The importance of cross-talk between a cancer and its microenvironment has been increasingly recognized. We hypothesized that mutational inactivation of the tumor-suppressor gene TP53 and genomic alterations in stromal cells of a tumor's microenvironment contribute to the clinical outcome. We performed TP53 mutation analysis and genomewide analysis of loss of heterozygosity and allelic imbalance on DNA from isolated neoplastic epithelial and stromal cells from 43 patients with hereditary breast cancer and 175 patients with sporadic breast cancer. Compartment-specific patterns and TP53 mutations were analyzed. Associations between compartment-specific TP53 status, loss of heterozygosity or allelic imbalance, and clinical and pathological characteristics were computed. TP53 mutations were associated with an increased loss of heterozygosity and allelic imbalance in both hereditary and sporadic breast cancers, but samples from patients with hereditary disease had more frequent mutations than did those from patients with sporadic tumors (74.4% vs. 42.3%, P=0.001). Only 1 microsatellite locus (2p25.1) in stromal cells from hereditary breast cancers was associated with mutated TP53, whereas there were 66 such loci in cells from sporadic breast cancers. Somatic TP53 mutations in stroma, but not epithelium, of sporadic breast cancers were associated with regional nodal metastases (P=0.003). A specific set of five loci linked to an increased loss of heterozygosity and allelic imbalance in the stroma of sporadic tumors was associated with nodal metastases in the absence of TP53 mutations. No associations were found between any of the clinical or pathological features of hereditary breast cancer with somatic TP53 mutations. Stroma-specific loss of heterozygosity or allelic imbalance is associated with somatic TP53 mutations and regional lymph-node metastases in sporadic breast cancer but not in hereditary breast cancer.

Research from JAMA — Molecular Classification of Patients With Unexplained Hamartomatous and Hyperplastic Polyposis — ContextSignificant proportions of patients with hamartomatous polyposis or with hyperplastic/mixed polyposis remain without specific clinical and molecular diagnosis or present atypically. Assigning a syndromic diagnosis is important because it guides management, especially surveillance and prophylactic surgery.ObjectiveTo systematically classify patients with unexplained hamartomatous or hyperplastic/mixed polyposis by extensive molecular analysis in the context of central rereview of histopathology results.Design, Setting, and PatientsProspective, referral-based study of 49 unrelated patients from outside institutions (n = 28) and at a comprehensive cancer center (n = 21), conducted from May 2, 2002, until December 15, 2004. Germline analysis of PTEN, BMPR1A, STK11 (sequence, deletion), SMAD4, and ENG (sequence), specific exon screening of BRAF, MYH, and BHD, and rereview of polyp histology results were performed.Main Outcome MeasuresMolecular, clinical, and histopathological findings in patients with unexplained polyposis.ResultsOf the 49 patients, 11 (22%) had germline mutations. Of 14 patients with juvenile polyposis, 2 with early-onset disease had mutations in ENG, encoding endoglin, previously only associated with hereditary hemorrhagic telangiectasia; 1 had hemizygous deletion encompassing PTEN and BMPR1A; and 1 had an SMAD4 mutation. One individual previously classified with Peutz-Jeghers syndrome had a PTEN deletion. Among 9 individuals with an unknown hamartomatous polyposis, 4 had mutations in STK11 (1), BMPR1A (2), and SMAD4 (1). Of the 23 patients with hyperplastic/mixed polyposis, 2 had PTEN mutations. Substantial discrepancies in histopathology results were seen.ConclusionsSystematic molecular classification of 49 patients with unexplained hamartomatous or hyperplastic polyposis uncovered a potential novel susceptibility gene, ENG, for juvenile polyposis. Importantly, given the substantial proportion of patients found to have germline mutations, more extensive analysis of the known susceptibility genes is indicated. Rereview of histology results by a dedicated gastrointestinal pathologist should be considered routinely, as organ-specific surveillance rests on defining syndromic diagnosis.

Preventive medicine has been dramatically improved by cancer genetics. The identification of susceptibility genes for hereditary forms of cancers in the past decades opened avenues for detection of second primary and recurrent tumors. Once a given germline mutation is detected, newly identified carriers are clinically investigated, and thus the diagnosis of tumors in an asymptomatic stage in the relatives of carriers becomes possible. Pheochromocytoma, paraganglioma, and associated inherited diseases served in this direction as important pacesetters. The susceptibility genes—including RET as causing multiple endocrine neoplasia type 2 (RefSeq NM_020975.4); VHL for von Hippel-Lindau disease (RefSeq NM_000551.3); SDHD, SDHC, and SDHB (succinate dehydrogenase subunits D [RefSeq NM_003002.3], C [RefSeq NM_003001.3], and B [RefSeq NM_003000.2]) for paraganglioma syndromes types 1, 3, and 4; and NF1 for neurofibromatosis type 1 (RefSeq NM_000267.3), herein summarized as classic susceptibility genes—have served as effective molecular tools for preventive medicine studies and practice in this field in the first years of the new millenium.^1-8 These studies led to the end of the 10% rule for the frequency of hereditary pheochromocytoma and instead pointed to at least a 24% hereditary fraction.^6,9 By 2010 and 2011, additional susceptibility genes for pheochromocytomas and paragangliomas were reported, including SDHA (succinate dehydrogenase subunit A [RefSeq NM_004168.3]), TMEM127 (transmembrane protein 127 [RefSeq NM_017849.3]), MAX (Myc-associated factor X [RefSeq NM_002382.4]), and SDHAF2 (succinate dehydrogenase complex assembly factor 2 [RefSeq NM_017841.2]).^10-13 In contrast to the classic susceptibility genes, recommendations of the last International Symposium for Pheochromocytoma (2014) do not provide clinical management guidelines for those with mutations in the susceptibility genes analyzed and characterized herein.¹⁴ The main reasons are the limited number of sufficiently large registries, leading to limited clinical data associated with mutations of these genes. The much-needed and important process of returning to the clinical roots is a labor-intensive one. Thus, our comprehensive genetic and clinical characterization study intends to close the gap between finding a mutation in 1 of these 4 new susceptibility genes and the associated clinical data so that gene-informed risk assessment, counseling, and management can be performed.

Summary: Objective  To evaluate the efficacy, safety and tolerability of octreotide LAR^® (long‐acting repeatable octreotide) in the primary therapy of acromegaly.Design and patients  Ninety‐eight previously untreated acromegalics were recruited into this prospective multicentre study. A total of 68 patients successfully completed 48 weeks of the study period, received 12 doses of octreotide LAR 10–30 mg every 4 weeks, and constituted the population used for this analysis.Measurements and results  A clinically relevant reduction (i.e. to ≤ 5 µg/l) in mean GH (mGH) was recorded in 72% of patients after 24 weeks of treatment, and 42% reached a ‘safe’ GH value (≤ 2·5 µg/l). At week 48, 16 more patients were considered partial GH responders (GH > 2·5 µg/l and ≤ 5 µg/l) and 44% had reached a GH level ≤ 2·5 µg/l. IGF‐1 levels normalized in 38% and 34% of patients after 24 and 48 weeks of treatment, respectively. At study completion, 10 patients (14·7%) who had not normalized their IGF‐1 levels had achieved at least a 50% decrement in this marker. In eight microadenoma patients, tumour volume decreased from a mean baseline level of 298 ± 145 mm³ to 139 ± 94 mm³ after 24 weeks and to 99 ± 70 mm³ after 48 weeks of therapy. In 60 patients with macroadenoma, the corresponding values were 3885 ± 5077 mm³ at baseline and 2723 ± 3435 and 2406 ± 3207 mm³ after 24 and 48 weeks, respectively. At weeks 24 and 48, a significant (> 20%) tumour volume reduction was reported in 63% and 75% of patients, respectively. A reduction in the severity of symptoms of acromegaly was observed early in treatment and was maintained throughout the study period.Conclusion  Octreotide LAR represents a viable alternative to surgery for primary treatment of acromegaly leading to a progressive regression of tumour volume, a sustained control of biochemical abnormalities and an adequate relief of symptoms of the disease.