Germline investigation in male breast cancer of DNA repair genes by next-generation sequencing.

PURPOSE: In order to better define the breast cancer (BC) genetic risk factors in men, a germline investigation was carried out on 81 Male BC cases by screening the 24 genes involved in BC predisposition, genome stability maintenance and DNA repair mechanisms by next-generation sequencing. METHODS: Germline DNAs were tested in a custom multi-gene panel focused on all coding exons and exon-intron boundaries of 24 selected genes using two amplicon-based assays on PGM-Ion Torrent (ThermoFisher Scientific) and MiSeq (Illumina) platforms. All variants were recorded and classified by using a custom pipeline. RESULTS: Clinical pathological data and the family history of 81 Male BC cases were gathered and analysed, revealing the average age of onset to be 61.3 years old and that in 35 cases there was a family history of BC. Our genetic screening allowed us to identify a germline mutation in 22 patients (23%) in 4 genes: BRCA2, BRIP1, MUTYH and PMS2. Moreover, 12 variants of unknown clinical significance (VUS) in 9 genes (BARD1, BRCA1, BRIP1, CHEK2, ERCC1, NBN, PALB2, PMS1, RAD50) were predicted as potentially pathogenic by in silico analysis bringing the mutation detection rate up to 40%. CONCLUSION: As expected, a positive family history is a strong predictor of germline BRCA2 mutations in male BC. Understanding the potential pathogenicity of VUS represents an extremely urgent need for the management of BC risk in Male BC cases and their own families.

Genetic Profiling of Primary Orbital Melanoma: An Analysis of 6 Cases with Clinicopathologic Correlation.

PURPOSE: To analyze the genetic profile of 6 cases of primary orbital melanoma with clinicopathologic correlation. DESIGN: Retrospective noninterventional study to analyze the genetic profile of 6 cases of primary orbital melanoma and to correlate the genetic findings with prognosis and clinicopathologic features. Inclusion criteria were patients with primary orbital melanoma with no evidence of primary eyelid skin, conjunctival, uveal, or remote melanoma at extraocular sites. PARTICIPANTS: The study involved 6 primary orbital melanomas from 6 patients. Four patients were exenterated and 2 had incisional biopsies performed. METHODS: Clinical notes and radiologic records were assessed to ascertain clinical tumor behavior. Sections were stained with hematoxylin-eosin and exposed to immunohistochemistry for S100, MelA, HMB45, Sox10, and BAP1. Melanoma DNA was exposed to array comparative genomic hybridization to assess gross chromosomal copy number changes. Point mutation assessment and Sanger sequencing were performed for GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX. MAIN OUTCOME MEASURES: These were the presence of gross chromosomal copy number changes and the presence of mutations in GNAQ, GNA11, BRAF, NRAS, pTERT, SF3B1, and EIF1AX; the presence of metastases and time period between diagnosis and death from melanoma; and correlation between the tumor genetic profile and the clinical behavior of the tumor. RESULTS: One of the 6 cases was clinically associated with oculodermal melanocytosis. Of the 6 patients, 3 died of melanoma metastases and 1 of unrelated causes; 2 remain alive at last review. Three of the 6 cases were histologically associated with a benign precursor lesion. All melanomas expressed S100, MelA, HMB45, and Sox10. One patient showed loss of BAP1 nuclear staining. The most frequent chromosomal gains across the 6 cases, in order of frequency, were 6p, 8q, 17q, 6q, and 20p. The most frequently lost regions were 1p, 9p, 16q, and 17p. One patient showed monsomy 3 and gain of 8q (and showed the BAP1 loss). Mutations were found in GNAQ (1 case), GNA11 (1 case), SF3B1 (2 cases), NRAS (2 cases), and pTERT (2 cases). CONCLUSIONS: The data point to 2 genetic groups for primary orbital conjunctiva melanoma-like and a uveal melanoma-like group. A larger study would help confirm this suggestion.

Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy.

It is well-known that male breast cancer (MBC) susceptibility is mainly due to high-penetrance BRCA1/2 mutations. Here, we investigated whether common low-penetrance breast cancer (BC) susceptibility alleles may influence MBC risk in Italian population and whether variant alleles may be associated with specific clinicopathological features of MBCs. In the frame of the Italian Multicenter Study on MBC, we genotyped 413 MBCs and 745 age-matched male controls at 9 SNPs annotating known BC susceptibility loci. By multivariate logistic regression models, we found a significant increased MBC risk for 3 SNPs, in particular, with codominant models, for rs2046210/ESR1 (OR = 1.71; 95 % CI: 1.43-2.05; p = 0.0001), rs3803662/TOX3 (OR = 1.59; 95 % CI: 1.32-1.92; p = 0.0001), and rs2981582/FGFR2 (OR = 1.26; 95 % CI: 1.05-1.50; p = 0.013). Furthermore, we showed that the prevalence of the risk genotypes of ESR1 tended to be higher in ER- tumors (p = 0.062). In a case-case multivariate analysis, a statistically significant association between ESR1 and ER- tumors was found (OR = 1.88; 95 % CI: 1.03-3.49; p = 0.039). Overall, our data, based on a large and well-characterized MBC series, support the hypothesis that common low-penetrance BC susceptibility alleles play a role in MBC susceptibility and, interestingly, indicate that ESR1 is associated with a distinct tumor subtype defined by ER-negative status.

Treatment of invasive male breast cancer: a 40-year single-institution experience.

PURPOSE: We conducted a retrospective analysis to evaluate the management and outcome of invasive male breast cancer treated in a single-institution over a period of 40 years. MATERIALS AND METHODS: We reviewed the clinical and pathological features of 60 male patients affected by breast carcinoma treated at our Radiotherapy Unit between 1971 and 2011. Tumours were classified according to histological type and the updated 2010 TNM classification of malignant tumours. RESULTS: At a median follow-up of 8.9 [range, 0.6-20; standard deviation (SD), 4.98] years, 32 patients (53.3%) were alive and 16 patients died (26.7%) due to disease progression and 12 (20%) due to other causes. At univariate analysis for overall survival, pathological tumour size (p=0.031), histological subtype (p=0.013) and nodal status (p=0.006) emerged as significant predictors of death. At multivariate analysis, independent death predictors were advanced pathological tumour size (p=0.016), positive nodal status (p=0.003) and invasive cribriform histological type (p=0.0003). CONCLUSIONS: In consideration of the rarity of the disease, many issues are still being debated, and future collaborative studies are required. However, our experience confirms the prognostic role of greater pathological tumour size and positive nodal status as unfavourable features for survival in male breast cancer.

Periocular changes following long-term administration of latanoprost 0.005%.

This is a case series of 3 patients who presented with periocular changes in the treated eye following chronic administration of unilateral latanoprost 0.005%. The clinical changes included worsening of dermatochalasis, deepening of superior sulcus and hollowness of the lid. This similar observation was previously described in usage of bimatoprost 0.03% and travoprost 0.004%. However this has not been reported in latanoprost instillation. Therefore, patients should be made aware of these potential side effects.

Holding back the tears: is there a role for marsupialisation?

OBJECTIVE: Medial eyelid tumours may result in the loss of the proximal lacrimal system during staged excision and delayed reconstruction, to achieve tumour margin clearance. The remnant canaliculus was marsupialised during reconstruction. The aim was to understand how many patients experienced symptomatic epiphora as a consequence of this. METHODS AND ANALYSIS: A retrospective study including patients over a 15-year period with medial eyelid tumours, where the proximal lacrimal system was sacrificed to achieve tumour margin clearance. Included were all who had marsupialisation of the remnant distal stump as part of their delayed reconstruction. All who had pre-existing epiphora were excluded. The primary objective was the rate of epiphora following the procedure. A systematic literature review of postoperative epiphora occurring in patients with lid tumours requiring lacrimal system injury/sacrifice during tumour excision. RESULTS: There were 22 eyes (22 patients). All were basal cell carcinomas except for 1 (4.5%) tarsal conjunctival squamous cell carcinoma. All cases involved the lower lid. There were two (9.1%) patients who developed epiphora. One patient underwent a superior three-snip punctoplasty, botulinum toxin to the lacrimal gland and conjunctivodacryocystorhinostomy with Lester Jones tube insertion. The other patient was not overly troubled and did not require further treatment. The literature review showed the median postoperative rate of epiphora in these patients was 12.5% (range 0%-100%). CONCLUSION: Marsupialisation of the remnant canaliculus during delayed reconstruction is a straightforward and effective surgical option, which may help prevent postreconstruction epiphora when the proximal lacrimal system is sacrificed for tumour margin clearance. TRIAL REGISTRATION NUMBER: 10391.

To implant or not to implant: emergency orbital eviscerations with primary orbital implants.

BACKGROUND/OBJECTIVES: To evaluate the outcomes of orbital evisceration with primary implant placement in acutely infected/inflamed eyes, using implant exposure/extrusion as a surrogate of success. To contextualise this with previously published literature. SUBJECTS/METHODS: A retrospective case series of all patients with acutely infected/inflamed eyes undergoing urgent orbital evisceration with primary implants, at a British tertiary centre between January 2006 and August 2018. A systematic literature review of orbital eviscerations with primary implant placement in acute endophthalmitis/infection and recent trauma. RESULTS: Twenty-six eyes were eviscerated in the context of acute infection/inflammation. Twenty-four eyes had primary orbital implants. Indications for evisceration included endophthalmitis (18/26, 69%), microbial keratitis with corneal perforation (4/26, 15%), non-infectious corneal perforation (3/26, 12%), and recent trauma (1/26, 4.8%). The implants used were acrylic (15/24, 63%), MEDPOR (5/24, 21%), and silicone (4/24, 17%). The follow-up period was 15 months to 14 years. Implant exposure occurred in two (8.3%), managed with implant exchange and scleral reformation in one, and implant removal with dermis fat grafting in the other. One patient (4.2%) had conjunctival wound dehiscence with spontaneous healing. Six (25%) required further surgery for minor complications as follows: conjunctival prolapse, upper lid ptosis with slight sulcus loss, lower lid entropion with shortened fornix, and lower lid ectropion. The systematic literature review showed that the mean rate of orbital implant exposure/extrusion in this subset of patients was 7.8% (95% CI: 2.7%, 12.9%, SD 8.0%), range 0-27%. CONCLUSIONS: In acutely infected/inflamed eyes, the implant exposure/extrusion rate following orbital evisceration with primary implant placement is acceptable.

Management of recurrent sebaceous gland carcinoma.

OBJECTIVE: To evaluate the incidence and management of recurrent periocular sebaceous gland carcinoma at a tertiary ocular oncology service in the United Kingdom. METHODS: This was a retrospective cohort study of 62 patients with sebaceous gland carcinoma treated between 2004 and 2017. A total of 10 eyes were treated for local recurrence. The following variables were recorded: age and sex of patient; tumour location, histological subtype; recurrence type; treatment and outcome. RESULTS: Of the 62 cases with eyelid SGC, 10 (16%) had recurrences during the study period and satisfied inclusion criteria. There were six (60%) females and four males in the recurrent group. The mean time interval between initial excision and tumour recurrence was 37 months (median 23 months; range 4 to 84 months). Four patients received cryotherapy to the lids and conjunctiva to control recurrent disease and two patients were treated with topical or intralesional chemotherapy. Four patients (40%) underwent orbital exenteration during the study period. Metastasis occurred in 20% over a mean follow-up of 113 months (median 106; range 47-184 months). CONCLUSIONS: The risk factors for local recurrence of SGC after wide excision with paraffin section control were reported, and an approach to these recurrent lesions was proposed. The results of this study will help guide surgeons dealing with the medical and surgical conundrum of recurrent disease. The risk of recurrence is highest in the first 2 years after initial excision.

Frontalis suspension sling using palmaris longus tendon in chronic progressive external ophthalmoplegia.

A 26-year-old woman referred with bilateral ptosis was diagnosed to have underlying chronic progressive external ophthalmoplegia. The authors report satisfactory result at 18-month follow-up with palmaris longus tendon used as an autologous sling material for ptosis surgery in this patient.

Fibrin glue-assisted excision of a large recurrent microphthalmic cyst.

Microphthalmic cysts are rare. Although small cysts can be left in situ to promote orbital expansion, large cysts require drainage or surgical excision. Complete surgical excision is notoriously difficult, and incomplete excision may result in cyst reformation. We describe a novel method of using fibrin glue to aid successful complete removal of a large recurrent microphthalmic cyst in a 6-year-old child who previously had multiple drainage and surgical attempts.

Staged excision of primary periocular basal cell carcinoma: absence of residual tumour in re-excised specimens: a 10-year series.

AIMS: The aim is to study staged periocular basal cell carcinoma (BCC) excision in a tertiary oculoplastic referral centre in Sheffield, UK. In particular, we examined patients with close or positive margins and no tumour seen on re-excision to identify demographics and tumour characteristics in this population. METHODS: A retrospective review of medical records of 437 cases of staged periocular BCC excisions over a 10-year period (2007-2017) was carried out. Patients had surgical excision with 3 mm clinically clear margins. Staged excision was performed for all cases included in this study. Standard reconstruction techniques were employed. Histopathology was analysed for tumour type, subtype and stage. RESULTS: Over the 10-year period, of the 437 periocular BCCs, 156 had close or involved margins. Residual tumour was found in 29 (18.6%), whereas in 122 eyelids of 120 patients (78.2%) no residual tumour was identified on histological examination. Micronodular (54.1%) and nodular (23.7%) growth patterns of BCC, as well as lower eyelid location (72.1%), were the most prevalent in this population. Two patients (1.6%) had recurrence of BCC over a mean follow-up of 57 months (range 1-125 months). CONCLUSIONS: A significant proportion of BCCs transected on initial excision show no residual tumour in the re-excision specimens. In the interval between initial excision and re-excision, there may be eradication of the residual tumour. The exact mechanisms for this are unclear, however, and re-excision remains the appropriate recommended course in the presence of involved surgical margins of periocular BCC, particularly when high-risk tumour subtypes are encountered.

Long-term risk of recurrence after intact excision of pleomorphic adenomas of the lacrimal gland.

OBJECTIVE: To ascertain the need for follow-up after excision of pleomorphic adenoma of the lacrimal gland. METHODS: Medical records were reviewed for 133 patients and only those patients with 5 years or more of follow up were classified into the following 5 subgroups: those with intact excision (group IA, n = 46), those with surgically intact excision but areas of complete attenuation of the pseudocapsule at histologic analysis (group IB, n = 7), those with previous inadvertent incisional biopsy (group IIA, n = 9), those with breach of the pseudocapsule during attempted intact excision (group IIB, n = 5), and those undergoing definitive surgery because of tumor recurrence after previous incomplete excision (group III, n = 5). RESULTS: Seventy-two patients were followed up longer than 5 years; there were no known tumor recurrences among 61 patients excluded with shorter follow-up. Patients in groups IA and IB exhibited no tumor recurrences at 8.2 to 34.1 years of follow-up. A benign recurrence occurred along the superior orbital fissure in 1 patient in group IIA 12(1/2) years after the initial surgery and was resected. There were no recurrences in patients in groups IIB or III. CONCLUSIONS: Discharge would seem justified after intact excision of lacrimal gland pleomorphic adenoma, even when histologic examination shows extreme attenuation of the pseudocapsule. Long-term follow-up is, however, necessary when there has been tumor disruption, either inadvertently during previous biopsy or by capsular breach during definitive excision.

Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma.

A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF were associated with tumor-node-metastasis (TNM) stage and node status, whereas only DNA ploidy was related to depth of invasion. CB, CL, uPA, but not CD, levels were significantly higher in GC as compared to paired normal mucosa, whereas stefin A levels were lower in tumor tissues. CB levels were significantly associated with TNM stage, nodal status, histological grade, and DNA ploidy. At univariate analysis, only node involvement, advanced TNM stage, DNA aneuploidy, and high SPF proved to be significantly related to quicker relapse and to shorter overall survival, whereas depth of invasion was related only to survival. With multivariate analysis, only high SPF (>15.2%) was related to risk of relapse (RR = 8.50), whereas high SPF and DNA aneuploidy were independently related to risk of death (RR = 1.88 and 2.09, respectively). Our preliminary prospective study has identified SPF and DNA ploidy as important biological indicators for predicting the outcome of patients with GC.

Lacrimal Gland Intra-Lobular Duct Cysts Associated with Focal Vasculitis.

PURPOSE: Description of the clinical and histopathological features of unusual lacrimal gland intra-glandular duct cysts. PROCEDURES: A 38-year-old male presented with bilateral upper lid lumpiness, which was worse on the left. Computed tomography scan showed bilateral multiple lacrimal gland cysts, which were larger on the left compared to the right. After two unsuccessful attempts to excise the largest cyst on the left side, it was removed at the third attempt using a novel technique that incorporated the use of fibrin glue to fill the remaining cavity. RESULTS: The microscopy of the left-sided cyst comprised a cavity containing fibrin glue, lined by intra-lobular lacrimal gland duct epithelium. The cyst wall contained reactive lymphoid aggregates, plasma cells and eosinophils associated with fibrosis. Focally, there were small vessels affected by an acute vasculitis associated with eosinophils and a granulomatous component. CONCLUSIONS: We ascribe the cyst formation to the effects of tractional fibrosis secondary to focal vasculitis and to obstructive fibrosis of the lacrimal ductules. This case also described a novel use of Tisseel fibrin glue to assist intact removal of a lacrimal gland cyst.

DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective study.

PURPOSE: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01), histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. CONCLUSIONS: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.

Hereditary common cancers: molecular and clinical genetics.

This review focuses on the functional role and structural features of the genes involved in common hereditary cancers. Most of these tumors are sporadic and the genetic alterations responsible for their genesis take place over several cell generations; nevertheless, 5 to 10% of the human tumors are hereditary, with a rapid development. Cancer susceptibility genes have been classified as "gatekeepers" (e.g. RB1, ki-ras) and "caretakers" (e.g. hMLH1 and hMSH2, BRCA1). The first step in identifying individuals at high risk of developing a specific inherited form of cancer, and who should therefore undergo genetic tests, is the detailed construction of family history (an accurate cancer family history that includes at least three generation pedigrees, an appropriate cancer risk assessment and an effective genetic counseling). At present, the most useful methods of risk assessment are those performed on the following genes: BRCA1 and BRCA2 especially for hereditary breast and ovarian cancer, hMLH1 and hMSH2 for hereditary non polyposis colorectal cancer, APC for familial adenomatous polyposis, ret for medullary thyroid carcinoma, p53 for the Li-Fraumeni syndrome, p16 for melanoma and RB1 for retinoblastoma. In conclusion, the development of new diagnostic tests will permit a more accurate assessment of risk in individuals who have not so far shown any sign or symptom of the disease.

Clinical characteristics and overall survival in genitourinary sarcomas treated with curative intent: a multicenter study.

OBJECTIVES: Adult soft tissue sarcomas in general, and those arising from the urological organs in particular, are a group of rare tumours with a generally poor prognosis, only a few studies are available. We report our experience with this type of tumours in a multicenter study carried out in a single region of Central Italy (Tuscany). METHODS: Pre-treatment and follow-up data were obtained from 22 adult patients, all residing in Tuscany, treated consecutively between 1984 and 2002 for primary or locally recurrent genito-urinary sarcomas in 8 urology departments in the area. All cases were classified according to the French Federation of Cancer Center System Grading Scheme for Adult Sarcomas (FFCC) and Broders System. The crude survival probability was estimated by using the Kaplan-Meier method and differences between patient sub-groups were assessed by the log rank test. RESULTS: The study series included 18 males and 4 females. The mean age at diagnosis was 61+/-21.5 years (range: 15.3-89.1). The most common site was paratesticular (n=9, 40.9%), followed by kidney (n=8, 36.4%), prostate (n=3, 13.6%) and penis and bladder (1 case each, 4.6%). 15 cases (68.2%) were classified as FFCC III, and 16 (72.7%) as Broders IV. The most common histological type was leiomyosarcoma (8 cases, 36.7%), followed by liposarcoma (6, 27.3%), rhabdomyosarcoma (3, 13.6%) and other histological types (5, 22.7%). At the last follow-up (mean: 3.66+/-3.25 years; range 0.15-10.0), 11 of the 22 patients (50%) were still alive. The overall survival rate at 1, 3 and 5 years was 85.9%, 62.0% and 48.8%, respectively. There were no significant differences in survival according to sex, age or histological type. When we compared paratesticular vs. kidney and prostate cancer cases, a significant difference in survival emerged (p=0.02). According to size and grade of the tumour we also found a significant difference in survival (p=0.0006 and p=0.01, respectively). CONCLUSIONS: In our representative series, 3 tumor parameters (site, size and grade) appeared to represent the most important prognostic factors in adult genitourinary sarcomas.

Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population.

OBJECTIVES: Host genetic factors, including the IL1 gene cluster, play a key role in determining the long-term outcome of Helicobacter pylori infection. The aim of the study was to investigate the relationship between selected IL1 loci polymorphisms and gastric cancer risk in an Italian population. METHODS: In a case-control study we compared the IL1B-31 and IL1B+3954 biallelic and IL1RN pentaallelic variable number of tandem repeats (VNTR) polymorphisms in 185 gastric cancer patients and 546 controls randomly sampled from the general population of an area at high gastric cancer risk (Tuscany, Central Italy). RESULTS: Genotype frequencies of the IL1B-31 T/C, IL1B+3954 C/T, and IL1RN polymorphisms among our population controls were in Hardy-Weinberg equilibrium. In multivariate analyses, no increase in gastric cancer risk was observed for the IL1B-31*C- and IL1B+3954*T- carriers; a significant 50% increase emerged for IL1RN*2 allele carriers (OR = 1.49; 95% CI: 1.01-2.21). Analyses based on combined genotypes showed also that the association with IL1RN*2 allele was limited to two-variant allele carriers who were also homozygous for the IL1B-31*T allele (OR = 2.23; 95% CI: 1.18-4.23) with a statistically significant interaction between these two genotypes (p= 0.043). Haplotype analysis showed an increased risk for the haplotype IL1RN*2/IL1B-31*T. CONCLUSIONS: Our results suggest that host genetic factors (such as the IL1RN and the IL1B-31 polymorphisms) interact in the complex process of gastric carcinogenesis in this high-risk Italian population. Overall, this effect appears more modest than previously reported in other populations, supporting the hypothesis that other still-to-be-defined factors are important in gastric carcinogenesis. These findings might be due to a haplotype effect.