The INK4a-ARF locus: role in the genetic predisposition to familial melanoma and in skin carcinogenesis]

The INK4a-ARF locus, localized on 9p21, encodes two tumor suppressor proteins, p16INK4a and p14ARF, acting respectively through the CDK4-pRb and the p53 pathways. Familial melanoma (comprising between 8 and 12% of all melanoma cases) is a genodermatosis transmitted as an autosomal dominant trait, often associated with clinically atypical moles (AN). Germline mutations of p16INK4a are found in up to 20-30% of melanoma prone families. Mutated families often contain more than three family members affected and/or comprise at least one relative with multiple melanomas. Most of these mutations have been shown to affect p16INK4a protein function (i.e. CDK4 binding or pRB phosphorylation). Germline mutations of p16INK4a are also found in a lesser extend in sporadic multiple melanoma and in familial pancreatic cancer. The INK4a-ARF locus plays also an important role in skin carcinogenesis. P16INK4a UV induced mutations (CC:GG > TT:AA tandem transition or C:G > T:A transition at dipyrimidic site) are found in 12% of sporadic skin carcinomas, mainly in epidermoid tumors, and seem to occur independently of p53 mutations. Xeroderma pigmentosum (XP) is characterized by an inheritable DNA repair defect (involving the nucleotid excision repair (NER) system) predisposing to skin carcinomas. In skin tumors from (XP) patients, p16INK4a UV induced mutations occur more frequently, are often multiple, and significantly associated with the presence of p53 mutations. Such data, which could be related to the XP genetic instability and indicates a possible cooperative effect of inactivation of these pathways in the tumoral process of XP skin tumors.     

Genes involved in the WNT and vesicular trafficking pathways are associated with melanoma predisposition

Multifactorial predisposition to melanoma includes genes involved in pigmentation, immunity and DNA repair. Nonetheless, missing heritability in melanoma is still important. We studied the role of 335 candidate SNPs in melanoma susceptibility by using a dedicated chip and investigating 110 genes involved in different pathways. A discovery set was comprised of 1069 melanoma patients and 925 controls from France. Data were replicated using validation phases II (1085 cases and 801 controls from Spain) and III (1808 cases and 1894 controls from Germany and a second set of Spanish samples). In addition, an exome sequencing study was performed in three high‐risk French melanoma families. Nineteen SNPs in 17 genes were initially associated with melanoma in the French population. Six SNPs were replicated in phase II, including two new SNPs in the WNT3 (rs199524) and VPS41 (rs11773094) genes. The role of VPS41 and WNT3 was confirmed in a meta‐analysis (3940 melanoma cases and 3620 controls) with two‐side p values of 0.002, (OR = 0.86) and 4.07 × 10^?10 (OR = 0.80), respectively. Exome sequencing revealed a non‐synonymous VPS41 variant in one family that was shown to be strongly associated with familial melanoma (OR = 4.46, p = 0.001) in an independent sample of 178 melanoma families. WNT3 belongs to WNT pathway known to play a crucial role in melanoma, whereas VPS41 regulates vesicular trafficking and is thought to play a role in pigmentation. Our work identified two new pathways involved in melanoma predisposition. These results may be useful in the future for identifying individuals highly predisposed to melanoma.     

Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients

ObjectiveAbout 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients.DesignMismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres.Results231 patients (median age: 81, range: 75–100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05–6.44; p = 0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%).Conclusiondeficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients.     

Attributable morbidity and mortality of catheter-related septicemia in critically ill patients: a matched, risk-adjusted, cohort study.

OBJECTIVE: To determine the attributable risk of death due to catheter-related septicemia (CRS) in critically ill patients when taking into account severity of illness during the intensive-care unit (ICU) stay but before CRS. DESIGN: Pairwise-matched (1:2) exposed-unexposed study. SETTING: 10-bed medical-surgical ICU and an 18-bed medical ICU. PATIENTS: Patients admitted to either ICU between January 1, 1990, and December 31, 1995, were eligible. Exposed patients were defined as patients with CRS; unexposed controls were selected according to matching variables. METHODS: Matching variables were diagnosis at ICU admission, length of central catheterization before the infection, McCabe Score, Simplified Acute Physiologic Score (SAPS) II at admission, age, and gender. Severity scores (SAPS II, Organ System Failure Score, Organ Dysfunction and Infection Score, and Logistic Organ Dysfunction System) were calculated four times for each patient: the day of ICU admission, the day of CRS onset, and 3 and 7 days before CRS. Matching was successful for 38 exposed patients. Statistical analysis was based on nonparametric tests for epidemiological data and on Cox's models for the exposed-unexposed study, with adjustment on matching variables and prognostic factors of mortality. RESULTS: CRS complicated 1.17 per 100 ICU admissions during the study period. Twenty (53%) of the CRS cases were associated with septic shock. CRS was associated with a 28% increase in SAPS II. Crude ICU mortality rates from exposed and unexposed patients were 50% and 21%, respectively. CRS remained associated with mortality even when adjusted on other prognostic factors at ICU admission (relative risk [RR], 2.01; 95% confidence interval [CI95], 1.08-3.73; P=.03). However, after adjustment on severity scores calculated between ICU admission and 1 week before CRS, the increased mortality was no longer significant (RR, 1.41; CI95, 0.76-2.61; P=.27). CONCLUSION: CRS is associated with subsequent morbidity and mortality in the ICU, even when adjusted on severity factors at ICU admission. However, after adjustment on severity factors during the ICU stay and before the event, there was only a trend toward CRS-attributable mortality. The evolution of patient severity should be taken into account when evaluating excess mortality induced by nosocomial events in ICU patients.     

Occurrence of BAP1 germline mutations in cutaneous melanocytic tumors with loss of BAP1‐expression: A pilot study

Melanocytic BAP1‐associated intradermal tumors (MBAITs) can either be sporadic or associated with a cancer‐predisposition syndrome. In this study we explored the clinical status of 136 patients in which at least one MBAIT was found. 49/136 (36%) of them gave their signed consent for an oncogenetic BAP1 blood test. 28/136 patients (20%) diagnosed with an MBAIT had other MBAITs and/or a personal or familial history of BAP1‐related cancers that could clinically designate them as potential carriers of a BAP1 germline mutation. 17 of these 28 patients underwent oncogenetic testing. A deleterious mutation of BAP1 was confirmed in 12/17 cases. 4/17 cases were wild‐type; all had a single MBAIT and a history of skin melanoma. A variant of unknown significance was found in one case with multiple MBAITs. Among the 12 mutated cases, multiple MBAITs were present in 10/12 cases and were the only clinical sign in 4/12 cases. The remaining 32/49 blood‐tested cases with an isolated MBAIT were wild type for BAP1 in 25/32 cases or showed a variant of unknown significance in 7/32 cases. We recommend, following the diagnosis of a MBAIT, performing a BAP1 immunohistochemistry in all other cutaneous melanocytic tumors removed previously or simultaneously and all skin melanomas. This screening could help clinicians prioritize which patients would most benefit from oncogenetic testing.     

Primary Tumor Response to Induction Chemotherapy as a Predictor of Histological Status of Axillary Nodes in Operable Breast Cancer Patients

Background: Routine use of axillary lymph node dissection is being questioned, especially in clinically N0 patients. The goal of this study was to determine whether primary tumor response to induction chemotherapy (IC) can predict the histological volume of residual axillary disease in patients who were candidates for breast conservation surgery after IC.Methods: Forty-seven patients with stage II or IIIA breast cancer who received breast conservation surgery were selected from a population of patients randomized to receive four cycles of IC. Largest clinical tumor size before and after IC was determined by physical examination, mammography, and breast ultrasound. Clinical nodal status was determined by physical examination and axillary ultrasound and compared with histological findings.Results: In patients with at least 50% reduction in primary tumor size after IC, 12 of 14 (86%) N0 patients and 11 of 17 (65%) N1 patients were histologically negative. In patients with a less than 50% reduction, 0 of 3 N0 patients and 2 of 13 (15%) N1 patients were histologically negative.Conclusions: There is significantly less axillary disease in responders than in nonresponders after IC. For N0 responders, axillary irradiation may be an acceptable alternative to axillary lymph node dissection, and could easily be incorporated into the postsurgical radiotherapy that is standard protocol for breast conservation therapy. The more aggressive disease in nonresponders is best treated by axillary lymph node dissection, pending further study.Presented at the 52nd Annual Meeting of the Society of Surgical Oncology, Orlando, Florida, March 4–7, 1999.     

Cytogenetic, molecular and testicular tissue studies in an infertile 45,X male carrying an unbalanced (Y;22) translocation: case report

(Y;autosome) translocations have been reported in association with male infertility. Different mechanisms have been suggested to explain the male infertility, such as deletion of the azoospermic factor (AZF) on the long arm of the Y chromosome, or meiosis impairment. We describe a new case with a de novo unbalanced translocation t(Y;22) and discuss the genotype-phenotype correlation. A 36 year old male with azoospermia was found to have a mosaic 45,X/46,X, + mar karyotype. Fluorescence in situ hybridization (FISH) showed the presence of a derivative Y chromosome containing the short arm, the centromere and a small proximal part of the long-arm euchromatin of the Y chromosome and the long arm of chromosome 22. The unstable small marker chromosome included the short arm and the centromere of chromosome 22. This unbalanced translocation t(Y;22)(q11.2;q11.1) generated the loss of the long arm of the Y chromosome involving a large part of AZFb, AZFc and Yq heterochromatin regions. Testicular tissue analyses showed sperm in the wet preparation. Our case shows the importance of documenting (Y;autosome) translocations with molecular and testicular tissue analyses.