https://hdl.handle.net/20.500.14178/904 Sat, 10 Oct 2026 19:53:46 GMT 2026-10-10T19:53:46Z https://hdl.handle.net/20.500.14178/3990 Discordant familial risks between rare cancers Hemminki, Kari Jussi; Zitrický, František; Sundquist, Kristina; Sundquist, Jan; Hemminki, Akseli; Försti, Asta Background: Recent large-scale DNA sequencing data indicate extensive genetic sharing between different types of cancer. Familial clustering of cancers at different sites was also confirmed by earlier population-wide epidemiological data. Cross-cancer familial risks tend to be lower in magnitude compared to cancer-specific risks and their reliable detection requires substantial sample sizes. Methods: In this study we utilize the 2021 update of the Swedish family and cancer data, the largest resource of its kind, to systematically study discordant familial clustering between 22 cancers, excluding the 4 most common cancers of the breast, prostate, lung and colorectum, as these have been covered in earlier publications. Familial risks were estimated as standardized incidence ratio (SIR), comparing the number of cases in a group with specified family history to background population. Separate analyses were conducted for groups with 1 and 2 probands diagnosed with the same cancer, that allowed quantification of familial risks and confirmation of associations in two independent populations. Results: Bidirectional 2-proband associations were observed for melanoma with squamous cell skin cancers and thyroid cancer with endocrine tumors; SIRs were 2.0 and 4.5, respectively. The second group included 7 cancer pairs that were significant in one 2-proband analysis, supported by 1-proband significance; endocrine and kidney cancers were the most common partners in these pairs. The final group of 14 cancer pairs were bidirectionally significant in 1-proband associations. Conclusions: The observed range of risk magnitudes reflected distinct etiological mechanisms spanning from shared environmental exposures to polygenic and possibly syndromic genetic influence, offering guidance to molecular studies. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3990 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3989 Familial histology-specific risks for 22 rare solid cancers in Sweden Hemminki, Kari Jussi; Zitrický, František; Sundquist, Kristina; Sundquist, Jan; Hemminki, Akseli; Försti, Asta Recognition of familial cancer has become increasingly important in oncology as it can help guide treatment and find individuals at risk. However, reliable data on the prevalence and risk of familial cancer are limited to the most common cancers. We use here Swedish population and cancer data resources on 16 million individuals to characterize risks of familial cancer (risk in those with a first-degree family member diagnosed with the same cancer compared to those without an affected relative) up to year 2021. Cancers include 22 solid cancers, excluding breast, prostate, colorectal and lung cancers. Familial risks between two relatives were significantly increased for 20 of 22 cancers, relative risk ranging from 1.56 (cervix and brain cancers) to 4.27 (thyroid cancer) and 5.46 (testis cancer). A total of 16 cancers had three affected family members, resulting in high familial risks, from above 3.0 for bladder, skin, brain and stomach cancers to those of the testis (24.7), gallbladder (31.9), thyroid (56.6), small intestine (67.0) and other nervous system (143). For many cancers, histology-specific cancers showed distinct familial risks, with thyroid cancer as a prime example: common adenocarcinoma, SIR 3.86 and rare medullary cancer, 465. Risks for concordant histology were higher than for discordant histology, suggesting contribution of genetic constitution on histology. The main conclusion is that familial clustering is common also for rare cancers which should alert oncology clinics to request information about affected family members at diagnosis of rare cancers and prepare for mutation analysis when genetic causes are likely. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3989 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3988 Spatial comparison and prognostic significance of macrophages in matched primary colorectal cancer and liver metastases: a retrospective study Ali, Esraa; Ye, Wenjing; Pavlov, Sergii; Červenková, Lenka; Ambrożkiewicz, Filip; Vyčítal, Ondřej; Hošek, Petr; Zitrický, František; Hlaváč, Viktor; Daum, Ondřej; Liška, Václav; Hemminki, Kari Jussi; Trailin, Andriy Analyzing the spatial distribution and prognostic significance of tumor-associated macrophages (TAMs) in primary colorectal cancer (pCRC) and matched liver metastases (LM) may provide insights into the immunological mechanisms behind malignancy and inform therapeutic strategies. Specimens of pCRC and LM were retrospectively collected from patients who underwent curative resection of both tumors, including those with synchronous LM (n = 55) and metachronous LM (n = 44). Immunohistochemical staining was applied and then pan-macrophages (CD68+), M1 (CD80+), and M2 (CD163+ and CD206+) TAMs were quantified across different regions of interest (ROI) within both pCRC and LM. TAM densities and their ratios were assessed in relation to overall survival (OS) in both groups and to time to liver metastasis (TLM) in metachronous group. In both the synchronous and metachronous groups, CD163+ cells showed the highest densities, whereas CD80+ cells were consistently the least abundant across all ROI. Outer margin (OM) and peritumoral zone (PT) of LM exhibited higher CD163+ and lower CD80+ cell densities compared with the corresponding regions in pCRC (all P < 0.05). CD163+ TAMs also displayed higher densities than CD206+ TAMs across all ROI in both groups (all P < 0.001). In the metachronous group, high CD80+ density in the OM of pCRC correlated with longer OS but shorter TLM. In the synchronous group, a high CD80/CD206 ratio in the PT of pCRC was associated with shorter OS, whereas a high CD80/CD163 ratio in the corresponding region of LM predicted improved survival. Our findings demonstrate a strong polarization of TAMs toward the M2 phenotype across both synchronous and metachronous groups and in both pCRC and LM, with this shift being more pronounced in LM. High densities of CD80+ M1 macrophages in OM of pCRC of the metachronous group were associated with longer OS but shorter TLM, indicating their dual prognostic role. The results related to M1/M2 ratios further emphasize that the prognostic relevance of TAMs depends critically on the balance between macrophage subsets. Importantly, this balance varies according to whether M2 macrophages are defined by CD163 or CD206 expression and whether macrophages are assessed in the primary tumor or within the metastatic liver microenvironment. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3988 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3982 Spatial Profiling and Prognostic Role of CD169+ Macrophages in Colorectal Cancer From Adjacent Nontumor Mucosa to Liver Metastasis Ye, Wenjing; Pavlov, Sergii; Ali, Esraa; Ambrożkiewicz, Filip; Červenková, Lenka; Vyčítal, Ondřej; Hošek, Petr; Daum, Ondřej; Liška, Václav; Hemminki, Kari Jussi; Trailin, Andriy BACKGROUND: CD169+ cells represent a distinct subset of macrophages with potential immunomodulatory roles, but their function in colorectal cancer (CRC) progression remains unclear. This study focuses on the spatial profiling and prognostic significance of CD169+ macrophages in adjacent nontumor mucosa (NM), primary CRC (pCRC), and synchronous or metachronous liver metastases (LM). MATERIALS AND METHODS: We enrolled into this retrospective cohort study patients who underwent resection of both pCRC with adjacent NM and synchronous LM (N = 55) or metachronous LM (N = 44). We applied immunohistochemical staining and computer-assisted image analysis to quantify CD169+ cell density in the NM, pCRC, synchronous, and metachronous LM. Correlations between CD169+ macrophages and T cells were evaluated. Associations between CD169+ cell density and overall survival (OS) of the patients were assessed. RESULTS: CD169+ cell density was greater in NM than in the tumor center (TC) of pCRC and in the peritumor (PT) region of LM compared to pCRC. The synchronous group exhibited a higher density of CD169+ cells than the metachronous group in the inner margin (IM) of pCRC, the TC, and the outer margin (OM) of LM. CD169+ cells were more abundant in the exterior than in the interior tumor areas in both pCRC and LM. Positive correlations were observed between densities of CD169+ macrophages with CD3+ and CD8+ lymphocytes. In the synchronous group, a high density of CD169+ macrophages in the TC of pCRC was associated with longer OS, whereas a high density in the PT of LM was associated with shorter OS. High density of CD169+ macrophages in the OM of metachronous LM was associated with poor survival. CONCLUSION: Our study highlights context-dependent prognostic associations of CD169+ macrophages in CRC. While high CD169+ macrophage density in the TC of pCRC was linked to favorable survival in the synchronous group, increased density in both synchronous and metachronous LM was associated with adverse outcomes. Further prospective studies and functional investigations are needed to validate these observations. Thu, 01 Jan 2026 00:00:00 GMT https://hdl.handle.net/20.500.14178/3982 2026-01-01T00:00:00Z