Gang Yuan

A novel BRCA2 mutation in prostate cancer sensitive to combined radiotherapy and androgen deprivation therapy

ABSTRACT Genetic factors contribute to more than 40% of prostate cancer risk, and mutations in BRCA1 and BRCA2 are well-established risk factors. By using target capture-based deep sequencing to identify potential pathogenic germline mutations, followed by Sanger sequencing to determine the loci of the mutations, we identified a novel pathogenic BRCA2 mutation caused by a cytosine-to-guanine base substitution at position 4211, resulting in protein truncation (p.Ser1404Ter), which was confirmed by immunohistochemistry. Analysis of peripheral blood also identified benign polymorphisms in BRCA2 (c.7397T>C, p.Val2466Ala) and SRD5A2 (c.87G>C, p.Lys29Asn). Analysis of tumor tissues revealed seven somatic mutations in prostate tumor tissue and nine somatic mutations in esophageal squamous carcinoma tissue (single nucleotide polymorphisms, insertions, and deletions). Five-year follow-up results indicate that ADT combined with radiotherapy successfully treated the prostate cancer. To our knowledge, we are the first to report the germline BRCA2 mutation c.4211C>G (p.Ser1404Ter) in prostate cancer. Combined ADT and radiotherapy may be effective in treating other patients with prostate cancer caused by this or similar mutations.

Different RET Gene Mutation-Induced Multiple Endocrine Neoplasia Type 2A in 3 Chinese Families

Backgroud: Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma. Little is reported about MEN2A syndrome in the Chinese population. Methods: All members of the 3 families along with specific probands of MEN2A were analyzed for their clinical, laboratory, and genetic characteristics. Exome sequencing was performed on the 3 probands, and specific mutation in RET was further screened on each of the family members. Results: Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3. Proband 1 mainly showed pheochromocytoma with MTC, both medullary thyroid carcinoma and pheochromocytoma were seen in proband 2, and proband 3 showed medullary thyroid carcinoma. Conclusion: The genetic evaluation is strongly recommended for patients with a positive family history, early onset of age, or multiple sites of masses. If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.

A retrospective case study of sunitinib treatment in three patients with Von Hippel-Lindau disease

Abstract Von Hippel-Landau (VHL) disease is characterized by malignant and benign tumors in multiple organs. Sunitinib, a tyrosine kinase inhibitor, has been clinically available for treating sporadic patients with recurrent or unresectable and metastatic clear renal cell carcinomas (cRCCs) and metastatic lesions of the lung, but its effect on VHL disease-associated tumors remains poorly understood. This retrospective case series examined the effect of sunitinib on RCC, hemangioblastomas, pheochromocytomas, and pancreatic neuroendocrine tumors in patients with confirmed VHL. Of note, three patients with VHL disease who were treated with sunitinib were identified from a review of their medical records. The efficacy of sunitinib was evaluated by comparing computed tomography (CT) or magnetic resonance imaging (MRI) scans conducted before and after treatment. Adverse side effects associated with sunitinib were assessed and recorded. All three patients with VHL disease exhibited clinical improvement after treatment with sunitinib. Patient 1 exhibited a decrease in the size of both their pheochromocytoma and RCC after 19 months of sunitinib treatment. RCCs in Patients 2 and 3 exhibited stable response to sunitinib for approximately 1 and 6 years, respectively. All the patients reported tolerable side effects. Therefore sunitinib treatment was associated with either partial response or stable control of VHL-related RCCs, pheochromocytomas and pancreatic neuroendocrine tumor (NET) with acceptable side effects. Further evaluation of sunitinib in patients with VHL disease in larger prospective studies is warranted.

Pathogenesis and Preventive Strategies of Chronic Dysfunction of Renal Allograft

Novel immunosuppressants have decreased the incidence rate of acute rejection significantly, but fail to prevent chronic allograft dysfunction (CAD). Around 40% patients develop CAD gradually in several months or several years after renal transplantation. They present with progressive deterioration of long-term allograft function and allograft failure, and end up with resuming dialysis. It has also been demonstrated that CAD may increase the cardiovascular mortality after renal transplantation. Therefore, it is crucial for promoting long-term allograft survival to investigate the pathogenesis and preventive and therapeutic strategies of CAD. CAD, formerly termed chronic rejection (CR), is also known as late graft loss (LGI) or chronic allograft nephropathy (CAN), since it involves both immune factors (transplantation antigen dependent) and non-immune factors (transplantation antigen independent). CAD refers to progressive functional impairment of allograft, with pathologic changes including tubular atrophy, interstitial fibrosis, progressive glomerulosclerosis, and arterial fibrous intimal thickening and arteriole hyalinosis. These pathologic changes include immune and non-immune injury to allograft. Chronic rejection is usually associated with acute rejection or subclinical rejection, HLA mismatch, panel reactive antibodies (PRA), and donor specific antibodies (DSA). In contrast, non-immune allograft injury is usually associated with calcineurin inhibitors (CNI), preexisting delayed graft function (DGF), hypertension, hyperlipidemia, proteinuria, viral infection, chronic obstruction and chronic pyelonephritis. In addition, CAD includes recurrent kidney disease, de novo nephritis, posttransplantation lymphoproliferative diseases (PTLD). Many of the above-mentioned factors that lead to CAD usually exist simultaneously; thus, the pathologic manifestations of CAD are complex and not specific, making the treatment of CAD difficult. In short, there are many factors influencing the incidence and development of CAD, and the pathogenesis of CAD remains largely unclear. Microcirculation injury mediated by donor specific antibodies is thought to be the major cause for long-term allograft dysfunction.