Palmirotta Raffaele, Matera Sabino, Curia Maria Cristina, Aceto Gitana, el Zhobi Bassam, Verginelli Fabio, Guadagni Fiorella, Casale Vincenzo, Stigliano Vittoria, Messerini Luca, Mariani-Costantini Renato, Battista Pasquale, Cama Alessandro
Department of Oncology and Neurosciences, University Gabriele D'Annunzio, Chieti, Italy.
Fam Cancer. 2004;3(2):117-21. doi: 10.1023/B:FAME.0000039864.19083.3a.
Hereditary nonpolyposis colorectal cancer (HNPCC) is widely considered to be a syndrome of defective mismatch repair (MMR). A major concern with genetic diagnosis of HNPCC is the variable, often low, percentage of pathogenic germline mutations that can be detected in MMR genes using common screening methods. The variable percentage of mutation detected is in part related to the sensitivity of conventional screening methods and may also depend on the heterogeneous genetics of HNPCC. Thus, identification of phenotypic criteria predictive of germline mutations in MMR genes may be helpful in efficient HNPCC genetic testing. Clinical diagnostic criteria, initially developed for HNPCC (e.g., Amsterdam I and II, or Bethesda criteria), can be used to clinically select patient candidates that carry germline mutations in MMR genes. More useful criteria were previously developed by analyzing families with germline MMR mutations. Using a complementary approach based on tumor microsatellite instability analysis, we confirm that the Amsterdam criteria are significantly better than the Bethesda criteria in predicting families with MSI-H tumors (P = 0.0227). Our results also suggest that a cutoff at < 50 years' mean age at diagnosis of HNPCC-related cancers (especially colorectal and endometrial cancer) may be an additional tool for the identification of families with defective MMR. Recent advances in MMR mutation screening are expected to improve detection of pathogenic MMR mutations in these families. Conversely, the high proportion of MSS tumors observed in our series of families with advanced age at cancer diagnosis is consistent with the low percentage of MMR mutations detected by previous studies in families with this phenotype. These families probably carry mutations in other genes that may or may not be related to MMR. Additional studies are necessary to clarify the molecular basis for HNPCC in families with MSS tumors.
遗传性非息肉病性结直肠癌（HNPCC）被广泛认为是一种错配修复（MMR）缺陷综合征。HNPCC基因诊断的一个主要问题是，使用常规筛查方法在MMR基因中检测到的致病种系突变的比例变化不定，且往往较低。检测到的突变比例变化不定，部分原因与传统筛查方法的敏感性有关，也可能取决于HNPCC的遗传异质性。因此，确定预测MMR基因种系突变的表型标准可能有助于高效进行HNPCC基因检测。最初为HNPCC制定的临床诊断标准（如阿姆斯特丹I和II标准或贝塞斯达标准）可用于临床选择携带MMR基因种系突变的患者。以前通过分析具有种系MMR突变的家系制定了更有用的标准。使用基于肿瘤微卫星不稳定性分析的补充方法，我们证实阿姆斯特丹标准在预测MSI-H肿瘤家系方面明显优于贝塞斯达标准（P = 0.0227）。我们的结果还表明，HNPCC相关癌症（尤其是结直肠癌和子宫内膜癌）诊断时的平均年龄<50岁这一切断值可能是识别MMR缺陷家系的另一种工具。预计MMR突变筛查的最新进展将改善这些家系中致病MMR突变的检测。相反，在我们诊断时年龄较大的癌症家系系列中观察到的MSS肿瘤比例较高，这与先前研究在具有这种表型的家系中检测到的MMR突变比例较低一致。这些家系可能携带其他基因的突变，这些基因可能与MMR有关，也可能无关。需要进一步研究以阐明MSS肿瘤家系中HNPCC的分子基础。
