Genetics: What do you need to know in practice

53. Slide 4: Hereditary Breast and Ovarian Cancer Approximately 5% of breast cancer and 10% of ovarian cancer results from such genetic mutations passed down from either the father or mother.1 The majority (approximately 84%) of hereditary breast and ovarian cancer results from inherited mutations in two genes called BRCA1 (52%) and BRCA2 (32%). 2,5 Although sometimes referred to as the �breast cancer genes,� BRCA1 and BRCA2 are also associated with the majority of hereditary cancers of the ovary. Although the risk of breast or ovarian cancer may sometimes be increased in other hereditary cancer syndromes, there do not appear to be other genes (such as a so-called "BRCA3") that are responsible for a significant proportion of hereditary breast and ovarian cancer. Recent studies have in fact indicated that �if there are additional genes, they are of minor importance, compared with BRCA1 and BRCA2, in families with breast and ovarian cancer.� 3-5 References: Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-24. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. AJHG 1998;62:676-89. Gayther SA, Russell P, Harrington P et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: No evidence for other ovarian cancer- susceptibility genes. AJHG 1999;65:1021-9. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004 ;4(9):665-76. Frank TS, Deffenbaugh AM, Reid JE et al: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: Analysis of 10,000 individuals. Journal of Clinical Oncology. 2002 20:1480-1490. Slide 4: Hereditary Breast and Ovarian Cancer Approximately 5% of breast cancer and 10% of ovarian cancer results from such genetic mutations passed down from either the father or mother.1 The majority (approximately 84%) of hereditary breast and ovarian cancer results from inherited mutations in two genes called BRCA1 (52%) and BRCA2 (32%). 2,5 Although sometimes referred to as the �breast cancer genes,� BRCA1 and BRCA2 are also associated with the majority of hereditary cancers of the ovary. Although the risk of breast or ovarian cancer may sometimes be increased in other hereditary cancer syndromes, there do not appear to be other genes (such as a so-called "BRCA3") that are responsible for a significant proportion of hereditary breast and ovarian cancer. Recent studies have in fact indicated that �if there are additional genes, they are of minor importance, compared with BRCA1 and BRCA2, in families with breast and ovarian cancer.� 3-5 References: Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-24. Ford D, Easton DF, Stratton M, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. AJHG 1998;62:676-89. Gayther SA, Russell P, Harrington P et al. The contribution of germline BRCA1 and BRCA2 mutations to familial ovarian cancer: No evidence for other ovarian cancer- susceptibility genes. AJHG 1999;65:1021-9. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004 ;4(9):665-76. Frank TS, Deffenbaugh AM, Reid JE et al: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: Analysis of 10,000 individuals. Journal of Clinical Oncology. 2002 20:1480-1490.

54. BRCA1 and BRCA2 are said to produce a truncated protein product leading to a loss of protein function, although some missense mutations cause loss of function without truncation. Essentially when new cells are �made� TS genes work like a' spell check� on your computer locatring and helping to correct mistakes made. So when one of the TS genes is not functioning the person is at increased risk of developing a cancer. BRCA1 and BRCA2 are said to produce a truncated protein product leading to a loss of protein function, although some missense mutations cause loss of function without truncation. Essentially when new cells are �made� TS genes work like a' spell check� on your computer locatring and helping to correct mistakes made. So when one of the TS genes is not functioning the person is at increased risk of developing a cancer.

55. Women who carry a gene mutation/misprint in BRCA1 are at increased risk of developing more then one separate breast cancer as well as ovarian cancerWomen who carry a gene mutation/misprint in BRCA1 are at increased risk of developing more then one separate breast cancer as well as ovarian cancer

56. Women carrying a BRCA2 gene mutation/misprint are again at risk for more then one breast cancer as well as ovarian cancer Men carrying a BRCA2 mutation are at increased risk of breast cancer as well as an increased risk of prostate cancerWomen carrying a BRCA2 gene mutation/misprint are again at risk for more then one breast cancer as well as ovarian cancer Men carrying a BRCA2 mutation are at increased risk of breast cancer as well as an increased risk of prostate cancer

57. Prophylactic bilateral mastectomy May reduce breast CA risk up to 90% Prophylactic bilateral oophorectomy May reduce risk for ovarian CA by 50-90% studies need validation May reduce risk for breast CA by 50% - studies also need validationProphylactic bilateral mastectomy May reduce breast CA risk up to 90% Prophylactic bilateral oophorectomy May reduce risk for ovarian CA by 50-90% studies need validation May reduce risk for breast CA by 50% - studies also need validation

71. ~75% of cases of CRC are sporadic only 7% of sporadic cases occur <55 ~15-20% are �familial� / multifactorial � genetic testing not generally available for low penetrance genes associated with increased risk of CRC ~5-8% are hereditary (defined cancer susceptibility syndromes caused by single genes) Feuer EJ: DEVCAN: National CA Inst. 1999 ~75% of cases of CRC are sporadic only 7% of sporadic cases occur <55 ~15-20% are �familial� / multifactorial � genetic testing not generally available for low penetrance genes associated with increased risk of CRC ~5-8% are hereditary (defined cancer susceptibility syndromes caused by single genes) Feuer EJ: DEVCAN: National CA Inst. 1999

72. Typical age of onset is 40-50, range from 14-82 yrs Preponderance of right-sided/proximal tumors � 60% Polyps may be present (usually few to < 100), multiple primaries common. Can overlap AFAP so consider this diagnosis if >20 colon polyps detected. Typical age of onset is 40-50, range from 14-82 yrs Preponderance of right-sided/proximal tumors � 60% Polyps may be present (usually few to < 100), multiple primaries common. Can overlap AFAP so consider this diagnosis if >20 colon polyps detected.

73. Cancer Risk with HNPCC: CRC - 80% lifetime, 40% for 2nd primary Cancer Risk with HNPCC: CRC - 80% lifetime, 40% for 2nd primary

74. Autosomal dominant condition caused by mutations in one of a number of mismatch repair genes MSH2, MLH1, MSH6, PMS1, or PMS2, others Sequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCC Microsatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCC Genetic testing should be done on an affected family member, only after genetic counseling and informed decision-making Autosomal dominant condition caused by mutations in one of a number of mismatch repair genes MSH2, MLH1, MSH6, PMS1, or PMS2, others Sequencing of the MSH2 and MLH1 genes can identify up to 60-70% of HNPCC Microsatellite Instability (MSI) and Immunohistochemistry (IHC) testing on tumor tissue can be used to screen for possible HNPCC Genetic testing should be done on an affected family member, only after genetic counseling and informed decision-making

76. Test Method Mutations Detected Mutation Detection Rate �1 Test Availability Sequence�analysisAPC sequence�alterationUp to 90%Clinical  Mutation�scanning ~80-90% Protein�truncation�testing (PTT) Premature truncation of APC protein ~80% Duplication/deletion analysis Duplication/deletion of one or more exons ~8-12% �2Test Method Mutations Detected Mutation Detection Rate �1 Test Availability Sequence�analysisAPC sequence�alterationUp to 90%Clinical Mutation�scanning ~80-90% Protein�truncation�testing (PTT) Premature truncation of APC protein ~80% Duplication/deletion analysis Duplication/deletion of one or more exons ~8-12% �2

78. MSI-H tumor, Signet ring type differentiation, Crohn�s-like lymphocytic reaction, Medullary growth pattern MSI-H tumor, Signet ring type differentiation, Crohn�s-like lymphocytic reaction, Medullary growth pattern