Validation and Extension of the PREMM Model for Inherited Colorectal Cancer

描述（由申请人提供）：我们最近开发了PREMM 1，2，6模型，这是一种临床预测规则，设计用于医疗保健提供者估计概率 个体在MLH 1、MSH 2和MSH 6错配修复（MMR）基因中携带突变（Balmana等，JAMA 2006，Kastrinos等，al Gastroenterology 2011）。 PREMM 1，2，6是在数千名接受林奇综合征（最常见的遗传性结肠癌）遗传评估的患者中开发和验证的。 自该模型开发以来，另外两个基因PMS 2和EPCAM与该疾病有关。 除了PREMM 1、2、6模型之外，我们还开发了息肉病模型（Grover等人，JAMA 2012），其预测个体携带APC和MYH基因中的生殖系突变的可能性，与家族性腺瘤性息肉病和MYH相关息肉病相关。 该模型是由9000多名接受过这两种基因基因检测的个体开发的，但需要独立的外部验证，这需要大规模的多中心合作努力。 最后，尽管PREMM 1，2，6模型（可在Dana-Farber癌症研究所网站www.dfci.org/premm上获得）被世界各地熟悉该综合征的提供者广泛使用，但我们的工作和其他人的工作一直表明，许多有家族性癌症综合征风险的患者未被识别或转介进行基因检测。 风险评估的系统方法是必要的，以识别和正确管理患者的遗传形式的癌症，一个问题，将越来越重要的癌症易感基因的数量被认为是扩大和测试解释的复杂性增加。 考虑到这些问题，作为我们先前工作的扩展，本次R 01更新申请的目的是（1）使用未发表的12，000例患者队列进行模型开发，扩展和验证PREMM 1、2、6，以包括PMS 2和EPCAM基因突变预测，和国际家系登记联合会的数据进行模型验证~（2）为了验证遗传性息肉病综合征的临床预测模型的性能，家族性腺瘤和MYH相关息肉病，在通过国际合作者联盟招募的受试者中~和（3）（i）将Lynch综合征和息肉病模型改编为单一风险评估工具，患者可在移动终端上以电子方式完成，随后由医生用于生成患者携带MMR、APC或MYH基因突变的可能性，用于共同决策，以及（ii）通过将其预测与遗传咨询师和医疗保健提供者导出的模型估计值进行比较来验证患者应用。

DESCRIPTION (provided by applicant): We have recently developed the PREMM1,2,6 model, a clinical prediction rule designed to be used by healthcare providers to estimate the probability that an individual carries a mutation in the MLH1, MSH2 and MSH6 mismatch repair (MMR) genes (Balmana et al. JAMA 2006, Kastrinos et. al Gastroenterology 2011). PREMM1,2,6 was developed and subsequently validated in thousands of patients who were undergoing genetic evaluation for Lynch Syndrome, the most common form of hereditary colon cancer. Since the development of the model, two additional genes, PMS2 and EPCAM, have been implicated in the condition. In addition to the PREMM1,2,6 model, we have developed a Polyposis model (Grover et al., JAMA 2012) which predicts the likelihood of an individual carrying a germline mutation in the APC and MYH genes, related to Familial Adenomatous Polyposis and MYH-Associated Polyposis. This model was developed from over 9000 individuals who had undergone genetic testing for these two genes but requires independent, external validation that necessitates a large, multicenter collaborative effort. Finally, although the PREMM1,2,6 model, (available on the Dana-Farber Cancer Institute website at www.dfci.org/premm) is widely used by providers around the world who are familiar with the syndrome, our work and that of others have consistently shown that many patients who are at risk for a familial cancer syndrome are not identified or referred for genetic testing. Systematic approaches of risk assessment are necessary to identify and correctly manage patients with inherited forms of cancer, an issue that will be increasingly important as the number of cancer susceptibility genes to be considered expands and complexity of test interpretation increases. In consideration of these issues, and as an expansion of our prior work, the aims of this R01 renewal application are (1) To expand and validate PREMM1,2,6 to include PMS2 and EPCAM gene mutation prediction using an unpublished cohort of 12,000 patients for model development, and data from an international consortium of family registries for model validation~ (2) To validate the performance of the clinical prediction model for the inherited polyposis syndromes, Familial Adenomatous and MYH-associated Polyposis, in subjects enrolled through an international consortium of collaborators~ and (3) (i) To adapt the Lynch Syndrome and Polyposis models into a single risk assessment tool that can be completed by patients electronically on a mobile device and subsequently used by physicians to generate individualized prediction risk scores of the patient's likelihood of carrying MMR, APC or MYH gene mutations for shared decision making, and (ii) to validate the patient application by comparing its predictions to those made when the model estimates were derived by genetic counselors and healthcare providers.