BackgroundApproximately 5% to 10% of pancreatic ductal adenocarcinoma (PDAC) has a hereditary basis. In most of these defined hereditary cancer syndromes, PDAC is not the predominant cancer type. Traditional criteria for publicly funded genetic testing typically require the presence of a set combination of the predominant syndrome-associated cancer types in the family history.We report the identification of a CDKN2A pathogenic variant in a PDAC-prone family without the cutaneous features of multiple moles or melanoma that are characteristic of the Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome identified in a universal testing algorithm for inherited mutations in pancreatic cancer patients.Case presentationWe present the case of two brothers of English ancestry diagnosed with PDAC within the same 12 month period, at the respective ages of 63 and 64 years of age. Neither brother reported a personal history of multiple moles or melanoma. Family history was positive for two second-degree relatives diagnosed with PDAC but was negative for other cancers or multiple moles in first- and second-degree relatives. Due to the absence of melanoma, this family did not meet provincial criteria for publicly funded genetic testing. Clinical genetic testing offered through a research grant identified a pathogenic variant in the CDKN2A gene c.377 T > A (p.Val126Asp). This variant is a North American founder mutation believed to pre-date colonization.ConclusionsThis case reminds clinicians to consider the possibility of a germline CDKN2A mutation in families with a high prevalence of PDAC, even in the absence of moles or melanoma. This case supports recent guidelines published by the American College of Medical Genetics and Genomics (ACMG) that genetics referrals are indicated in families with three or more cases of PDAC regardless of other cancer types in the family. A multi-gene panel approach is of particular benefit in diagnosing inherited cancer susceptibility in PDAC-only families.

中文翻译：

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没有家族性非典型多痣黑色素瘤 (FAMMM) 综合征皮肤特征的胰腺导管腺癌患者的 CDKN2A 创始人突变

背景大约 5% 到 10% 的胰腺导管腺癌 (PDAC) 具有遗传基础。在大多数这些确定的遗传性癌症综合征中，PDAC 不是主要的癌症类型。公共资助基因检测的传统标准通常要求家族史中存在一组主要的综合征相关癌症类型。我们报告在没有多颗痣皮肤特征的 PDAC 易感家族中鉴定出 CDKN2A 致病性变异在胰腺癌患者遗传突变的通用测试算法中确定的家族性非典型多痣黑色素瘤 (FAMMM) 综合征特征的黑色素瘤。 , 分别为 63 岁和 64 岁。两个兄弟都没有报告多颗痣或黑色素瘤的个人病史。两名被诊断患有 PDAC 的二级亲属的家族史为阳性，但一级和二级亲属的其他癌症或多发痣为阴性。由于没有黑色素瘤，这个家庭不符合省政府资助的基因检测标准。通过研究资助提供的临床基因检测确定了 CDKN2A 基因 c.377 T > A (p.Val126Asp) 中的致病变异。这种变异是一种北美创始人突变，据信早于定植。结论该病例提醒临床医生考虑在 PDAC 高患病率的家庭中存在种系 CDKN2A 突变的可能性，即使在没有痣或黑色素瘤的情况下也是如此。该病例支持美国医学遗传学和基因组学学院 (ACMG) 最近发布的指南，即遗传转诊适用于有 3 例或更多 PDAC 病例的家庭，无论家庭中的其他癌症类型如何。多基因组方法对于诊断仅 PDAC 家族的遗传性癌症易感性特别有益。