Hereditary Cancer in Clinical Practice最新文献

Background: Aim of the study is to evaluate the role of ultrasound guided fine needle aspiration cytology (FNAC) in the restaging of node positive breast cancer after preoperative systemic therapy (PST).

Methods: From January 2016 - October 2020 106 node positive stage IIA-IIIC breast cancer cases undergoing PST were included in the study. 18 (17 %) were carriers of pathogenic variant in BRCA1/2. After PST restaging of axilla was performed with ultrasound and FNAC of the marked and/or the most suspicious axillary node. In 72/106 cases axilla conserving surgery and in 34/106 cases axillary lymph node dissection (ALND) was performed.

Results: False Positive Rate (FPR) of FNAC after PST in whole cohort and BRCA1/2 positive subgroup is 8 and 0 % and False Negative Rate (FNR) - 43 and 18 % respectively. Overall Sensitivity - 55 %, specificity- 93 %, accuracy 70 %.

Conclusion: FNAC after PST has low FPR and is useful to predict residual axillary disease and to streamline surgical decision making regarding ALND both in BRCA1/2 positive and negative subgroups. FNR is high in overall cohort and FNAC alone are not able to predict ypCR and omission of further axillary surgery. However, FNAC performance in BRCA1/2 positive subgroup is more promising and further research with larger number of cases is necessary to confirm the results.

Background: Although extended colectomy (EC) was recommended for HNPCC patients, previous studies did not show significantly improved overall survival. Immunohistochemical (IHC) stain of mismatch repair (MMR) gene protein expression is now a feasible and reliable test clinically. Therefore, we tried to investigate whether we could use MMR IHC stain to select operation types in HNPCC patients.

Patients and methods: Between 1995 and 2013, 186 HNPCC patients were collected. Status of MMR protein expression, perioperative clinic-pathological variables and post-operative follow up status were analyzed by multivariate analyses.

Results: Sixty-five percent (121 of 186) patients of these HNPCC patients demonstrated loss of at least one MMR protein. There were several significant differences existing between deficient MMR (dMMR) and proficient MMR (pMMR) subgroups in terms of clinic-pathological characteristics. With the average follow-up duration of 93.9 months, we observed significantly high risk of developing metachronous CRC between SC and EC subgroups (crude rate 8.5% vs. 0%, p = 0.035). However, no significant difference was observed among the presence of extra-colonic tumors (12.4% vs. 5.8%, p = 0.284). The positive and negative prediction rate of metachronous CRC in dMMR subgroup was 12.8 and 87.2% while 1.9 and 98.1% in the pMMR subgroup. Survival outcomes were significantly affected by MMR status and resection types by multivariate analysis. Significantly better OS in dMMR subgroup (HR = 0.479, 95% CI: 0.257-0.894, p = 0.021) comparing with pMMR subgroup was observed. However, significant improved DFS (HR = 0.367, 95% CI: 0.172-.0787, p = 0.010) but not significant for OS (HR = 0.510, 95% CI: 0.219-1.150, p = 0.103) for EC subgroup compared with SC subgroup. Differences existing among different subgroups by combing extent of resection and MMR status. In dMMR subgroup, SC, compared with EC, demonstrated significantly worse DFS by multivariate analyses (HR = 3.526, 95% CI: 1.346-9.236, p = 0.010) but not for OS (HR = 2.387, 95% CI: 0.788-7.229, p = 0.124), however, no significantly differences of OS and DFS in pMMR subgroup between SC and EC were found.

Conclusions: Significantly better overall survival and higher rate of metachronous CRC exist in dMMR subgroup of HNPCC patients comparing with pMMR subgroup. Extended colectomy significantly improved DFS and was thus recommended for dMMR subgroup but not pMMR subgroup of HNPCC patients.

Background: Endometrial cancer is often the sentinel cancer in women with Lynch syndrome, among which endometrioid endometrial cancer is the most common. We found a Korean case of uterine carcinosarcoma associated with Lynch syndrome. And we reviewed 27 Korean women with endometrial cancer associated with Lynch syndrome already released in case report so far.

Case presentation: The proband, a 45-year-old Korean woman received treatment for endometrioid adenocarcinoma. Her older sister and niece were treated for endometrioid adenocarcinoma and carcinosarcoma, respectively. Family history met the Amsterdam II criteria and immunohistochemical analysis revealed a loss of MLH1 and PMS2. They all harbored a previously unreported germline likely pathogenic variant in c.1367delC in MLH1. They underwent staging operations including total hysterectomy, bilateral salpingo-oophorectomy, pelvic/paraaortic lymph node dissection, and washing cytology. All three women were healthy without evidence of relapse for over 4 years.

Conclusion: This report indicates a novel germline c.1367delC variant in MLH1, and presents a Korean case of uterine carcinosarcoma associated with Lynch syndrome. Furthermore, the c.1757_1758insC variant in MLH1 was suggested as a founder mutation in Lynch syndrome in Korean women.

DNA mismatch repair (MMR) genes play an important role in maintaining genome stability. Germline mutations in MMR genes disrupt the mismatch repair function and cause genome instability. Carriers with MMR germline mutations are more likely to have MMR deficiency and microsatellite instability (MSI) than non-carriers and are prone to develop colorectal cancer (CRC) and extracolorectal malignancies, known as Lynch syndrome (LS). MMR gene testing for suspected mutation carriers is a reliable method to identify the mutation types and to discover mutation carriers. Given that carriers of MMR germline mutations have a higher risk of LS-related cancers (LS-RC) and a younger age at onset than non-carriers, early surveillance and regular screening of relevant organs of carriers are very important for early detection of related cancers. This review mainly focuses on the general status of MMR carriers, the approaches for early detection and screening, and the surveillance of MMR mutation carriers in China. Population screening of MMR germline mutation carriers in China will be helpful for early detection, early diagnosis and treatment of MMR mutation carriers, which may improve the 5-year survival, and reduce mortality and incidence rate in the long term.

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant condition that predisposes patients to colorectal cancer. FAP is the result of a loss of APC function due to germline pathogenic variants disrupting gene expression. Genotype-phenotype correlations are described for FAP. For example attenuated forms of the disease are associated with pathogenic variants at the 5' and 3' ends of APC whilst severe forms of the disease appear to be linked to variants occurring in the mutation cluster region (MCR) of the gene. Variants occurring in the MCR are phenotypically associated with hundreds to thousands of adenomas carpeting the colon and rectum and patients harbouring changes in this region have a high propensity to develop colorectal cancer. Not all patients who carry pathogenic variants in this region have severe disease which may be a result of environmental factors. Alternatively, phenotypic variation observed in these patients could be due to modifier genes that either promote or inhibit disease expression. Mouse models of FAP have provided several plausible candidate modifier genes, but very few of these have survived scrutiny. One such genetic modifier that appears to be associated with disease expression is CD36. We previously reported a weak association between a polymorphism in CD36 and a later age of disease onset on a relatively small FAP patient cohort.

Methods: In the current study, we enlarged the FAP cohort. 395 patients all carrying pathogenic variants in APC were tested against three CD36 Single Nucleotide Polymorphisms (SNP)s (rs1049673, rs1761667 rs1984112), to determine if any of them were associated with differences in the age of disease expression.

Results: Overall, there appeared to be a statistically significant difference in the age of disease onset between carriers of the variant rs1984112 and wildtype. Furthermore, test equality of survivor functions for each SNP and mutation group suggested an interaction in the Log Rank, Wilcoxon, and Tarone-Ware methods for rs1049673, rs1761667, and rs1984112, thereby supporting the notion that CD36 modifies disease expression.

Conclusions: This study supports and strengthens our previous findings concerning CD36 and an association with disease onset in FAP, AFAP and FAP-MCR affected individuals. Knowledge about the role CD36 in adenoma development may provide greater insight into the development of colorectal cancer.

Background: This nationwide study assessed the impact of nationally agreed cancer genetics guidelines on use of BRCA1/2 germline testing, risk management advice given by health professionals to women with pathogenic BRCA1/2 variants and uptake of such advice by patients.

Methods: Clinic files of 883 women who had initial proband screens for BRCA1/2 pathogenic variants at 12 familial cancer clinics between July 2008-July 2009 (i.e. before guideline release), July 2010-July 2011 and July 2012-July 2013 (both after guideline release) were audited to determine reason given for genetic testing. Separately, the clinic files of 599 female carriers without a personal history of breast/ovarian cancer who underwent BRCA1/2 predictive genetic testing and received their results pre- and post-guideline were audited to ascertain the risk management advice given by health professionals. Carriers included in this audit were invited to participate in a telephone interview to assess uptake of advice, and 329 agreed to participate.

Results: There were no significant changes in the percentages of tested patients meeting at least one published indication for genetic testing - 79, 77 and 78% of files met criteria before guideline, and two-, and four-years post-guideline, respectively (χ = 0.25, p = 0.88). Rates of documentation of post-test risk management advice as per guidelines increased significantly from pre- to post-guideline for 6/9 risk management strategies. The strategies with the highest compliance amongst carriers or awareness post-release of guidelines were annual magnetic resonance imaging plus mammography in women 30-50 years (97%) and annual mammography in women > 50 years (92%). Of women aged over 40 years, 41% had a risk-reducing bilateral mastectomy. Amongst women aged > 40 years, 75% had a risk-reducing salpingo-oophorectomy. Amongst women who had not had a risk-reducing bilateral mastectomy, only 6% took risk-reducing medication. Fear of side-effects was cited as the main reasons for not taking these medicines by 73% of women.

Conclusions: Guidelines did not change the percentages of tested patients meeting genetic testing criteria but improved documentation of risk management advice by health professionals. Effective approaches to enhance compliance with guidelines are needed to improve risk management and quality of care.

Background: We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant. Here, we focused the study on a potentially isolated rectal cancer syndrome in this family.

Methods: We included seven family members (six obligate carriers). Whole-exome sequencing and whole-genome sequencing data were analyzed and filtered for shared coding and splicing sequence and structural variants among the affected individuals.

Results: When considering family members with rectal cancer or advanced adenomas as affected, we found six new potentially cancer-associated variants in the genes CENPB, ZBTB20, CLINK, LRRC26, TRPM1, and NPEPL1. All variants were missense variants and none of the genes have previously been linked to inherited rectal cancer. No structural variant was found.

Conclusion: By massive parallel sequencing in a family suspected of carrying a highly penetrant rectal cancer predisposing genetic variant, we found six genetic missense variants with a potential connection to the rectal cancer in this family. One of them could be a high-risk genetic variant, or one or more of them could be low risk variants. The p.(Glu438Lys) variant in the CENPB gene was found to be of particular interest. The CENPB protein binds DNA and helps form centromeres during mitosis. It is involved in the WNT signaling pathway, which is critical for colorectal cancer development and its role in inherited rectal cancer needs to be further examined.

It's still not clear whether the mutational status of BRCA-mutated healthy hematopoietic stem cells (HSCs) donors could have an impact on the engraftment. Comparing the studies present in literature, we focused on the correlation between BRCA mutations and the development of hematological malignancies and Fanconi anemia (FA); then, we explored HSCs types, frequencies, and functions in the presence of BRCA mutations, as well as the reconstitution of hematopoiesis after chemotherapy and radiation treatments. The role of BRCA mutations in the FA showed a possible involvement in the onset of the disease; the mutation carriers, indeed, did not show any sign of the typical phenotype of the FA. BRCA mutational status can be considered as a risk factor for hematological malignancies, but only for secondary malignancies and/or in the presence of bone marrow stress factors. Currently we don't know if a conditioning regimen could be compensated by BRCA mutated HSCs, even if murine models tried to show the possible differences between fully mutated, haploinsufficient and normal HSCs. Thus, given the downregulating effect of the mutations on hematopoiesis, it could be questionable to use the HSCs of a BRCA-mutated donor in the presence of another available donor with the same compatibility.

Although CDKN2A is well-known as a susceptibility gene for melanoma and pancreatic cancer, germline variants have also been anecdotally associated with a broader range of neoplasms including neural system tumors, head and neck squamous cell carcinomas, breast carcinomas, as well as sarcomas. The CDKN2A gene encodes for two distinct tumor suppressor proteins, p16^INK4A and p14^ARF, however, the independent association of germline alterations affecting these two proteins with cancer is under-appreciated. Here, we reviewed CDKN2A germline alterations reported among individuals and families with cancer in the literature, specifically addressing the cancer phenotypes in relation to the molecular consequence on p16^INK4A and p14^ARF. While melanoma is observed to associate with variants affecting both p16^INK4A and p14^ARF transcripts, it is noted that variants affecting p14^ARF are more frequently observed with a heterogenous range of cancers. Finally, we reflected on the implications of this inferred genotype-phenotype association in clinical practice and proposed that clinical management of CDKN2A germline variant carriers should involve dedicated cancer genetics services, with multidisciplinary input from various healthcare professionals.