Multiple germline mutations in rare inherited cancer syndrome genes

Inherited cancer predisposition is rare and characterized by large phenotypic variability. This variability can be explained by factors such as allelic heterogeneity, environmental effects or the presence of mutations on two or more inherited cancer genes in the same individual. Considering that inherited mutations are thought to play a role in about 5-10 % of all cancers and that there are more than fifty hereditary cancer syndromes described (Garber et al., 2005; Lindor et al., 2008) there is potential for an individual being affected by multiple rare inherited cancer syndromes. The standard clinical practice for diagnosis has been to test inherited cancer genes until a mutation is detected. After detecting a mutation in a specific gene the clinician may attribute any tumors that are not typical of the detected syndrome to phenotypic variability. Thus, the patient may receive suboptimal treatment and any risks to relatives might be incorrectly estimated. Next-generation sequencing (NGS) techniques now offer the opportunity of simultaneous testing of large numbers of inherited cancer genes. Studying patients with multiple mutations in different cancer syndrome genes could provide insights into how the functions of the relevant genes products may be related and result in an enhanced or novel phenotype.

A recent study by Whitworth et al. (2016) reports five new cases of multiple germline mutations in inherited cancer syndrome genes, three of them involve the combination of mutations in FLCN with NF1TP53, and MSH2, respectively.

Case 1 – A 39-year-old male presented with testicular seminoma and a pheochromocytoma. Subsequently he developed pneumothoraces and a CT scan revealed renal cell carcinomas (RCCs). Further investigation identified gastrointestinal stromal tumors (GISTs) and a malignant peripheral nerve sheath tumor (MPNT). Skin examination showed neurofibromas but no fibrofolliculomas. Patient was clinically diagnosed with neurofibromatosis type 1 (NF1), this was considered to be the cause of MPNT, pheochromocytoma and GIST but the RCCs and pneumothoraces were considered unrelated. NGS of 94 inherited cancer genes was performed and mutations in FLCN and NF1 were detected and confirmed by Sanger sequencing.  Mutations in  FLCN cause Birt-Hogg-Dube (BHD) syndrome, a rare condition that predisposes patients to pneumothoraces, fibrofolliculomas and RCC. The patient had relatives with RCCs, fibrofolliculomas, a FLCN mutation and pneumothorax, but no known family history of NF1. In this case, only testicular seminoma has not been associated with mutations in either gene suggesting that it might result from the combination of FLCN and NF1 mutations or be coincidental.

Case 2 – A 32-year-old male presented with dysphagia and a history of ulcerative colitis. Examination revealed a rectal adenocarcinoma and a gastroesophageal adenocarcinoma, staging imaging demonstrated a kidney tumor later confirmed as RCC. Skin examination showed facial fibrofolliculomas. History of cancer in relatives included esophageal squamous cell carcinoma, brain tumor and oropharyngeal carcinoma. Genetic testing revealed mutations in FLCN and TP53. TP53 has been reported as a somatic mutation on multiple occasions, including in colorectal adenocarcinoma. RCC is a feature of BHD syndrome and it has also been reported in TP53 mutation carriers (Schneider et al., 2013). The relationship between colorectal cancer and BHD syndrome is controversial (Toro et al., 2008; Nahorski et al., 2010), but an increased risk of colorectal cancer has been reported in TP53 mutation. Oesophageal cancers have not been reported in FLCN mutation carriers but have occurred in Li-Fraumeni syndrome patients (Schneider et al., 2013).

Case 3 – A 53-year-old woman presented with a rectal adenocarcinoma and pneumothorax. Immunohistochemical analysis of the tumor showed no abnormality, but the colon cancer of a relative with pneumothoraces showed loss of staining of MSH2 and MSH6 proteins. Genetic testing identified a FLCN mutation. The patient’s sister presented pneumothorax, fibrofolliculomas and endometrial cancer. Genetic testing demonstrated the familial FLCN mutation and a MSH2 mutation. Another sister had pneumothoraces, RCC, and colorectal polyps and carried both mutations, as did a brother with fibrofolliculomas. Colorectal and endometrial cancers are typical of Lynch syndrome caused by MSH2 mutations. However, the proband did not carry the MSH2 mutation like her siblings so part of her phenotype may be a phenocopy. Also, a role for the FLCN mutation in the development of the colorectal tumors cannot be excluded.

Two more cases were studied involving combination of mutations in MLH1 and XPA, and in NF1 and BRCA2. In addition, authors reviewed previously published literature and identified 82 cases involving 17 inherited cancer genes. A case of combination of FLCN and APC mutations has been reported (Kashiwada et al., 2012) where colonic polyps, colorectal cancer, pneumothoraces and facial papules occurred. The features are consistent with an independent mechanism but the authors suggested that the FLCN mutation could have enhanced tumorigenesis.

Authors suggest that clinicians should consider this phenomenon referred as multilocus inherited neoplasia alleles syndrome (MINAS) in patients with unexpected inherited cancer syndrome phenotypes. Increasing detection will help understand if combinations of mutations are likely to result in a synergistic severe phenotype or whether the phenotype has an independent effect typical of each mutation. To facilitate studies of novel cases a database was established to gather information and guide clinicians to what the effect of each combination of mutations might be and to increase knowledge on this rare but emerging phenomenon.

  • Whitworth J, Skytte AB, Sunde L, Lim DH, Arends MJ, Happerfield L, Frayling IM, van Minkelen R, Woodward ER, Tischkowitz MD, & Maher ER (2016). Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review. JAMA oncology, 2 (3), 373-9 PMID: 26659639
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