Hereditary cancer syndromes.pdf

CLS: Hereditary cancer syndromes (fixed) Thursday, 25 April 2024 2:58 PM Somatic mutation found in tumour itself Affects readability of code; affects function of gene Do not alter function of gene...

CLS: Hereditary cancer syndromes (fixed) Thursday, 25 April 2024 2:58 PM Somatic mutation found in tumour itself Affects readability of code; affects function of gene Do not alter function of gene Predictive testing not offered for class 3 and below SNPS common in many cells; may be associated with small increase in risk in cancer; generally not tested for; in future, polygenic risk assessment incorporating well recognised SNPs may be offered either individually or inc combination with monogenic risk Ax Variants with moderate increase in cancer risk but impact single genes like rad51c and rad51d; still genes tested for in isolation As time goes on, for many moderate risk genes, if look at polygenic risk Ax alongside monogenic variation, polygenic risk Ax may well impact penetrance within individuals; not yet readily available, maybe in near future High penetrance genes impacts function of gene; high risk of cancer during lifetime; e.g. BRAC1 Oncology ^M Pall care Page 1 Oncology ^M Pall care Page 2 Oncology ^M Pall care Page 3 Oncology ^M Pall care Page 4 Oncology ^M Pall care Page 5 Oncology ^M Pall care Page 6 Notes from slides that were broken Unlikely to live until adulthood/reproduce; mutational effect dies out Prevalence of variant 1% of more Varies with age/tumour type HGSOC = high grade serous ovarian cancer Tumour types matter and age matters when predicting likelihood of pathogenic variant DNA repair, or cell differentiation MMR pathway, homologous recombination repair pathway particularly All these genes also associated with ovarian cancer to an extent and to lesser degree prostate and pancreatic CDH1 gastric cancer May have implications regarding other cancers that may need to screen for Breast, prostate, upper GI cancers etc may also be associated with hereditary mutation in one of the MMR genes Risk starts earlier in presence of FHx But also if looking at impact of BRCA2; significantly greater than if no history of breast Ca in family FHx has implications regarding starting cancer risk management for cancers associated with gene 50% chance of inheritance in offspring Important when taking FHx Many manifest when gene passed onto female offspring RAD51c may be carried by dad, but not until variant passed onto daughter where start to see ovarian/breast cancers arising Rare conditions High risk of young onset or paediatric Biallelic change; neurological and intellectual disorder of ataxia telangiectasia; also increased risk of neoplasia; monogenic inheritance of ATM confers moderately increased risk of breast cancer and small risk of other cancer types Proportion of pts affected by pathogenic variant starts to increase This is founder effect Small ancestral population limited in terms of mix of genetic change because of low rate of migration/isolation/sociocultural reasons for non-mixing to allow for increased genetic variation Most commonly here is Ashkenazi Jewish ancestry Increased proportion carrying BRCA 1 or BRCA2 1/40 vs 1/500 As soon as start to see breast/ovarian cancer; likelihood of pathogenic variant seen in family increases Young onset of brain tumours If both parents -ve for pathogenic variant identified in child, siblings not at risk but offspring at risk; 50% for AD inheritance Important to ask about likelihood of non-paternity (reported father not father) Not one paternal aunt and one maternal grandmother with same cancer; talking about same side of family being affected by same type of cancer or combination of cancers like breast and ovarian; >1 ca in one individual like bilateral breast ca or metachronous colorectal ca Greater likelihood of pathogenic variant in triple negative If very young with triple -ve breast ca, BRCA2 and PALB2; if older age then almost equivalence between ER+ and PR+ tumours in these two genes Other genes like ATM and CHEK2 where DCIS just as likely seen as invasive BC CDH1 gene associated with invasive lobular cancer but not invasive ductal cancer Oncology ^M Pall care Page 7 CDH1 gene associated with invasive lobular cancer but not invasive ductal cancer Some genes give clue regarding increased risk for certain histological subtype Associated with genes linked to homologous recombination deficiency like BRCA1/2 and PALB2 Genes in terms of expression of dimerised proteins show absence of expression in protein associated with that gene This shows normal expression in MSH6 and MSH2 but absence of MLH1 and PMS 2; implying that something is affecting MLH1 gene function; so dimerised pair between MLH1 and PMS2 and MSH2/MSH6; if loss of expression of MSH2/6 this would imply functional effect to MSH2 protein production (either pathogenic variant in MSH2 or an EPCAM causing downstream effect in MSH2); if isolated loss in PMS2 or MLSH6 on other hand; isolated loss in PMHS2 implies something affecting function in PMS2; isolated loss in MSH6 indicates something affecting MSH6 functional capacity of gene Co-existent BRAF mutation assessment often used to triage likelihood where have dimerised loss of MLH1/PMS2 or working out whether pt needs to go to family cancer centre for germ line testing If find co-existent mutation in BRAF, can assume the tumour has loss off expression of MLH1 and PMS2 because acquired hypermethylation of MLH1 (rather than somatic tumoural pathogenic variant or germline pathogenic variant) acquired Somatic is non-hereditary DNA mismatch repair (MMR) proteins are essential for the recognition and correction of sporadic genetic mutations that occur during DNA replication. Deficient MMR function (dMMR) leads to an increased risk of development of neoplasia. Also rebate for MMR germ line function if concordant loss of IHC expression of MMR genes If individual with CRC they'll be provided with gene testing for genes associated with increased risk of colonic polyps and CRC Or if breast ca individual, panel of genes associated with increased breast cancer risk offered to individual Particularly breast/ovarian; growing for MMR tumours Higher risk if younger at first cancer Evidence for survival advantage in women