Heterozygous Germline Missense Mutation Research Articles

Hereditary Bilateral Synchronous Pheochromocytomas in a Tibetan Pedigree With a Germline Adenomatous Polyposis Coli (APC) Mutation

Background: Germline pathogenic mutations associated with pheochromocytoma (PHEO) are present in most patients with hereditary bilateral PHEOs. Adenomatous polyposis coli (APC) gene has previously been identified as a tumor suppressor gene in familial adenomatous polyposis and colorectal cancers, but not PHEO. Methods: A father and a son from Tibet were clinically diagnosed with bilateral synchronous PHEOs. The son underwent staged retroperitoneal laparoscopic bilateral total adrenalectomy, and the father underwent retroperitoneal laparoscopic left adrenalectomy. A pedigree investigation was performed with a follow-up of 4 years. Whole-exome sequencing was performed to reveal the susceptibility genes in the pedigree. Results: The adrenal masses in the father and son were pathologically diagnosed as hereditary bilateral synchronous PHEOs. A pedigree investigation of 26 family members spanning 3 generations was performed. Multiple endocrine gland–related tumors, including PHEO, pancreatic neuroendocrine tumor, and pituitary adenoma, were diagnosed in the family. DNA sequencing identified a novel heterozygous germline missense mutation (c.896C>G) of the APC gene in the proband. The same heterozygous germline mutation of the APC gene was also present in the pedigree. Conclusions: We reported a pedigree from Tibet with hereditary bilateral synchronous PHEOs, which revealed a novel heterozygous germline missense mutation of the APC gene that may predispose to PHEO.

Next-generation sequencing reveals germline mutations in an infant with synchronous occurrence of nephro- and neuroblastoma

ABSTRACTAlthough neuro- and nephroblastoma are common solid tumors in children, the simultaneous occurrence is very rare and is often associated with syndromes. Here, we present a unique case of synchronous occurrence of neuro- and nephroblastoma in an infant with no signs of congenital anomalies or a syndrome. We performed genetic testing for possible candidate genes as underlying mutation using the next-generation sequencing (NGS) approach to target 94 genes and 284 single-nucleotide polymorphisms (SNPs) involved in cancer. We uncovered a novel heterozygous germline missense mutation p.F58L (c.172T→C) in the anaplastic lymphoma kinase (ALK) gene and one novel heterozygous rearrangement Q418Hfs*11 (c.1254_1264delins TTACTTAGTACAAGAACTG) in the Fanconi anemia gene FANCD2 leading to a truncated protein. Besides, several SNPs associated with the occurrence of neuroblastoma and/or nephroblastoma or multiple primary tumors were identified. The next-generation sequencing approach might in the future be useful not only in understanding tumor etiology but also in recognizing new genetic markers and targets for future personalized therapy.

AIP Mutation Identified in a Patient with Acromegaly Caused by Pituitary Somatotroph Adenoma with Neuronal Choristoma

Pituitary adenoma with neuronal choristoma (PANCH) is a rare condition that includes ganglion cells and GH-producing tumor that is characterized by sparsely granulated somatotroph cell type. However, the pathophysiology of this condition remains to be elucidated. We report a case of 46-year-old woman with acromegaly caused by PANCH. The patient had a large and invasive macroadenoma that was resistant to preoperative therapy with somatostatin analogue (SSA) and dopamine agonist. Histological examination showed typical diffuse, chromophobe-type adenoma containing ganglion cells, and sparsely granulated somatotroph cell type, which were consistent with PANCH. Genetic analysis showed heterozygous germline missense mutation in the AIP gene that results in Y261X amino acid substitution. The clinical characteristics of acromegaly associated with AIP mutations are reportedly macroadenomas with tumor extension and invasion, lower decreases in GH and IGF-I and less tumor shrinkage with SSA treatment, and sparsely granulated somatotroph cell type, which are comparable with those observed in PANCH. Taken together, the mutation in AIP gene may explain the clinical characteristics and pathogenesis of PANCH.

Cancer médullaire de la thyroïde familial isolé

The authors describe the cases of two patients from the same family who presented medullary thyroid carcinoma (MTC). Hormone measurement showed a significantly elevated basal calcitonin. The treatment was total thyroidectomy. Histological findings showed multifocal, bilateral MTC. Direct sequencing identified in both patients a heterozygous germline missense mutation TGC-TTC at codon 634 of exon 11 in the RET gene that causes an animosubstitution of cysteine to phenylalanine. The clinical outcome of the cases is considered to be favourable.

Study of the RET gene and his implication in thyroid cancer: Morocco case family

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant inherited cancer syndrome that affects multiple tissues derived from the neural crest. Inheritance of MTC is related to the presence of specific mutations in the RET proto-oncogene. Almost all mutations in MEN 2A involve one of the cysteines in the extracellular domain of the RET receptor. The objective of the present study was the biochemical and molecular characterization of the first Moroccan clinically established MEN 2A patient and at-risk family members. This is a study on a family presented with MTC referred to our institute in 2004. Peripheral blood leukocyte DNA samples were isolated and amplified by polymerase chain reaction followed by restriction enzyme analysis and DNA sequencing. We identified a heterozygous germ line missense mutation at codon 634 of exon 11 in the RET gene that causes a cysteine to arginine amino acid substitution in the DNA of the proband; this mutation was not found in the DNA of the parents or relatives. The detection of mutated MEN 2A gene carriers enables us to differentiate high-risk members from those who bear the wild-type gene. Occasionally, application of RET proto-oncogene testing may lead to the detection of unexpected de novo mutation that could be transmitted to children.

FEM1A is a candidate gene for polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, and is characterized by infertility, hyperandrogenism and insulin resistance in skeletal muscle. There is evidence for a PCOS gene localized to chromosome 19p13.3. The FEMIA gene maps to chromosome 19p13.3 and is highly expressed in skeletal muscle. FEMIA is a homolog of fem-1, a sex-determination gene of Caenorhabditis elegans that controls masculinization. In a pilot study of Caucasian PCOS patients from our local clinic, we found that one of these five patients exhibited a heterozygous germline missense mutation in FEM1A, designated FEM1A*H500Y. This mutation alters an amino acid conserved from human to C. elegans, and was not found in any of 198 control chromosomes. This missense allele was not found in any of a separate group of 30 PCOS patients from a different regional/ethnic background. Immunostaining of mouse ovary demonstrated that the mouse homolog of FEM1A is expressed in androgen-producing secondary interstitial cells, with a marked increase in expression after puberty, consistent with a key feature of PCOS – ovarian hyperandrogenism. In conclusion, FEM1A should be considered a candidate gene for PCOS, and more extensive analysis of FEM1A, both coding and regulatory sequences, is warranted in patients and families with PCOS.