Hereditary Cancer in Clinical Practice最新文献

Multiple polyposis syndromes include Familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), Juvenile polyposis syndrome (JPS), PTEN hamartoma tumor syndrome (PHTS), MUTYH-associated polyposis (MAP), NTHL1-associated polyposis (NAP), Polymerase proofreading-associated polyposis (PPAP), and MBD4-associated polyposis. Common to these syndromes is the presence of polyps in the large intestine and very high risk of developing colorectal cancer (CRC), which can reach up to 100% in the case of FAP. The development of FAP is associated with pathogenic variants of the APC gene. However, pathogenic variants are not always detected in patients with FAP, which poses a significant clinical challenge for both patients and their families, who may be at increased risk for developing the disease. A second strong predisposition to CRC is MAP, characterized by biallelic pathogenic variants in the MUTYH gene, with a phenotype similar to FAP. This mini review focuses on potential approaches to improve the diagnosis of patients in whom pathogenic variants in the APC and MUTYH genes are not detected by routine testing.

Background: Lynch syndrome is due to error in DNA mismatch repair (MMR) genes caused by germline pathogenic variants. For some families highly suspicious of Lynch syndrome, the diagnosis may not be confirmed.

Case presentation: We present a family where Lynch syndrome has been suspected for 20 years. Although haplotyping and tumor analyses suggested Lynch syndrome, newer sequencing methods such as whole-genome sequencing and long-read sequencing, were needed to detect the underlying genetic cause of their cancer predisposition. We identified a > 3kbp retrotransposon (RT) insertion in MSH6 to be the causative germline variant. Further, we reviewed the literature for RT events in Lynch syndrome families and found a total of 40 RT cases, making up about 0.5% of Lynch cases. Two-third of the RTs were shorter ALU-elements (< 500 bp).

Conclusions: Although RTs insertions do not seem to be a common cause of Lynch syndrome, the number might be underestimated because of the difficulties in detecting these variants with well-established methods like Sanger sequencing and NGS target sequencing.

Background: Hereditary colorectal cancer (CRC) predisposition syndromes account for 5-10% of all diagnosed CRC cases. Lynch syndrome (LS), Familial Adenomatous Polyposis (FAP), and MUTYH-associated polyposis (MAP) are well-characterized hereditary syndromes known to contribute to colorectal cancer predisposition. However, other inherited genetic factors beyond these established conditions remain underexplored. Recent advancements in next-generation sequencing (NGS) have facilitated the identification of germline pathogenic variants (gPV) in cancer predisposition genes, enhancing diagnostic and management strategies for hereditary CRC syndromes. Using this technology, this study aimed to investigate the genetic causes of CRC in 23 Turkish patients belonging to 23 different families.

Methods: Patients with a personal or familial history of colorectal cancer (CRC) or polyposis were selected from a cohort of 54 individuals examined between 2019 and 2022. Genetic testing was performed using the TruSight^® Cancer and Qiaseq panels on the Illumina NextSeq next-generation sequencing (NGS) platform.

Results: A total of 23 variants were identified, including 10 pathogenic or likely pathogenic variants, 5 of which were novel. These germline pathogenic/likely pathogenic variants were detected in the key genes MLH1, MSH6, PMS2, and APC, which are associated with LS and FAP. Variants were also found in other genes, including FANCC, CHEK2, ATM, and MUC16. Additionally, 13 variants of uncertain significance (VUS) were identified, 5 of which were novel. These VUS were detected in the genes MUTYH (linked to MAP), ATR, XRCC3, PALB2, ATM, SYNE1, RAD51D, NF1, ABRAXAS1, ERBB2, FGFR, and CHEK2, necessitating further investigation to determine their potential role in CRC predisposition.

Conclusion: These findings highlight the utility of NGS in identifying germline variants linked to hereditary CRC syndromes and emphasize the need for functional studies to assess the pathogenicity of VUS.

Medullary breast cancer is a rare subtype of invasive breast cancer, representing from 0.2% to 6% of all breast carcinomas, with a higher proportion among women with triple-negative breast cancer and among those with a BRCA1 mutation. This review article aims to investigate the frequency of medullary breast cancer among all breast cancers and to assess its association with BRCA1 mutations. We surveyed studies involving patients diagnosed with breast cancer that report both the histology of the breast cancer as well as the presence of BRCA1 mutations. Among women with medullary breast cancer, the proportion of cases that carry a BRCA1 mutation ranges from 3% up to 35.3%, depending on the study. Among BRCA1-mutated breast cancers, the proportion that are medullary ranges from 8 to 20%. Given the notable association between medullary breast cancer and BRCA1 mutations, we propose to consider medullary breast cancer as a criterion for genetic testing in order to improve the identification of a larger number of carriers, thereby enhancing screening and prevention strategies.

Background: Cancer-related worry can significantly impact psychosocial wellbeing and decision-making, especially among individuals with hereditary cancer risk. Although the Cancer Worry Scale is a commonly used instrument, no culturally adapted version exists for German speaking populations. This study aimed to translate, culturally adapt and pilot-test a German version of the 8-item Cancer Worry Scale in individuals carrying BRCA1 or BRCA2 pathogenic variants in Austria.

Methods: The scale was translated using a forward and backward translation process, and reviewed by an expert panel. Participants were recruited from a familial cancer clinic and completed the translated scale along with demographic questions. Participants provided feedback on item clarity and comprehension, which informed minor revisions. The final version was then pilot-tested with a small sample of BRCA1/2 carriers.

Results: Thirty-five individuals with BRCA1/2 pathogenic variants completed the scale. Most participants found the scale understandable, though eight reported difficulties with certain items. Based on this feedback, four items were revised to improve clarity. Descriptive analysis indicated similar worry patterns to those observed in international studies. Women who had not undergone risk-reducing surgery reported higher cancer worry, while male participants expressed elevated concern primarily for the health of their family members.

Conclusion: This pilot study presents the first pilot-tested German version of the 8-item Cancer Worry Scale. While initial results support its feasibility and comprehension, further research is needed to validate the psychometric properties of the instrument in larger German-speaking populations.

Background: The role of genetics in breast cancer management is becoming increasingly essential in sub-Saharan Africa (SSA). Harmonized Guidelines by the National Comprehensive Cancer Network (NCCN) for SSA outline the subset of patients requiring genetic testing for hereditary breast cancer as part of their treatment plan. However, in low-and middle-income countries (LMICs) like Nigeria, access to genetic counselling and testing remains limited. Additionally, the knowledge and acceptability of these available services from the healthcare provider (HCP) perspective are largely unknown. This study aimed to assess the knowledge and perceptions of hereditary breast cancer testing among HCPs in Nigeria.

Methods: In June 2022, we conducted a survey among 549 Nigerian HCPs. The 35-item survey was administered using Google Forms and distributed via WhatsApp. The survey collected demographic data and included three sections on genetic testing in breast cancer patients, focusing on knowledge, perceptions, and training.

Results: The results were analyzed using R Version 4.4.1 (R Core Team). Altogether 121 HCPs responded (22% response rate): 54 (44.6%) general surgeons, 4 (3.3%) breast surgical oncologists, 29 (24.0%) clinical and radiation oncologists, 31(25.6%) oncology nurses, and 3 (2.5%) breast radiologists. The survey results indicate that Nigerian HCPs were knowledgeable about hereditary breast cancer genetics, but the implementation of counselling and testing was low. Only 32.2% of respondents had requested genetic testing for their patients, and all testing was done through private laboratories. Only 9.9% had received formal clinical genetics training, and 13.2% reported having a genetic counsellor in their hospital. There was considerable interest in future genetics training programs using in person and online teaching modalities.

Conclusion: This survey highlights the need for specialized breast cancer genetic training tailored for Nigerian HCPs, which is essential in achieving breast cancer treatment parity. Addressing the substantial challenges in expanding genetic testing capacity in Nigeria is warranted for future progress.