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SF3B1hotspot mutations are associated with a poor prognosis in several tumor types and lead to global disruption of canonical splicing. Through synthetic lethal drug screens, we identify that SF3B1mutant (SF3B1MUT) cells are selectively sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi), independent of hotspot mutation and tumor site. SF3B1MUTcells display a defective response to PARPi-induced replication stress that occurs via downregulation of the cyclin-dependent kinase 2 interacting protein (CINP), leading to increased replication fork origin firing and loss of phosphorylated CHK1 (pCHK1; S317) induction. This results in subsequent failure to resolve DNA replication intermediates and G2/M cell cycle arrest. These defects are rescued through CINP overexpression, or further targeted by a combination of ataxia-telangiectasia mutated and PARP inhibition. In vivo, PARPi produce profound antitumor effects in multiple SF3B1MUTcancer models and eliminate distant metastases. These data provide the rationale for testing the clinical efficacy of PARPi in a biomarker-driven, homologous recombination proficient, patient population.

Collagen plays a key role in normal and malignant tissue homeostasis. While the prognostic significance of collagen fiber remodeling in invasive breast cancer has been studied, its role in ductal carcinoma in situ (DCIS) remains poorly defined. Using image analysis, we aimed to evaluate the prognostic significance of the geometric characteristics of collagen surrounding DCIS. A large well-characterized cohort of DCIS comprising pure DCIS (n= 610) and DCIS coexisting with invasive carcinoma (n= 180) were histochemically stained for collagen using picrosirius red. ImageJ software was used to assess collagen density, degree of collagen fiber dispersion and directionality in relation to DCIS ducts’ boundary. We developed a collagen prognostic index and evaluated its prognostic significance. A poor index was observed in 24% of the pure DCIS and was associated with determinants of high-risk DCIS including higher nuclear grade, comedo type necrosis, hormonal receptor negativity, HER2 positivity and high proliferation index. High collagen prognostic index was associated with the collagen remodeling protein prolyl-4-hydroxlase alpha subunit 2 and the hypoxia-related protein hypoxia inducible factor 1α. DCIS coexisting with invasive breast cancer had a higher collagen prognostic index than pure DCIS ( p< 0.0001). High index was an independent poor prognostic factor for DCIS recurrence for all recurrences (HR = 2.3, p= 0.005) and just invasive recurrences (HR = 3.4, p= 0.003). Interaction between collagen prognostic index and radiotherapy showed that the index was associated with poor outcome even with adjuvant radiotherapy ( p= 0.0001). Collagen reorganization around DCIS is associated with poor outcome and provides a potential predictor for disease progression and resistance to radiotherapy. Mechanistic studies are warranted to decipher the underlying mechanisms.

Collagen plays a key role in normal and malignant tissue homeostasis. While the prognostic significance of collagen fiber remodeling in invasive breast cancer has been studied, its role in ductal carcinoma in situ (DCIS) remains poorly defined. Using image analysis, we aimed to evaluate the prognostic significance of the geometric characteristics of collagen surrounding DCIS. A large well-characterized cohort of DCIS comprising pure DCIS (n= 610) and DCIS coexisting with invasive carcinoma (n= 180) were histochemically stained for collagen using picrosirius red. ImageJ software was used to assess collagen density, degree of collagen fiber dispersion and directionality in relation to DCIS ducts' boundary. We developed a collagen prognostic index and evaluated its prognostic significance. A poor index was observed in 24% of the pure DCIS and was associated with determinants of high-risk DCIS including higher nuclear grade, comedo type necrosis, hormonal receptor negativity, HER2 positivity and high proliferation index. High collagen prognostic index was associated with the collagen remodeling protein prolyl-4-hydroxlase alpha subunit 2 and the hypoxia-related protein hypoxia inducible factor 1α. DCIS coexisting with invasive breast cancer had a higher collagen prognostic index than pure DCIS ( p< 0.0001). High index was an independent poor prognostic factor for DCIS recurrence for all recurrences (HR = 2.3, p= 0.005) and just invasive recurrences (HR = 3.4, p= 0.003). Interaction between collagen prognostic index and radiotherapy showed that the index was associated with poor outcome even with adjuvant radiotherapy ( p= 0.0001). Collagen reorganization around DCIS is associated with poor outcome and provides a potential predictor for disease progression and resistance to radiotherapy. Mechanistic studies are warranted to decipher the underlying mechanisms.

Malignant melanomas have a high metastatic potential. Although the depth of tumour invasion is the single most important histological prognostic factor, in clinical practice this correlation is frequently challenged. In this study, we assessed the cohesion of malignant melanocytes in the dermal component of all primary melanomas in vertical growth phase with tumour thickness >0.76 mm diagnosed in our Department between 1990 and 1995. The rationale behind this morphological evaluation was based on the hypothesis that a change in the adhesion molecule profile of melanoma cells may manifest visually discrete changes in the way that cells group together in dermal aggregates. We used a dyscohesion score based on the proportion of invasive tumour occupied by dyscohesive neoplastic cells and assessed its clinical significance by correlating it with the incidence of recurrence, regional and distant metastases and survival of the patients. Follow-up was up to 12 years. We found that the degree of melanoma cell dyscohesion was associated with the probability of local recurrence or metastasis. This correlation was particularly significant when dyscohesion involving an area smaller than 25% (dyscohesion score 1) of the dermal component was compared to dyscohesion involving a larger area (scores 2–4). Melanomas in the latter group had significantly increased likelihood of recurrence or metastasis (P<0.025, log-rank test). This was particularly the case in T1–T3 melanomas (P<0.005). Similarly, T1–T3 melanomas with dyscohesion score 1 had a significantly higher survival rate (P<0.025). In the same cohort, both disease-free survival and survival were not significantly correlated to thickness, probably due to the limited number of cases. Finally, we showed that extent of dyscohesion was independent of Breslow thickness or tumour regression. We believe that estimation of melanoma cell dyscohesion is a reliable histological prognostic factor that may be appropriate in clinical practice.

Malignant melanomas have a high metastatic potential. Although the depth of tumour invasion is the single most important histological prognostic factor, in clinical practice this correlation is frequently challenged. In this study, we assessed the cohesion of malignant melanocytes in the dermal component of all primary melanomas in vertical growth phase with tumour thickness >0.76 mm diagnosed in our Department between 1990 and 1995. The rationale behind this morphological evaluation was based on the hypothesis that a change in the adhesion molecule profile of melanoma cells may manifest visually discrete changes in the way that cells group together in dermal aggregates. We used a dyscohesion score based on the proportion of invasive tumour occupied by dyscohesive neoplastic cells and assessed its clinical significance by correlating it with the incidence of recurrence, regional and distant metastases and survival of the patients. Follow-up was up to 12 years. We found that the degree of melanoma cell dyscohesion was associated with the probability of local recurrence or metastasis. This correlation was particularly significant when dyscohesion involving an area smaller than 25% (dyscohesion score 1) of the dermal component was compared to dyscohesion involving a larger area (scores 2–4). Melanomas in the latter group had significantly increased likelihood of recurrence or metastasis (P<0.025, log-rank test). This was particularly the case in T1–T3 melanomas (P<0.005). Similarly, T1–T3 melanomas with dyscohesion score 1 had a significantly higher survival rate (P<0.025). In the same cohort, both disease-free survival and survival were not significantly correlated to thickness, probably due to the limited number of cases. Finally, we showed that extent of dyscohesion was independent of Breslow thickness or tumour regression. We believe that estimation of melanoma cell dyscohesion is a reliable histological prognostic factor that may be appropriate in clinical practice.

Three distinct classes of epitopes on human CD164 have been identified. Two of these, recognized by the monoclonal antibodies 105A5 and 103B2/9E10, are the CD164 class I and class II functionally defined epitopes, which cooperate to regulate adhesion and proliferation of CD34+ cell subsets. In this article, we demonstrate that these 2 CD164 epitopes are expressed on CD34+ cells throughout ontogeny, in particular on CD34+ cell clusters associated with the ventral floor of the dorsal aorta in the developing embryo and on CD34+ hematopoietic precursor cells in fetal liver, cord blood, and adult bone marrow. While higher levels of expression of these CD164 epitopes occur on the more primitive AC133hiCD34hiCD38lo/- cell population, they also occur on most cord blood Lin-CD34lo/-CD38lo/- cells, which are potential precursors for the AC133hiCD34hiCD38lo/- subset. In direct contrast to these common patterns of expression on hematopoietic precursor cells, notable differences in expression of the CD164 epitopes were observed in postnatal lymphoid and nonhematopoietic tissues, with the class I and class II CD164 epitopes generally exhibiting differential and often reciprocal cellular distribution patterns. This is particularly striking in the colon, where infiltrating lymphoid cells are CD164 class I–positive but class II–negative, while epithelia are weakly CD164 class II–positive. Similarly, in certain lymphoid tissues, high endothelial venules and basal and subcapsular epithelia are CD164 class II–positive, while lymphoid cells are CD164 class I–positive. It therefore seems highly likely that these CD164 class I and II epitopes will mediate reciprocal homing functions in these tissue types.