New doctorial cancer research: germline genetic alterations affecting CDKN2A, MDM2, and CDKN1A in melanoma and breast cancer patients.

The main goal in this work was to characterize selected genetic alterations that were potentially cancer risk modulating in melanoma and breast cancer patients. During a study initiated to analyze factors possibly causing chemoresistance in malignant melanoma, one of the study participants was found to be of a family likely to harbor an inherited cancer syndrome. This family revealed abnormally high incidence of melanomas, including two individuals diagnosed with two or more primary melanomas. We aimed at identifying, and performing a full characterization of, the underlying genetic mechanism. We identified the genetic mechanism to be large genomic deletion of 10,150 bps within the CDKN2A gene (the gene encoding the tumor suppressors p16 and p14). One of the deletion breakpoints was located to position 6093 upstream of exon 1α, and the other to position 161 of exon 2, thus removing exon 1α and half of exon 2. Initially, the melanoma-prone family displayed linkage to 9p21 (location of CDKN2A), but no mutations in the CDKN2A gene were identifiable through use of routine screening methods. The observation leading us to the identification of the deletion came from cDNA-based analyses, with subsequent sequencing of BAC-clones carrying large genomic fragments. Based on this observation, we have postulated that at least some of the cases where inherited malignant melanoma display linkage to 9p21, but no mutations are identified, may be caused by deletions that are not easily identified through routine screening methods. In a previous breast cancer study performed by our group, focusing on the CDKN1A locus, the first observation of p21 is described. This polymorphism was found not to correlate to resistance to chemotherapy. Subsequently, we explored the possible association between this novel polymorphism and breast cancer risk. Through screening of the prevalence of p21 in different breast cancer cohorts and healthy controls, we found this polymorphism to be significantly correlated to the subgroup of locally advanced breast cancers (p = 0.0049). This is the first identified genetic change specific for locally advanced breast cancers.