Rush Medical College, Chicago, USA.
Division of Medical Oncology, Department of Internal Medicine, Rush University Medical Center, Chicago, USA.
Breast Cancer Res Treat. 2017 Nov;166(1):315-319. doi: 10.1007/s10549-017-4393-3. Epub 2017 Jul 12.
Genetic counseling and testing is recommended for women with a personal and/or family history of breast and other cancers (ovarian, pancreatic, male breast and others). Mutations in the BRCA1 and BRCA2 genes (BRCA1/2) are the most common causes of hereditary breast and ovarian cancer. Additional genetic counseling and testing with a multi-gene panel may be considered in breast cancer patients who tested negative for mutations in these two genes. In about 11% of BRCA1/2-negative patients, further genetic testing reveals pathogenic mutations in other high or moderate cancer risk genes. In 0.2% of cases, an individual may carry pathogenic mutations in more than one high penetrance gene (a double heterozygote). Finding one or more pathogenic mutations is important for cancer prevention in patients and/or their families.
Here we present a case of a breast cancer patient who did not have a pathogenic mutation in BRCA1/2 and had a family history of breast and stomach cancers. On an additional multi-gene panel testing, she was found to carry pathogenic mutations in the CDH1 and PMS2 genes, which cause Hereditary Diffuse Gastric Cancer and Lynch syndromes, respectively. To our knowledge, this is the first description of such a double heterozygote.
Clinical manifestations, genetics, and management of both syndromes are reviewed, including prophylactic surgery and screening for unaffected family members. Management challenges for a mutation carrier with advanced breast cancer are discussed. Our case supports the clinical utility of additional multi-gene panel testing for breast cancer patients who do not have a pathogenic mutation in BRCA1/2 genes.
遗传咨询和检测建议用于有个人和/或家族乳腺癌和其他癌症（卵巢癌、胰腺癌、男性乳腺癌等）病史的女性。BRCA1 和 BRCA2 基因（BRCA1/2）的突变是遗传性乳腺癌和卵巢癌的最常见原因。如果这两个基因的突变检测结果为阴性，乳腺癌患者可能需要考虑进行多基因面板的额外遗传咨询和检测。在约 11%的 BRCA1/2 阴性患者中，进一步的基因检测显示其他高或中度癌症风险基因存在致病性突变。在 0.2%的情况下，个体可能携带一个以上高外显率基因（双重杂合子）的致病性突变。发现一个或多个致病性突变对患者及其家属的癌症预防很重要。
这里我们介绍了一位乳腺癌患者的病例，她在 BRCA1/2 中没有致病性突变，并有乳腺癌和胃癌家族史。在额外的多基因面板检测中，她携带了 CDH1 和 PMS2 基因的致病性突变，分别导致遗传性弥漫性胃癌和林奇综合征。据我们所知，这是首例这种双重杂合子的描述。
分别综述了这两种综合征的临床表现、遗传学和管理，包括未受影响的家庭成员的预防性手术和筛查。讨论了携带晚期乳腺癌突变的患者的管理挑战。我们的病例支持对 BRCA1/2 基因无致病性突变的乳腺癌患者进行额外多基因面板检测的临床实用性。
