAGEB4, MAGEB1, NR0B1 | 9.4 | 44.8 | <0.01 |
Xp21.1–p11.4 | Gain | DMD, MIR3915, BC036103, FAM47A, TMEM47, FAM47B, MAGEB16, CXorf22, RP13-11B7.1, CHDC2, CXorf30, FAM47C, LOC442444, AK125992, FTH1P18, PRRG1, AK130368, LANCL3, XK, CYBB, TCTE1L, DYNLT3, CXorf27, SYTL5, SRPX, RPGR, OTC, TSPAN7, TM4SF2, MID1IP1, LOC286442, AY316592, BCOR, ATP6AP2, BC010395, MPC1L, CXorf38, BC025334, AL832829, CRSP2, MED14 | 11.4 | 45.1 | <0.01 |
Xq21.1–q21.31 | Gain | APOOL, SATL1, ZNF711, ZNF6, BC067294, AK128541, AK026445, AK025039, POF1B, AF309774, BC017500, FLJ38564, CHM, BC032237, DACH2, AK022715, KLHL4, AB051474, LAMR1P15, CPXCR1 | 9.1 | 42.6 | <0.01 |
Xq22.3 | Gain | MID2, TEX13B, VSIG1, PSMD10, ATG4A, APG4A, AK054927, COL4A6 | 11.9 | 42.6 | 0.001 |
Xq13.1 | Gain | EDA, MIR676, DGAT2L4, AWAT2, OTUD6A, HSHIN6, IGBP1 | 4.2 | 35.1 | 0.001 |
Xq22.1–q22.2 | Gain | BEX4, BEXL1, TCEAL8, TCEAL5, BEX2, TCEAL7, WBP5 | 13.5 | 43.8 | 0.002 |
Xp11.22 | Gain | LOC401589, SNORA11D, SNORA11E, AF329733, MAGED4, MAGED4B, XAGE2B, XAGE1A, XAGE1C, XAGE1D, XAGE1E, XAGE1, BC009538, XAGE1A, XAGE1B, XAGE2, XAGE1D, XAGE1B, SSX8, SSX7, SSX2, SSX2B, SPANXN5, SPANX-N5, XAGE5 | 8.5 | 39.6 | 0.004 |
Xq21.1 | Gain | BX649166, HDX, CXorf43 | 11.2 | 41.6 | 0.008 |
Xp22.12 | Gain | AK131412, MAP3K15 | 16.95 | 47.4 | 0.010 |
Xq22.1 | Gain | RAB40AL, BEX1 | 10.2 | 40.4 | 0.010 |
Xq13.1 | Gain | KIF4A, GDPD2, DLG3, AB033058 | 14.7 | 45.6 | 0.016 |
Xq22.3 | Gain | MUM1L1, AK056478 | 8.5 | 38.6 | 0.019 |
Xq23 | Gain | AMOT | 10.2 | 40.4 | 0.020 |
Xq26.2 | Gain | AL832725, PHF6, HPRT1 | 17.3 | 48.2 | 0.022 |
Xq22.3 | Gain | AK001040, CXorf57, BC070110, FLJ10178, AK024253, RNF128 | 11.9 | 42.1 | 0.023 |
Xq23 | Gain | SLC6A14 | 12.3 | 44.3 | 0.028 |
Xp11.23 | Gain | WDR45, GPKOW, MAGIX, FLJ21687, PLP2, PRICKLE3, LMO6, SYP, SSX1 | 18.97 | 49.7 | 0.030 |
Xq22.2 | Gain | RAB40A | 11.4 | 42.3 | 0.030 |
Xq27.1 | Gain | SRD5A1P1, F9 | 11.9 | 42.1 | 0.040 |
Xq28 | Gain | AFF2, FMR2 | 11.9 | 42.1 | 0.042 |
Yp11.31–p11.2 | Loss | SRY, RPS4Y1, ZFY, LINC00278, TGIF2LY, PCDH11Y, TTTY23, TTTY23B, TSPY1, TSPY2, TTTY1B, TTTY1, TTTY2B, TTTY2, TTTY21, TTTY7B, TTTY8B, TTTY8 | – | 67.89 | <0.01 |
Yp11.2 | Loss | PRKY, TTTY16, TTTY12 | – | 54.6 | <0.01 |
Yq11.1–q11.221 | Loss | GYG2P1, TTTY15, USP9Y, DDX3Y, UTY, BC071744, TMSB4Y, VCY, VCY1B, BC032567, NLGN4Y, NLGN4Y-AS1 | – | 57.4 | <0.01 |
Yq11.222–q11.223 | Loss | TTTY9A, HSFY2, NCRNA00185, CYorf14, CD24, TTTY14, BCORL2, BCORP1, CYorf15A, TXLNG2P, BC035312, CYorf15B, D87072, KDM5D, SMCY, TTTY10, EIF1AY, RPS4Y2, U88898, RBMY2EP, AK026367, RBMY1A1, BC070298, RBMY1F, RBMY1B, TTTY13, RBMY1D, RBMY1E, RBMY1A1, TTTY6, PRY, PRY2, AY597808, TTTY6B, RBMY1F, RBMY1J, RBMY1A1, BC047768, TTTY5, RBMY2FP, TTTY6 | – | 60.01 | <0.01 |
2.4. Clinicopathological Significance
Characteristics | Feminized Male CRC (Total = 26) No. (%) | Non-Feminized Male CRC (Total = 31) No. (%) | Total Males (Total = 57) No. (%) | p-Value |
---|---|---|---|---|
MSS—wild type BRAF | 24 (92.3) | 17 (56.7) | 41 (72.0) | 0.0026 * |
Wild-type BRAF | 26 (100) | 23 (74.2) | 49 (86.0) | 0.0088 * |
MMR proficient | 24 (92.3) | 19 (61.2) | 43 (75.4) | 0.0107 * |
3. Discussion
4. Materials and Methods
4.1. Patients and Tissue Samples
4.2. Array Comparative Genomic Hybridization (aCGH)
4.3. Fluorescence in Situ Hybridization (FISH)
4.4. Multiplex Ligation-Dependent Probe Amplification (MLPA)
4.5. Allelotyping
4.6. Clinicopathological Correlation and Statistical Analysis
5. Conclusions
Supplementary Materials
Supplementary Files
Supplementary File 1Acknowledgments
Author Contributions
Conflicts of Interest
References
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Ali, R.H.; Marafie, M.J.; Bitar, M.S.; Al-Dousari, F.; Ismael, S.; Haider, H.B.; Al-Ali, W.; Jacob, S.P.; Al-Mulla, F. Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells. Int. J. Mol. Sci. 2014, 15, 17344-17365. https://doi.org/10.3390/ijms151017344
Ali RH, Marafie MJ, Bitar MS, Al-Dousari F, Ismael S, Haider HB, Al-Ali W, Jacob SP, Al-Mulla F. Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells. International Journal of Molecular Sciences. 2014; 15(10):17344-17365. https://doi.org/10.3390/ijms151017344
Chicago/Turabian StyleAli, Rola H., Makia J. Marafie, Milad S. Bitar, Fahad Al-Dousari, Samar Ismael, Hussain Bin Haider, Waleed Al-Ali, Sindhu P. Jacob, and Fahd Al-Mulla. 2014. "Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells" International Journal of Molecular Sciences 15, no. 10: 17344-17365. https://doi.org/10.3390/ijms151017344