Frameshift mutational target gene analysis identifies similarities and differences in constitutional mismatch repair-deficiency and Lynch syndrome.

Mismatch-repair deficient (MMR-D) malignancies include Lynch Syndrome (LS), which is secondary to germline mutations in one of the MMR genes, and the rare childhood-form of constitutional mismatch repair-deficiency (CMMR-D); caused by bi-allelic MMR gene mutations. A hallmark of LS-associated cancers is microsatellite instability (MSI), characterized by coding frameshift mutations (cFSM) in target genes. By contrast, tumors arising in CMMR-D patients are thought to display a somatic mutation pattern differing from LS. This study has the main goal to identify cFSM in MSI target genes relevant in CMMR-D and to compare the spectrum of common somatic mutations, including alterations in DNA polymerases POLE and D1 between LS and CMMR-D. CMMR-D-associated tumors harbored more somatic mutations compared to LS cases, especially in the TP53 gene and in POLE and POLD1, where novel mutations were additionally identified. Strikingly, MSI in classical mononucleotide markers BAT40 and CAT25 was frequent in CMMR-D cases. MSI-target gene analysis revealed mutations in CMMR-D-associated tumors, some of them known to be frequently hit in LS, such as RNaseT2, HT001, and TGFßR2. Our results imply a general role for these cFSM as potential new drivers of MMR-D tumorigenesis.

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Primary tumor response to chemoradiotherapy in limited-disease small-cell lung cancer correlates with duration of brain-metastasis free survival.

The brain represents a crucial site of failure in limited-disease (LD) small-cell lung cancer (SCLC). However, no data about correlation between response of primary tumor to chemoradiotherapy (CRT) and brain metastases (BM)--free survival time in LD SCLC are available. A total of 125 LD SCLC patients with initial performance score of WHO 2-3 were successfully treated with CRT. Prophylactic cranial irradiation (PCI) was applied after complete response. Cranial MRI was performed in patients at initial diagnosis, in complete responders before PCI, and by individual symptoms. A total of 30 patients (24 %) developed BM after CRT; 5 of them (17 %) developed BMs after PCI. Ten patients (33 %) show BM after complete, 5 (17 %) after partial and 15 (50 %) after non-response of primary tumor (p < 0.0001) to applied CRT. BM-free survival time for the entire cohort was 298 days (95 CI: 218-377): 567 days (95 CI: 322-811) in complete, 298 days (95 CI: 244-351) in partial and 252 days (95 CI: 217-286) in non-responders (p < 0.0001). PCI prolonged BM-free survival time in complete responders: 640 days (95 CI: 483-796) with PCI versus 482 days (95CI: 111-926) without PCI (p = 0.047) versus 273 days (95 CI: 243-302) for partial and non-responders. The duration of BM-free survival was shown to correlate with long-term outcome in the Pearson and Spearman's tests (p < 0.0001). The response of primary tumor to CRT strongly affects duration of BM-free survival in LD SCLC and should be considered by planning of the timing of PCI.

Timing of failure in limited disease (stage I-III) small-cell lung cancer patients treated with chemoradiotherapy: a retrospective analysis.

AIMS AND BACKGROUND: Follow-up in limited disease (stage I-III) small cell lung cancer could be further optimized by assessment of the temporal and locational distribution of treatment failure after completion of chemoradiotherapy. METHODS AND STUDY DESIGN: Follow-up was retrospectively analyzed in 125 limited disease (stage I-III) small cell lung cancer patients with initial performance status WHO <3 who had successfully completed chemoradiotherapy. Thoracic irradiation was applied in the concurrent or sequential mode. Time from initial pathological diagnosis and treatment end to local, distant and brain recurrence was documented. RESULTS: One- and two-year progression-free survival rates were 50% and 27.2% in patients treated with concurrent and 45.2% and 14.2% in those treated with sequential chemoradiotherapy, respectively. Local relapse was documented in 14% patients treated with concurrent and 16% with sequential chemoradiotherapy. The distant failure rate was 43% in both subgroups. Up to the end of the follow-up period, more patients treated with concurrent chemoradiotherapy had developed brain metastases than those treated sequentially (37% vs 20%, P = 0.049). Median time (in days) to local relapse was 376 and 401 from the initial diagnosis, 200 and 309 from the end of chemotherapy, and 316 and 196 from the end of thoracic irradiation; to distant failure was 275 and 298 from the initial diagnosis, 151 and 157 from the end of chemotherapy and 180 and 84 from the end of thoracic irradiation; to brain relapse was 330 and 273 from the initial diagnosis, 123 and 151 from the end of chemotherapy and 213 and 73 from the end of thoracic irradiation in patients treated with concurrent and sequential chemoradiotherapy, respectively. There was no significant difference in the temporal distribution of treatment failure in either subgroup. CONCLUSIONS: In more than half of the patients who developed a distant recurrence, including brain metastases, treatment failure occurred in the first year after the initial diagnosis. Intensified follow-up can be recommended at least in the first year, because no sufficient eradication of the systemic small cell lung cancer with the applied chemoradiotherapy protocol could be achieved.

Incidence, therapy and prognosis of colorectal cancer in different age groups. A population-based cohort study of the Rostock Cancer Registry.

PURPOSE: Determination of frequency, treatment modalities used and prognoses of colorectal cancer in a population-specific analysis in relation to age. MATERIAL AND METHODS: In 1999 and 2000, 644/6,016 patients were documented as having colorectal carcinomas in the Cancer Registry of Rostock. 39 patients were excluded (16 cases: "in situ" carcinomas; 23 cases: insufficient data). Three age groups were formed: < 60 years, 60-74 years; > or = 75 years. RESULTS: The relative percentage of colorectal cancer increases with advanced age (< 60 years 7%; 60-74 years 12%, > or = 75 years 15%; p < 0.001). In older patients with stage III carcinomas, adjuvant treatment was done less frequently in accordance with the treatment recommendations (< 60 years 83-89%; 60-74 years 67-77%; > or = 75 years 29-36% according to stage and tumor localization); in stage IV, the use of chemotherapy was reduced (< 60 years 87.5-100%; 60-74 years 38-47%; > or = 75 years 33-37%). In the univariate analysis, age > or = 75 years (4-year survival rates: < 60 years 68 +/- 4.1%; 60-74 years 58 +/- 2.8%; > or = 75 years 38 +/- 3.7%), UICC stage and surgical treatment had a significant effect on prognosis. Adjuvant treatment had no significant effect on the whole population but on patients with UICC stage III and IV. In the multivariate analysis, however, the only independent prognostic parameters were age > or = 75 years (p = 0.001), performance of chemotherapy (colon cancer) or radiochemotherapy (rectal cancer; p = 0.004-0.001), and tumor stage (p = 0.045-0.001). Sex (p = 0.063) and age between 60 and 74 years (p = 0.067) had a borderline influence. CONCLUSION: With increasing age, there is a departure in daily practice from the treatment recommendations. The patient's prognosis is dependent upon age (especially > or = 75 years), tumor stage, and therapy.