Diagnostyka niedoboru alfa-1-antytrypsyny we francuskim szpitalu ogólnym — przypadkowe rozpoznania czy systematyczny skrining?

WSTĘP: Poddano analizie procedurę badania przesiewowego w kierunku niedoboru alfa-1-antytrypsyny (A1AT) w Szpitalu w Nevers (Francja) oraz badań elektroforezy białek surowicy wykonanych w celu wykrycia niedoboru A1AT. MATERIAŁ I METODY: Badanie miało charakter retrospektywny. Przeanalizowano wyniki oznaczenia niedoboru alfa-1-antytrypsyny wykonanych na bezpośrednie zlecenie w okresie 3 lat oraz wyniki badań przesiewowych w kierunku niedoboru A1AT realizowanych zgodnie z międzynarodowymi rekomendacjami. Oceniono również wyniki elektroforezy białek surowicy uzyskane w tym samym okresie. WYNIKI: Na bezpośrednie badanie stężenia alfa-1-antytrypsyny skierowano 102 pacjentów, podczas gdy 1392 pacjentów spełniało wskazania do badania przesiewowego. Nie wykryto żadnego przypadku niedoboru wśród zbadanych 102 pacjentów. W tym czasie w laboratorium wykonano 5551 badań elektroforezy białek surowicy. Obniżenie frakcji alfa-1 globulin stwierdzono u 68 badanych. U 17 pacjentów oznaczono stężenie alfa-1-antytrypsyny i u 14 stwierdzono niedobór. WNIOSKI: Niedobór alfa-1-antytrypsyny częściej wykrywa się przypadkowo w badaniu elektroforezy białek surowicy niż w wyniku badania przesiewowego. Badanie niedoboru alfa-1 globulin za pomocą elektroforezy białek surowicy wydaje się wciąż najbardziej skuteczną metodą detekcji i powinno być wykonywane systematycznie. Co więcej, badaniem tą metodą powinni być objęci wszyscy pacjenci poddani badaniu skriningowemu, realizowanemu zgodnie z międzynarodowymi wytycznymi.WSTĘP: Poddano analizie procedurę badania przesiewowego w kierunku niedoboru alfa-1-antytrypsyny (A1AT) w Szpitalu w Nevers (Francja) oraz badań elektroforezy białek surowicy wykonanych w celu wykrycia niedoboru A1AT. MATERIAŁ I METODY: Badanie miało charakter retrospektywny. Przeanalizowano wyniki oznaczenia niedoboru alfa-1-antytrypsyny wykonanych na bezpośrednie zlecenie w okresie 3 lat oraz wyniki badań przesiewowych w kierunku niedoboru A1AT realizowanych zgodnie z międzynarodowymi rekomendacjami. Oceniono również wyniki elektroforezy białek surowicy uzyskane w tym samym okresie. WYNIKI: Na bezpośrednie badanie stężenia alfa-1-antytrypsyny skierowano 102 pacjentów, podczas gdy 1392 pacjentów spełniało wskazania do badania przesiewowego. Nie wykryto żadnego przypadku niedoboru wśród zbadanych 102 pacjentów. W tym czasie w laboratorium wykonano 5551 badań elektroforezy białek surowicy. Obniżenie frakcji alfa-1 globulin stwierdzono u 68 badanych. U 17 pacjentów oznaczono stężenie alfa-1-antytrypsyny i u 14 stwierdzono niedobór. WNIOSKI: Niedobór alfa-1-antytrypsyny częściej wykrywa się przypadkowo w badaniu elektroforezy białek surowicy niż w wyniku badania przesiewowego. Badanie niedoboru alfa-1 globulin za pomocą elektroforezy białek surowicy wydaje się wciąż najbardziej skuteczną metodą detekcji i powinno być wykonywane systematycznie. Co więcej, badaniem tą metodą powinni być objęci wszyscy pacjenci poddani badaniu skriningowemu, realizowanemu zgodnie z międzynarodowymi wytycznymi

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer

Fundamental optical processes in armchair carbon nanotubes

Single-wall carbon nanotubes provide ideal model one-dimensional (1-D) condensed matter systems in which to address fundamental questions in many-body physics, while, at the same time, they are leading candidates for building blocks in nanoscale optoelectronic circuits. Much attention has been recently paid to their optical properties, arising from 1-D excitons and phonons, which have been revealed via photoluminescence, Raman scattering, and ultrafast optical spectroscopy of semiconducting carbon nanotubes. On the other hand, dynamical properties of metallic nanotubes have been poorly explored, although they are expected to provide a novel setting for the study of electronﾖhole pairs in the presence of degenerate 1-D electrons. In particular, (n,n)-chirality, or armchair, metallic nanotubes are truly gapless with massless carriers, ideally suited for dynamical studies of TomonagaﾖLuttinger liquids. Unfortunately, progress towards such studies has been slowed by the inherent problem of nanotube synthesis whereby both semiconducting and metallic nanotubes are produced. Here, we use post-synthesis separation methods based on density gradient ultracentrifugation and DNA-based ion-exchange chromatography to produce aqueous suspensions strongly enriched in armchair nanotubes. Through resonant Raman spectroscopy of the radial breathing mode phonons, we provide macroscopic and unambiguous evidence that density gradient ultracentrifugation can enrich ensemble samples in armchair nanotubes. Furthermore, using conventional, optical absorption spectroscopy in the nearinfrared and visible range, we show that interband absorption in armchair nanotubes is strongly excitonic. Lastly, by examining the G-band mode in Raman spectra, we determine that observation of the broad, lower frequency (G!) feature is a result of resonance with non-armchair “metallic” nanotubes. These !ndings regarding the fundamental optical absorption and scattering processes in metallic carbon nanotubes lay the foundation for further spectroscopic studies to probe many-body physical phenomena in one dimension

Homologous recombination DNA repair defects in PALB2-associated breast cancers.

Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD.ER

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases

Erratum: Publisher Correction: Homologous recombination DNA repair defects in PALB2-associated breast cancers.

[This corrects the article DOI: 10.1038/s41523-019-0115-9.]

Homologous recombination DNA repair defects in PALB2- associated breast cancers

Abstract: Mono-allelic germline pathogenic variants in the Partner And Localizer of BRCA2 (PALB2) gene predispose to a high-risk of breast cancer development, consistent with the role of PALB2 in homologous recombination (HR) DNA repair. Here, we sought to define the repertoire of somatic genetic alterations in PALB2-associated breast cancers (BCs), and whether PALB2-associated BCs display bi-allelic inactivation of PALB2 and/or genomic features of HR-deficiency (HRD). Twenty-four breast cancer patients with pathogenic PALB2 germline mutations were analyzed by whole-exome sequencing (WES, n = 16) or targeted capture massively parallel sequencing (410 cancer genes, n = 8). Somatic genetic alterations, loss of heterozygosity (LOH) of the PALB2 wild-type allele, large-scale state transitions (LSTs) and mutational signatures were defined. PALB2-associated BCs were found to be heterogeneous at the genetic level, with PIK3CA (29%), PALB2 (21%), TP53 (21%), and NOTCH3 (17%) being the genes most frequently affected by somatic mutations. Bi-allelic PALB2 inactivation was found in 16 of the 24 cases (67%), either through LOH (n = 11) or second somatic mutations (n = 5) of the wild-type allele. High LST scores were found in all 12 PALB2-associated BCs with bi-allelic PALB2 inactivation sequenced by WES, of which eight displayed the HRD-related mutational signature 3. In addition, bi-allelic inactivation of PALB2 was significantly associated with high LST scores. Our findings suggest that the identification of bi-allelic PALB2 inactivation in PALB2-associated BCs is required for the personalization of HR-directed therapies, such as platinum salts and/or PARP inhibitors, as the vast majority of PALB2-associated BCs without PALB2 bi-allelic inactivation lack genomic features of HRD