The mismatch repair gene hPMS2 is mutated in primary breast cancer.

Mismatch repair (MMR) genes play a fundamental role in the correction of replication errors and their mutation leads to cancer development. In the present study we have analyzed the hPMS2 MMR gene for mutation using 20 primary breast cancers and seven breast tissues obtained from areas adjacent to breast cancer. For this purpose we have used cDNA sequence analysis and Western blotting using the specific antibody against the amino-terminal domain E-19. In primary breast cancers we found that the hPMS2 gene had 9 missense mutations [codons: 513 (by change of Ser x Asp) in 14 tumors, 520 (Ala x Val) in 8 tumors, 573 (by change of Thr x Ser in 19 tumors), 578 (by change of Arg x Leu in 9 tumors), 587 (by change of Ser x Asp in 7 tumors), 590 (by change of Ile x Leu in 12 tumors), 598 (by change of Gln x His in 5 tumors), 601 (by change of Ser x Leu in 13 tumors), 608 (by change of Ala x Ser in 9 tumors. Nine out of 20 breast cancers had a non-sense mutation in nucleotide 1862 by changing Adenine by Thymine (AAG x TAG), which corresponded with a change in codon 613 by a change of Lys by stop codon. This non-sense mutation is responsible for the premature truncation of the protein hPMS2, which is reflected in the Western blotting by two bands, one corresponding with the wild-type form (100 kDa) and a lower one (75 kDa) corresponding with the truncated form of the hPMS2 MMR protein. This truncated protein and the mutations in the hPMS2 gene were also detected in two samples of normal-appearing tissue adjacent to their corresponding cancerous lesion. Altogether the present report demonstrates that primary breast cancers harbor mutations in this MMR gene and that normal-appearing breast tissue adjacent to the primary lesion also harbors the same mutations before the neoplastic process is manifested.