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10.1245/s10434-007-9790-0
Annals of Surgical Oncology 15:1070-1080 (2008)
© 2008 Society of Surgical Oncology
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Original Article

Frequent Deletion and Methylation in SH3GL2 and CDKN2A Loci are Associated with Early- and Late-onset Breast Carcinoma

Satyabrata Sinha, MSc1, Neelanjana Chunder, PhD2, Nupur Mukherjee, MSc1, Neyaz Alam, MS3, Anup Roy, MD4, Susanta Roychoudhury, PhD5 and Chinmay Kumar Panda, PhD1

1 Department of Oncogene Regulation, Chittaranjan National Cancer Institute, 37, S.P. Mukherjee Road, Kolkata, 700026, India
2 Department of Pathology, The Joseph Stokes, Jr. Research Institute, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
3 Department of Surgical Oncology, Chittaranjan National Cancer Institute, Kolkata, India
4 Department of Pathology, Medical College, Kolkata, India
5 Molecular and Human Genetics Division, Indian Institute of Chemical Biology, Kolkata, India

Correspondence: Address correspondence and reprint requests to: Chinmay Kumar Panda, PhD; E-mail: ckpanda.cnci{at}gmail.com

Background: This study attempts to understand the association of candidate tumour suppressor genes SH3GL2, CDKN2A (p16–p14) and CDKN2B (p15) in development of early-onset (group A) and late-onset (group B) breast carcinoma (BC).

Methods: Deletion, methylation, and mutation of the candidate tumour suppressor genes (TSGs) were analysed in 47 group A and 59 group B samples. Immunohistochemical analysis was used to identify the expression status of SH3GL2 and p16. Clinicopathological correlation of the alterations was analysed by the chi-square and log-rank tests.

Results: Higher frequency of overall alterations (46–62%) in SH3GL2 and p16-p14 than p15 (22–26%) indicated their importance in BC. Deletion frequencies were in the following order: group A: p14 (43%) > p16 (42%) > SH3GL2 (38%) > p15 (33%) and group B: p14 (36%) > p16 (33%) > SH3GL2 (31%) > p15 (14%) while, methylation frequencies were: group A: SH3GL2 (34%) > p16 (28%) > p14 (26%) > p15 (15%) and group B: SH3GL2 (36%) > p16 (31%) > p14 (29%) > p15 (15%). Infrequent mutation was observed only in CDKN2A common exon-2. Immunohistochemical analysis showed significant association between expression of SH3GL2 and p16 with their deletion (P = 0.01 and 0.02, respectively) and methylation status (P = 0.007 and 0.01, respectively). In group A, overall alterations of SH3GL2 showed significant association with CDKN2A locus with significant prognostic implications, whereas CDKN2A and CDKN2B loci were associated in both groups.

Conclusions: The molecular mechanisms involving CDKN2A inactivation seem to follow similar pathway in the pathogenesis of both age groups of BC while significant association of SH3GL2 with CDKN2A might play a synergistic role in the development of group A.

Key Words: Breast carcinoma • SH3GL2 • p16INK4A • p14ARF • p15INK4B






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