Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with 328
Background: Ovarian cancer represents the fourth most common cause of mortality among Algerian women. Of all gynecological malignancies, ovarian cancer causes the highest number of deaths in women in Algeria. In the present study, we sought to determine for the first time, clinical, tumor and genetic characteristics associated with ovarian cancer in Algerian women. We also screened for specific mutations in BRCA1 and BRCA2 genes in patients with positive family history of ovarian cancer. Materials and Methods: The study population included 244 patients diagnosed with ovarian cancer. Ovarian carcinomas were diagnosed between 2011 and 2016. Data were collected from cancer registries of public hospitals that covered 10 provinces of Algeria. Patient and tumor information included: age at diagnosis, histological type, histological grade, TNM stage, preoperative tumors markers CEA and CA-125 serum levels, family history with ovarian cancer or any cancer, age at menarche, oral contraception and breast feeding. BRCA1 exon 11 and BRCA2 exon 22 were screened by PCR-direct sequencing in 11 patients with a family history of ovarian cancer for two common mutations that were previously found in Algerian population, respectively. Results: The median age at diagnosis cancer was 51.02 years. The mean age at menarche was 13.04 years. We noticed that 43.85 % of women have been diagnosed with ovarian cancer at younger age (< 50 years). The proportion of ovarian cancer patients with premenopausal status was 39.75%. The commonest histological subtypes was serous adenocarcinoma (52.45%) followed by endometrioid (10.65%), mucinous (9.43%) and clear cell carcinoma (4.09%). We found that the proportion of tumors with histological grade II (41.8%) and grade III (27.86%) was commonest in 70% of the patients. Our results showed that 61.46% of the patients were diagnosed at stage II (39.34%), stage III (8.6%) and stage IV (13.52%), respectively. 73.36% and 18.08% of the patients were positive for CA-125 and CEA, respectively. We noticed that 29 patients (11.88%) had a positive family history of ovarian cancer. 141 patients (57.78%) had breastfed and 107 patients (43.85%) were using contraception.The BRCA1 mutation c.2125_2126insA and BRCA2 mutation c.8940delA have not been detected in our patients. Conclusions: For the first time, we report here some clinical, biological, tumor and genetic characteristics of ovarian cancer in Algerian women. Our study showed that ovarian cancer in Algerian women has some similar clinicopathological and biological features with women of European descent. Interestingly, the median age of diagnosis in ovarian cancer patients was younger than average age in Europe and America. High frequency of patients with positive family history of ovarian cancer could be linked to genetic background of Algerian population. Further studies are needed to reaffirm our findings. BRCA1 and BRCA2 analysis are ongoing in our patients. Citation Format: Farid Cherbal, Chiraz Mehemmai, Lamia Boumehdi, Feriel Khider, Amina Boucheffa, Hadjer Gaceb, Hassen Mahfouf, Rabah Bakour. Clinicopathological and genetic study of ovarian cancer in Algerian women: First report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2208.
Background To date, 5% to 6 % of all colorectal cancers (CRCs) are associated with germline pathogenic variants in cancer predisposition genes that confer inherited predisposition to CRC. The use of genetic testing to identify individuals at risk for hereditary CRC syndromes can help to prevent the development of cancer and in the clinical management of the colorectal patients in the areas of both prevention and treatment. We report here the experience of our research laboratory of genetic testing for hereditary polyposis syndromes and Lynch syndrome (LS), respectively, in 126 patients. Methods Fifty four (54) severe familial adenomatous polyposis (FAP) patients and 72-suspected Lynch syndrome (LS) patients, respectively, were selected from 2851 consecutive colorectal patients at five public hospitals during 2012-2019. Family histories of cancer were obtained from interviews, pedigrees and medical records of patients. Index cases and relatives diagnosed with FAP syndrome or Lynch syndrome have been tested for germline variants in APC, MLH1, MSH2, MSH6 and PMS2 genes, respectively, using PCR-Sanger Sequencing or by NGS using a cancer panel of 30 hereditary cancer genes (Color Genomics). Results We detected 13 germline pathogenic variants in APC gene in 17 unrelated families, one germline pathogenic variant in BMPRA1 gene in juvenile polyposis syndrome (JPS) patient; seven (7) germline pathogenic variants and 2 variants of uncertain clinical significance (VUS) in MMR genes. Interestingly, 4 novel germline pathogenic variants in APC gene and 3 novel germline pathogenic variants in MMR genes, respectively, have been detected in our study. The most occurring germline pathogenic variants in APC gene were c.3927_3931del and c.4728dup that were identified in four and two index cases in 6 unrelated FAP families, respectively. In Lynch syndrome patients, the rare germline pathogenic variant MLH1 c.1546C>T has been found in 21 individuals from 9 LS families, 6 of them related, with two large kindreds. In addition, the recurrent germline pathogenic variant MSH2 c.942+3A>T has been detected in five unrelated index cases with a strong family history of LS syndrome. Moreover, the rare germline VUS PMS2 c.989-107_989-106insA has been detected in 14 unrelated LS patients and could be reclassified as likely benign. Interestingly, our NGS analysis detected the novel BMPR1A pathogenic variant c.1474-1G>C in young JPS patient that has been misdiagnosed as FAP. The in-silico analysis for this novel variant showed an alteration of the wild type acceptor site and an activation of a cryptic acceptor site, respectively, most probably affecting splicing. Conclusions Our current study will contribute to the molecular genetics characterization of hereditary colorectal cancer syndromes in Algerian population that is relevant for clinical management in the areas of genetic testing, early diagnosis, treatment and prevention. Citation Format: Farid Cherbal, Asma-Lamia Boumehdi, Feriel Khider, Karima Landelouci, Abdelwahab Zemam, Sarah Sabri, Adam.Walid Damache, Mohammed Oukkal, Hassen Mahfouf, Ferhat Zebboudj, Mustapha Maaoui. Genetic testing for hereditary colorectal cancer syndromes in Algerian patients: A multicenter study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4177.
Background Colorectal carcinoma is the third most common form of cancer worldwide. It is the second most common cancer in men and women in Algeria.The aim of this study was to determine clinicopathological and genetic features of colorectal cancer in Algerian patients. For the genetic study, we focused on the two major forms of hereditary colorectal cancer, Familial Adenomatous Polyposis (FAP) and Lynch Syndrome (LS), respectively. Materials and Methods The study population included 366 patients diagnosed with colorectal cancer (CRC). Colorectal carcinoma was diagnosed between January 2017 to March 2018. Clinical and tumor data: age at diagnosis, site of tumor and TNM stage were collected from the medical records of the patients. We screened by PCR-direct sequencing exon 15 of APC gene in 30 patients with a strong family history of classic FAP. 30 patients with Lynch syndrome who fulfilled Amsterdam criteria were screened by PCR- direct sequencing for germline mutations in the MMR genes: MLH1 (exons 9,10,13,16), MSH2 (exons 5,6,7,12) and MSH6 (exon 4). Two FAP patients and two LS patients were screened by NGS using a cancer panel of 30 hereditary cancer genes (Color Genomics, California, USA). Results In this retrospective study, there were 183 women (50%) and 183 men (50%).The median age at diagnosis cancer was 58 years old. The highest proportions of CRC were observed for the age groups 60-69, 50-59 and 40-49 years, 25.4%, 23.49%, 20.49% respectively. We noticed that colorectal tumors were not uniformly distributed through the large bowel. Rectum was the most common site (26.8%) followed by right colon (20.5%), sigmoid colon (18.9%) left colon (13.7%) and caecum (7.4%). Our results showed that 75.95% of the CRC patients were diagnosed at TNM stage II (9.02%), stage III (48.63%) and stage IV (18.31%), respectively. The analysis of DNA samples of FAP patients revealed that 6 patients carried pathogenic variants in APC gene. 3 distinct pathogenic variants: c.1605dupT ( one patient), c.3784delT (2 related patients), and c.3927_3931delAAAGA (3 unrelated patients) were identified in APC gene. Moreover, three distinct germline mutations: c.55_63delATCGCGGCGinsT in exon 1 of MLH1 (one patient), c.1165C>T in exon 7 of MSH2 ( one patient) and the Newfoundland mutation c.942 +3A>T in exon 5 of MSH2 (3 unrelated patients) were detected in 5 Lynch syndrome families.The APC c.1605dupT and c.3784delT and the MLH1 c.55_63delATCGCGGCGinsT new variants have never been reported in LOVD, UMD and ClinVar databases and could be specific of Algerian FAP patients and Lynch syndrome patients, respectively. Haplotype analysis of the APC c.3927_3931delAAAGA and the c.942+3A>T MSH2 variants will establish their genetic origin in Algeria. Conclusions The accumulative knowledge about clinicopathological and genetic characteristics of colorectal cancer in Algerian patients will impact on clinical management in the areas of both prevention and treatment. Citation Format: Farid Cherbal, Asma Lamia Boumehdi, Feriel Khider, Fatma Narimane Nouredine, Karim Layaida, Hassen Mahfouf, Mustapha Maaoui. Clinicopathological and genetic features of colorectal cancer in Algerian patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 655.
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