Hiroki Inui

Cancer and neurologic degeneration in xeroderma pigmentosum: long term follow-up characterises the role of DNA repair

Background The frequency of cancer, neurologic degeneration and mortality in xeroderma pigmentosum (XP) patients with defective DNA repair was determined in a four decade natural history study. Methods All 106 XP patients admitted to the National Institutes of Health from 1971 to 2009 were evaluated from clinical records and follow-up. Results In the 65 per cent (n=69) of patients with skin cancer, non-melanoma skin cancer (NMSC) was increased 10 000-fold and melanoma was increased 2000-fold in patients under age 20. The 9 year median age at diagnosis of first non-melanoma skin cancer (NMSC) (n=64) was significantly younger than the 22 year median age at diagnosis of first melanoma (n=38)—a relative age reversal from the general population suggesting different mechanisms of carcinogenesis between NMSC and melanoma. XP patients with pronounced burning on minimal sun exposure (n=65) were less likely to develop skin cancer than those who did not. This may be related to the extreme sun protection they receive from an earlier age, decreasing their total ultraviolet exposure. Progressive neurologic degeneration was present in 24% (n=25) with 16/25 in complementation group XP-D. The most common causes of death were skin cancer (34%, n=10), neurologic degeneration (31%, n=9), and internal cancer (17%, n=5). The median age at death (29 years) in XP patients with neurodegeneration was significantly younger than those XP patients without neurodegeneration (37 years) (p=0.02). Conclusion This 39 year follow-up study of XP patients indicates a major role of DNA repair genes in the aetiology of skin cancer and neurologic degeneration.

Mutations of a novel human RAD54 homologue, RAD54B , in primary cancer

Association of breast tumor susceptibility gene products BRCA1 and BRCA2 with the RAD51 recombination protein suggested that cancer could arise through defects in recombination. The identification of NBS1, responsible for Nijmegen breakage syndrome, from the MRE11/RAD50 recombination protein complex also supports this hypothesis. However, our mutation analysis revealed that known members of the RAD52 epistasis group are rarely mutated in human primary cancer. Here we describe the isolation of a novel member of the SNF2 superfamily, characterized with sequence motifs similar to those in DNA and RNA helicases. The gene, designated RAD54B, is significantly homologous to the RAD54 recombination gene. The expression of RAD54B was high in testis and spleen, which are active in meiotic and mitotic recombination. These findings suggest that RAD54B may play an active role in recombination processes in concert with other members of the RAD52 epistasis group. RAD54B maps to human chromosome 8q21.3-q22 in a region associated with cancer-related chromosomal abnormalities. Homozygous mutations at highly conserved positions of RAD54B were observed in human primary lymphoma and colon cancer. These findings suggest that some cancers arise through alterations of the RAD54B function.

Health-related quality of life in breast cancer: A cross-cultural survey of German, Japanese, and South Korean patients

PurposeThe aim of this study was to evaluate health-related quality of life (HRQOL) in breast cancer patients across countries, and to cross-culturally examine the impact of psychosocial factors on HRQOL.Patients and methodsA total of 413 women with breast cancer from Germany (n=195), Japan (n=112), and Korea (n=106) completed a survey assessing HRQOL and HRQOL-related factors. HRQOL was measured using the Short-Form Health Survey (SF-8). Measures of psychological distress (Hospital Anxiety and Depression Scale and Impact of Event Scale-Revised), coping (Dealing with Illness Inventory-German Revised), and social support (Illness-Specific Social Support Scale-German Revised) were included.ResultsThe effect of the factor country on physical QOL was seen to be significant, but small (P=0.049, ES=0.018). The scales of General Health (P=0.023), Vitality (P=0.004), and Role Emotional (P=0.003) differed across countries, with the South Korean patients having lower scores compared to the German and Japanese patients. The nature of the impact of psychosocial factors on HRQOL did not differ greatly across countries except with regard to avoidance, however, the degree to which these factors influence HRQOL did differ greatly. Overall, depression, depressive coping, and problematic support showed a strong detrimental effect on the HRQOL of breast cancer patients.ConclusionsResults from this study suggest that strategies which target an improvement of HRQOL in cancer patients should also consider the patients’ cultural and healthcare system contexts. Interventions are needed to improve detrimental psychosocial factors.

Mutations in the RAD54 recombination gene in primary cancers

Association of a recombinational repair protein RAD51 with tumor suppressors BRCA1 and BRCA2 suggests that defects in homologous recombination are responsible for tumor formation. Also recent findings that a protein associated with the MRE11/RAD50 repair complex is mutated in Nijmegen breakage syndrome characterized by increased cancer incidence and ionizing radiation sensitivity strongly support this idea. However, the direct roles of BRCA proteins and the protein responsible for NBS in recombinational repair are not clear though they are associated with the recombinational repair complexes. Since RAD51 forms a complex with other members of the RAD52 epistasis group and with BRCA proteins, it is reasonable to ask if alterations of members of the RAD52 epistasis group lead to tumor development. Here we describe missense mutations at functional regions of RAD54 and the absence of the wild-type RAD54 expression resulting from aberrant splicing in primary cancers. Since RAD54 is a recombinational protein associated with RAD51, this is the first genetic evidence that cancer arises from a defect in repair processes involving homologous recombination.

Infrequent mutations in the PTEN/MMAC1 gene among primary breast cancers

Recently PTEN/MMAC1, a candidate tumor suppressor gene, was isolated from chromosome 10q23‐24 and somatic mutations of this gene were detected in several malignancies including brain, prostate, and breast tumors. To investigate further the potential role of this gene in mammary carcinogenesis, we examined 69 primary breast cancers for mutations in PTEN/MMAC1 by means of polymerase chain reaction single‐strand conformation polymorphism and sequencing analysis. We detected only one somatic missense mutation, a change from T to C at codon 59 (TCA to CCA) resulting in substitution of Pro for Ser in the predicted protein. This site is located outside of phosphatase or phosphate‐acceptor motifs, but this codon encodes a residue that is conserved in homologous proteins, tensin and auxilin and is likely to be crucial for normal function of PTEN/MMAC1. Among the 69 tumors examined, three low‐frequency polymorphisms were found as well, one in the non‐coding region of exon 1 and one each in introns 2 and 7. Our results suggested that mutation of the PTEN/MMAC1 gene is not a major factor in the development of most primary breast cancers.

Quantitative analysis of the reconstructed breast using a 3-dimensional laser light scanner.

Postoperative cosmesis of the reconstructed breast depends on the interrelation of shape, size (volume), and symmetry. In this study, reconstructed breasts were analyzed with 3-dimensional projections generated by laser light scanning. Fifty-one cases of breast reconstruction following mastectomy (16 cases of rectus abdominis flap, 15 cases of latissimus dorsi flap, and 20 cases of tissue expansion) were evaluated 6 months postoperatively. Shape, volume, and symmetry were quantitatively evaluated. Captured images of the normal breast were mirror-reversed and superimposed on images of the reconstructed breast. Differences in the generated Moire patterns were used to quantitatively compare breasts. The method was rapid, reproducible, and accurate in comparison to thermoplaster casts. It was found that rectus abdominis flaps applied following total mastectomy and latissimus dorsi flaps applied following partial mastectomy gave the best results for their relatively low degree of asymmetry. Application of tissue expansion led to greater asymmetry and poorer overall cosmesis. In conclusion, a 3-dimensional laser light scanning system makes it possible to quantitate the cosmetic outcome following breast reconstruction.

Discrimination between worry and anxiety among cancer patients: development of a Brief Cancer-Related Worry Inventory.

Objectives: A psychometric scale for assessing cancer‐related worry among cancer patients, called the Brief Cancer‐Related Worry Inventory (BCWI), was developed.

Immunohistochemical Analysis of p53 and ras p21 Expression in Colorectal Adenomas and Early Carcinomas

To further investigate whether multiple genetic changes are involved in the development of colorectal cancer, we performed an immunohistochemical analysis of p53 and ras p21 protein expression in 139 specimens of colorectal adenoma with varying degrees of dysplasia, 57 specimens of early cancer with an adenomatous component, and 12 specimens of superficial early cancer without any adenomatous component. Positive p53 staining was found in 15% of the adenomas with moderate dysplasia and in 42% of the adenomas with severe dysplasia or intramucosal carcinoma (IMCA). Positive immunostaining of p53 was observed to be significantly correlated with the degree of dysplasia and the depth of invasion, as was the expression of ras p21. However, a closer correlation was observed with the increasing size of the adenomas. Furthermore, p53 staining was positive in 42% of the 12 superficial early cancer specimens, while ras staining was positive in only 1 specimen (8%). These results indicate that p53 gene overexpression may play some biological role in both the adenoma-to-carcinoma sequence and in de novo cancer development, whereas ras p21 expression may not be as involved in de novo cancer development as in the malignant conversion of colorectal adenomas.

Genetic alterations on chromosome 17 in human breast cancer: relationships to clinical features and DNA ploidy.

SummaryWe analyzed DNA from 105 primary breast cancers to assess amplification of the ERBB2 gene and loss of heterozygosity (LOH) on chromosome 17 using 4 polymorphic markers, and investigated the relationships of these genetic alterations to clinicopathological characteristics including DNA ploidy. Amplification of the ERBB2 gene was observed in 28% of the tumors. ERBB2 was amplified in tumors of all clinical stages and amplification was significantly linked to lymph node metastasis. LOH atD17S5 was observed in 28 of 57 informative tumors, while 17 of 62 informative tumors showed allelic loss atTP53. Among the 37 tumors informative for both loci, 32% showed LOH at these loci and 49% retained both alleles, indicating that there was a significant relationship between LOH atD17S5 and atTP53. We also examined LOH at theD17S74 andNME1 loci on chromosome 17q. LOH atD17S74 andNME1 was observed in 20% and 22% of the informative tumors, respectively, but there was no significant association between LOH at these loci. Of the 4 loci tested, LOH atTP53, D17S74, andNME1 was associated with clinical stage. Lymph node metastasis was correlated with LOH atNME1. Moreover, allelic loss was more frequent in aneuploid tumors than in diploid tumors. These results suggest that certain combinations of genetic alterations on chromosome 17 may cooperate in the development and/or progression of breast cancer. Furthermore, it seems likely that analysis of these alterations in breast cancer patients may provide useful prognostic information.

Identification of high-risk breast cancer patients from genetic changes of their tumors.

To identify the genetic prognostic markers for breast cancer, we analyzed loss of heterozygosity (LOH) at 11p, 16q, 17p, 17q, and 18q, as well as amplification of theERBB2, INT2, andMYC genes, in 131 patients with breast carcinoma, 49 of whom had lymph node involvement, but none of whom had distant metastases. Among the several chromosome arms tested, LOH at 17q was correlated with lymph node metastasis. Amplification of theERBB2, MYC, andINT2 genes was found more frequently in tumors from patients with lymph node metastases than in tumors from those without lymph node metastases. Univariate analysis demonstrated that LOH at 17q andINT2 amplification were factors influencing disease-free survival (DFS). A multivariate analysis was performed on 89 tumors that were able to be evaluated for both LOH at 17q andINT2 amplification, and the results showed that patients who had tumors with these genetic changes were more likely to have a poor prognosis. The findings of this study suggest that investigating genetic changes, in addition to conventional clinicopathologic factors, may contribute to defining groups of breast cancer patients with differences in prognosis.