Genetics and Cancer Sreekala Seepana

Overview Genetics and cancer Breast / Bowel cancers Breast / bowel cancer screening Clinical genetics referral Cases Others

What’s my risk, doc?? People whose relatives have cancer or have died of cancer may be worried that they too could develop cancer Patients who have cancer themselves may be concerned about whether other members of their family might be at risk Patients who are enrolled in programmes for cancer screening may become aware that their family history may predispose them to developing cancer

Genetics and cancer 5-10% of cancers due to genetic factors Cancer genes greatly increase the risk of a person developing cancer Genes that predispose to cancer are not in X or Y chromosome Family history is the most reliable way of assessing the familial risk of developing cancer Refer pts identified at high risk of developing cancer for screening and specialist assessment of family history

Cancer is a disease of the cell cycle

Genetics and Cancer Family history is vital Explore family history of 3 generations Family history should include those affected and those unaffected by cancer Specific type of cancer Age at which cancer developed Clues to familial cancers.....?

Familial cancers Clues: Two or more close relatives with same type of cancer Cancer at early age (usually < 40yrs) Cancer diagnosed more than once in the same person Many cancers in the family, not accounted for just by chance Cancer in a person who also has some birth defects Breast cancer /ovarian cancer Colorectal cancer Renal cell carcinoma (Von Hippel Lindau disease ) Wilms tumour Li Fraumeni syndrome (TP 53) Retinoblastoma, osteosarcoma

Family history of cancer All relatives must be on the same side of the family and blood relatives of the consultee and of each other First degree relatives: mother, father, daughter, son, sister, brother. Second degree relatives: grandparent, grandchild, aunt, uncle, niece, nephew, half sister, and half brother. Third degree relatives: first cousins.

Cancer genes Mutations occur in normal functioning genes Risk of cancer that these genes confer is organ specific People with mutated genes have an increased risk of developing cancer, but some may never develop cancer

Types of genes which may mutate to cause cancer Tumour suppressor genes oncogenes DNA repair genes telomerase Tp 53

Familial breast cancer

Estimated risk of developing breast cancer by age, females, UK, 2001–2005 Cancer Research UK

Risk factors for breast cancer Female sex Increasing age Previous h/o breast ca Benign breast disease Not breast feeding long term Current use of HRT /COCP Nulliparity Late pregnancy Early puberty Late menopause Obesity High alcohol intake Family h/o breast cancer

Important messages to share with women with concerns Most of breast cancers are not familial Increasing age is the greatest risk factor The great majority of women with a family history of breast cancer do not fall into a high risk category and do not develop breast cancer The great majority of women with a relative with breast cancer are not at substantially increased risk of breast cancer themselves NICE 2006

Breast cancer “Why do so many of my relatives have breast cancer...is this just plain bad luck or what?”

Breast cancer

BRCA 1 and 2 BRCA1 on 17(q) BRCA 2 on 13 (q) High penetrance genes, responsible for < 10% of breast cancers Called “breast cancer genes” but increase the risk of breast and ovarian ca. Life time risk of developing breast ca of up to 85% (UK population risk of 11%) and ovarian cancer of up to 60% (UK population risk of <2%)

Familial breast cancer BRCA % - breast cancer 20-30% - ovarian cancer Increased risk of prostate, laryngeal, pancreatic cancers BRCA 2 Causes 40% of familial breast cancers 50-70% - breast cancer 15-45% - ovarian cancer Increased risk of prostate and colon cancers

Rare familial cancer syndromes associated with breast cancer: Cancer Research UK

Which one of the following population groups have the highest incidence of having BRCA 1 & 2 : a.English b.Scottish c.Asian d.Chinese e.Jewish f.Polish

Which one of the following population groups have the highest incidence of having BRCA 1 & 2 : a.English b.Scottish c.Asian d.Chinese e.Jewish f.Polish Women with Jewish ancestry have about 5-10 times more likely to carry BRCA 1 &2 mutations

Relative risk for breast cancer by number of affected first degree female relatives Number of first degree relatives Relative risk for women < 50 years (99% CI) Relative risk for women >= 50 years(CI) (1.92 to 2.38)1.65 (1.53 to 1.78) (2.37 to 6.22)2.61 (2.03 to 3.34) (1.70 to 85.16)2.65 (1.29 to 5.46) Risk of familial breast ca is quantified with respect to the number of affected first degree relatives and by the age of affected first degree relative

Relative risk for breast cancer by age of affected first degree relative Age at time of diagnosis in first degree relatives Relative risk for women < 50 years (99% CI) Relative risk for women >= 50 years (CI) < 40 years13.5 (3.4 to 53.9)3.9 (1.8 to 8.6) >= 40 years7.8 (2.4 to 25.0)2.6 (1.8 to 3.7)

Risk categorization (NICE) Near population risk: –women at or near population risk of developing breast cancer (that is, a 10-year risk of less than 3% between age 40 and 50 years and a lifetime risk of less than 17%) are cared for in primary care Raised risk: –Women at raised risk of developing breast cancer (that is, a risk of 3–-8% between age 40 and 50 years or a lifetime risk of 17% or greater but less than 30%) are generally cared for in secondary care High risk: –Women at high risk of developing breast cancer (that is a risk of greater than 8% between age 40 and 50 years or a lifetime risk of 30% or greater) are cared for in tertiary care. High risk also includes a 20% or greater chance of a faulty BRCA1, BRCA2 or TP53 gene in the family

Referral to secondary care (likely to be at more than raised risk) Female breast cancers only: One 1st degree relative and one 2nd degree relative diagnosed before average age 50 Two 1st degree relatives diagnosed before average age 50 Three or more 1st or 2nd degree relatives diagnosed at any age

Referral to secondary care (likely to be at more than raised risk) Bilateral breast cancer One 1st degree relative where 1st primary diagnosed before age 50 For bilateral breast cancer, each breast has the same count value as one relative Male breast cancer One 1st degree male relative diagnosed at any age

Referral to secondary care (likely to be at more than raised risk) Breast and ovarian cancer One 1st or 2nd degree relative with ovarian cancer at any age and one 1st or 2nd degree relative with breast cancer at any age (one should be a 1st degree relative)

Referral to secondary care Likely to be at raised risk: (Female breast cancers only) One 1st degree relative diagnosed before age 40 One 1st degree relative and one 2nd degree relative diagnosed after average age 50 Two 1st degree relatives diagnosed after average age 50

Surveillance All women aged 40–49 years satisfying referral criteria to secondary or specialist care (at raised risk or greater) should be offered annual mammographic surveillance.

MRI surveillance Women who are known to have a genetic mutation should be offered annual MRI surveillance if they are: – BRCA1 and BRCA2 mutation carriers aged 30–49 years – TP53 mutation carriers aged 20 years or older.

MRI surveillance MRI surveillance should be offered annually when indicated: From 30–39 years: to women at a 10-year risk of greater than 8% From 40–49 years: to women at a 10-year risk of greater than 20%, or to women at a 10-year risk of greater than 12% where mammography has shown a dense breast pattern

Role of prophylactic surgery Prophylactic mastectomy in women at high genetic risk of developing breast cancer reduces the risk of breast cancer by up to 90%

Familial bowel cancers

Percentage distribution of cases by site within the large bowel, England,

Familial bowel cancers Familial adenomatous polyposis (FAP) Heriditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome Rare polyposis - Peutz-Jeghers syndrome and familial juvenile polyposis (autosomal dominant)

Familial adenomatous polyposis Gene for FAP is the APC (adenomatous polyposis coli) tumour suppressor gene on 5q21

Familial adenomatous polyposis Accounts for 1% of colorectal cancers Multiple (often thousands) of adenomas in large bowel Almost 100% risk of developing colorectal cancer by 40yr Prophylactic surgery is offered to affected individuals, usually in their teens.Prophylactic surgery

HNPCC (Lynch syndrome) Accounts for 2-5% of colorectal cancers Caused by fault in a DNA mismatch repair gene (MMR gene) MLH1 and MSH2 genes Characterized by early onset of bowel cancer

HNPCC (Lynch syndrome) Associated with non- colorectal cancers: endometrium, ovaries, stomach, pancreas / liver urinary tract

HNPCC (Lynch syndrome) Genetic testing for predisposing mutations in people with a strong family history of these cancers enables screening and prevention to be targeted to those most at risk. For people with a known mutation, especially young patients from HNPCC families, prophylactic surgery may be recommended

Cancer screening programmes (breast / bowel cancer)

Which of the following patients are offered NHS breast cancer screening: a. Every 2 yrs for women aged 50-70yrs b. Every 2 yrs for women aged 60-70yrs c. Every 3yrs for women aged 60-70yrs d. Every 2.5yrs for women aged 50-70yrs e. Every 3 yrs for women aged 50-70yr

Which of the following patients are offered NHS breast cancer screening: a. Every 2 yrs for women aged 50-70yrs b. Every 2 yrs for women aged 60-70yrs c. Every 3yrs for women aged 60-70yrs d. Every 2.5yrs for women aged 50-70yrs e. Every 3 yrs for women aged 50-70yr

Figure One: Number of new cases and rates for female breast cancer, by age, UK, 2006 Cancer research,UK

Breast cancer screening Aim is to detect early, non-palpable, local disease. Mammographic screening – reduced mortality rate of at least 25% in women over the age of 50. After 10 years, the UK screening programme is expected to produce a reduction of 1250 breast cancer deaths annually, with each woman in whom death from breast cancer is prevented, surviving, on average, an extra 20 years.

Breast cancer screening programme The main elements are: to invite three-yearly, all women in the year age group for single oblique-view mammography in static or mobile units, with the option of self-referral for older women to recall all women with mammographically detected abnormalities for further investigation in specialist assessment units, using clinical examination, special view mammography, ultrasonography, or fine needle aspiration cytology

UK NHS Breast Screening Programme results April 2006 to March 2007 Cancer research UK

NHS breast screening programme Women are invited to a specialised screening unit, which can be hospital based, mobile, or permanently based in another convenient location such as a shopping centre.

NHS breast cancer screening programme in Grimsby is based in : a.X-ray unit in Radiology dept, DPoW b.MRI unit in Radiology dept, DPoW c.CT unit in Radiology dept, DPoW d.Breast clinic, DPoW e.Opposite to Canteen, DPoW f.Car park opposite to library, DPoW

NHS breast cancer screening programme in Grimsby is based in : a.X-ray unit in Radiology dept, DPoW b.MRI unit in Radiology dept, DPoW c.CT unit in Radiology dept, DPoW d.Breast clinic, DPoW e.Opposite to Canteen, DPoW f.Car park opposite to library, DPoW

Who is eligible for NHS bowel cancer screening programme? a.Men and women aged over 50yrs every 2 yrs b.Men and women aged over yrs every 2 yrs c.Men and women aged over 45 yrs every 3 yrs d.Men and women aged yrs every 3yrs

Who is eligible for NHS bowel cancer screening programme? a.Men and women aged over 50yrs every 2 yrs b.Men and women aged over yrs every 2 yrs c.Men and women aged over 45 yrs every 3 yrs d.Men and women aged yrs every 3yrs

NHS bowel screening programme Life time risk of bowel ca in UK - 1 in 20 3 rd most common Ca in UK 2 nd most common cause of cancer death in UK Regular bowel screening reduces risk of dying from bowel ca by 16% Every 2 yrs from yrs > 70 yrs can request by phone

Numbers of new cases and age-specific incidence rates for colorectal cancer, by sex, UK, 2002

NHS bowel screening programme Aims to detect bowel cancer at an early stage (in people with no symptoms), when treatment is more likely to be effective Call and recall system to send out faecal occult blood (FOB) test kits, analyse samples and despatch results GPs are not directly involved in screening Screening centres are responsible to refer those requiring treatment to their local hospital MDT

Clinical Genetics referral

Reasons for clinical genetics referral Affected child/adult for investigation or diagnosis Family history of genetic disorder or condition with genetic component Fetal loss/abnormality Recurrent miscarriages Strong family history of cancer

Clinical Genetics referral Diagnostic testing Predictive testing Information Carrier testing Pre-natal testing

Clinical genetics services Genetic testing Assessment of risk based on family history and clinical features Genetic counselling Provide management options Refer to other specialists as needed Provide information Prognosis and long term outcome

Regional genetics Yorkshire regional genetics services, Leeds Sheffield regional genetics services

Genetics referral Patient information Name and address of the referrer Reason for the referral Information about the suspected diagnosis, if known Family history

Case 1 Mrs. Smith - 32 yr old lady, a busy marketing executive, mother of two girls aged 9 and 11 comes for a review for a repeat prescription for her COCP. She asks you whether she needs to have any form of breast cancer screening as she is on the pill for a long time? Also, She complains of feeling bloated and heavy in her tummy and attributes it to her not exercising due to busy work hrs How do you proceed?

Case 1 Why now? Ideas, concerns, expectations - risk with COC Any lumps – breast / abdomen Family history ? Does she need earlier screening? Where to refer ? What about her 2 daughters if she is BRCA 1 or 2 Role of prophylactic surgery? COCP to continue? Contraception – choice?

Breast disease and contraception (UKMEC) CHCPOPDMPA/ NET- EN IMPCu-IUDLNG IUS Benign breast disease Family h/o breast ca Carriers of breast ca genes (BRCA) Breast ca -Current -Past & no e/o current disease for 5yr FFPRHC

References NICE(2006) - The classification and care of women at risk of familial breast cancer in primary, secondary and tertiary care. BMJ learning e-GP Cancer research UK FFPRHC

Thank you