Low frequency of E-cadherin alterations in familial breast cancer

In order to explore the possible role of E-cadherin in familial cancer, 19 familial breast cancer patients, whose tumours demonstrated loss of heterozygosity (LOH) at the E-cadherin locus, were screened for germline mutations. No pathogenic germline alterations were detected in these individuals. However, a somatic mutation was found (49-2A→C) in one of the tumours. This tumour showed a pattern of both ductal and lobular histology. Another 10 families with cases of breast, gastric and colon cancer were also screened for germline mutations, and no mutations were found. A missense mutation in exon 12 of E-cadherin (1774G→A; Ala592Thr) was previously found in one family with diffuse gastric cancer, and colon and breast cancer. An allelic association study was performed to determine whether the Ala592Thr alteration predisposes to breast cancer. In total, we studied 484 familial breast cancer patients, 614 sporadic breast cancer patients and 497 control individuals. The frequencies of this alteration were similar in these groups. However, a correlation between the Ala592Thr alteration and ductal comedo-type tumour was seen. These results, together with previously reported studies, indicate that germline mutations and, more commonly, somatic mutations in E-cadherin may have an influence on the behaviour of the tumours, rather than predispose to breast cancer.

为探索E-钙粘蛋白（E-cadherin）在家族性癌症中的潜在作用，我们对19例肿瘤组织呈现E-钙粘蛋白位点杂合性缺失（LOH, loss of heterozygosity）的家族性乳腺癌患者进行了生殖系突变筛查。未在这些个体中检测到致病性生殖系变异。然而，在其中1例肿瘤中发现了体细胞突变（49-2A→C），该肿瘤同时呈现导管与小叶组织学特征。我们还对另外10个携带有乳腺癌、胃癌及结肠癌病例的家族开展了生殖系突变筛查，未检出相关突变。此前有研究在1个同时存在弥漫性胃癌、结肠癌与乳腺癌的家族中，检测到E-钙粘蛋白12号外显子的错义突变（1774G→A；Ala592Thr）。为明确Ala592Thr变异是否会增加乳腺癌易感风险，我们进行了等位基因关联研究，共纳入484例家族性乳腺癌患者、614例散发性乳腺癌患者及497例对照个体。该变异在三组人群中的频率相似，但观察到Ala592Thr变异与粉刺型导管癌存在相关性。上述结果结合既往研究提示，E-钙粘蛋白的生殖系突变，更常见的体细胞突变，可能并非通过增加乳腺癌易感风险，而是通过影响肿瘤的生物学行为发挥作用。